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Oxidative stress is a pathological condition characterized by an overload of oxidant products, named free radicals, which are not well counteracted by antioxidant systems. Free radicals induce oxidative damage to many body organs and systems. In neonatal red blood cells, free-radical mediated-oxidative stress leads to eryptosis, a suicidal death process of erythrocytes consequent to alteration of cell integrity. Neonatal red blood cells are targets and at the same time generators of free radicals through the Fenton and Haber-Weiss reactions. Enhanced eryptosis in case of oxidative stress damage may cause anemia if the increased loss of erythrocytes is not enough compensated by enhanced new erythrocytes synthesis. The oxidative disruption of the red cells may cause unconjugated idiopathic hyperbilirubinemia in neonates. High levels of bilirubin are recognized to be dangerous for the central nervous system in newborns, however, many studies have highlighted the antioxidant function of bilirubin. Recently, it has been suggested that physiologic concentration of bilirubin correlates with higher antioxidant status while high pathological bilirubin levels are associated with pro-oxidants effects. The aim of this educational review is to provide an updated understanding of the molecular mechanisms underlying erythrocyte oxidant injury and its reversal in neonatal idiopathic hyperbilirubinemia., (© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Background: Neonatal cholestasis is caused by a group of diseases that cause jaundice, which can be encountered in the neonatal period. Biliary atresia (BA) and idiopathic neonatal hepatitis (INH) are among neonatal cholestasis diseases., Aims: The aim of this study was to perform histopathological and ultra-structural examinations of liver biopsy tissue samples from BA and INH patients with liver biopsies taken during laparotomy to confirm the diagnosis of biliary atresia., Settings and Design: A total of patients undergoing Kasai surgery before the age of 60 days were included in an "early" group (n = 7), whereas patients undergoing surgery after the age of 60 days were included in a "late" group (n = 11). The control group (n = 11) included INH patients., Materials and Methods: For histopathological examinations, liver tissue samples obtained intra-operatively were subjected to routine histopathological procedures after being stained with caspase-3 and cytokeratin-7 antibodies. Ultra-structural evaluations were also performed. Statistical analysis used: For comparisons between the groups, a one-way analysis of variance (ANOVA) test and the Mann-Whitney U test were used for continuous variables., Results: Histopathological findings reflected the specific liver pathologic findings seen in biliary atresia. Although there was no significant difference between the BA groups, these parameters were not detected in the control group. The histopathological evaluations revealed no significant differences in the findings of liver parenchyma damage between the early, late, and control groups. Electron microscopic examinations showed that the patients in the late group had more severe signs of intra-cellular damage to the liver., Conclusions: Although the histopathological examination revealed no significant differences in liver damage between the three groups, in ultra-structural evaluation, intra-cellular damage was found to be less in groups with better prognosis. Electron microscopy evaluations of intra-cellular damage may be more useful in this respect., Competing Interests: None

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid-Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Hereditary pyropoikilocytosis is a subtype of hereditary elliptocytosis because of biallelic mutations of SPTA1, SPTB, and EPB41. The authors present a proband with neonatal jaundice and hemolytic anemia, with poikilocytosis in the blood film. Targeted next-generation sequencing identified Q267del trans to the αLELY allele in SPTA1. In addition, the proband presented coexisting Gilbert syndrome as determined by homozygous mutation of UGT1A1. Investigation of 13 relatives and his sibling revealed that only his sibling showed the same phenotype and genotype as the proband. This is the first report of molecular confirmation of coexisting hereditary pyropoikilocytosis and Gilbert syndrome and a novel mutation in SPTA1., Competing Interests: The authors have no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) is an autosomal recessive disease resulting from biallelic SLC25A13 mutations, and its diagnosis relies on genetic analysis. This study aimed to characterize the pathogenicity of 2 novel splice-site variants of SLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del]; [69+5G > A] in patient C0476 and c.[1453-1G > A]; [1751-5_1751-4ins (2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by computational analysis. The alternative splice variants in monocyte-derived macrophages from patient C0476 demonstrated exon 2 skipping [r.16_69del; p.(Val6_Lys23del)] in vivo, while minigene analysis revealed both exon 2-skipping and retained products from c.69+5G > A in vitro. In the patient C0556, an aberrant transcript [r.1453del; p.(Gly485Valfs*22)] resulting from c.1453-1G > A was detected on minigene splicing study. Thus, c.69+5G > A and c.1453-1G > A were both proved to be pathogenic. The 2 novel splice-site variants expanded the SLC25A13 mutation spectrum and provided reliable molecular markers for the definite diagnosis and genetic counseling of NICCD in the affected families., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

We measured end-tidal CO levels in 50 jaundiced newborns readmitted for phototherapy at age 54-244 hours. The median end-tidal CO level was 1.55 ppm, suggesting that hemolysis is not the primary contributor to the hyperbilirubinemia in many readmitted newborns., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hemorrhage of the adrenal glands in the neonatal period happens secondarily to birth trauma and to changes in venous pressure. Neonatal jaundice has as an infrequent etiology the presence of an adrenal gland hematoma. Symptomatic cases are rare, and if they manifest, it is usually as prolonged jaundice. We present the case of a neonate who was admitted at 20 hours of life due to isoimmune jaundice. Due to an increase in conjugatedbi]irubin, an abdominal ultrasound was requested at 10 days of life, which showed a non-vascularized right adrenal mass, 50 x 21 mm, with cystic images inside, compatible with bleeding of the right adrenal gland. Serial ultrasound showed a progressive resolution until its disappearance, keeping the baby asymptomatic and withoutj aundice. In cases of prolonged jaundice in the neonatal period, the possibility of significant adrenal hemorrhage must be assessed., Competing Interests: None, (Sociedad Argentina de Pediatría.)

Prolonged jaundice is a commonly evaluated condition. The aim of this study was to assess the risk factors of jaundice in healthy infants at one month of age. This prospective cohort study enrolled 509 healthy infants from 2013 to 2018. Those with gestational age (GA) less than 35 weeks, birth weight less than 2000 grams, and illness were not enrolled. Jaundice was defined as a transcutaneous bilirubin value ≥5 mg/dL at 25-45 days of age. Umbilical cord blood samples were obtained to examine seven common gene variants. The incidence of prolonged jaundice was 32.2%. Prolonged jaundice was more common in infants with exclusive breastfeeding (p < 0.001), GA 35~37 w (p = 0.001), stool passage >4 times/d (p < 0.001), previous phototherapy (p < 0.001), and gene variant of G to A at nt 211 of UGT1A1 (p = 0.004). A multivariate logistic regression analysis demonstrated the greatest risk for prolonged jaundice was exclusive breastfeeding (OR = 2.818, 95% CI = 1.851-4.292), followed by previous phototherapy (OR = 2.593, 95% CI = 1.716-3.919), GA 35~37 w (OR = 2.468, 95% CI = 1.350-4.512), and G to A at nt 211 of UGT1A1 (OR = 1.645, 95% CI = 1.070-2.528). In conclusion, infants with exclusive breastfeeding, GA 35~37 w, previous phototherapy, or G to A at nt 211 of UGT1A1 are at greater risk of prolonged jaundice. Healthcare professionals should consider these risk factors in their assessment of prolonged jaundice.

Objective: The prognosis of patients with biliary atresia undergoing Kasai portoenterostomy is related to the timing of the diagnosis and the indication for the procedure. The purpose of the present study is to present a practical flowchart based on 257 children who underwent Kasai portoenterostomy., Methods: We conducted a retrospective cohort study of patients who underwent Kasai portoenterostomy between 1981 and 2016., Results: During the first period (1981 to 2009), 230 infants were treated, and the median age at the time of surgery was 84 days; jaundice was resolved in 77 patients (33.5%). During the second period, from 2010 to 2016, a new diagnostic approach was adopted to shorten the wait time for portoenterostomy; an ultrasonography examination suggestive of the disease was followed by primary surgical exploration of the biliary tract without complementary examination or liver biopsy. Once the diagnosis of biliary atresia was confirmed, a portoenterostomy was performed during the same surgery. During this period, 27 infants underwent operations; the median age at the time of surgery was 66 days (p<0.001), and jaundice was resolved in 15 patients (55.6% - p=0.021), with a survival rate of the native liver of 66.7%., Conclusion: Primary surgical exploration of the biliary tract without previous biopsy was effective at improving the prognostic indicators of patients with biliary atresia undergoing Kasai portoenterostomy.

Background: Hemoglobin (Hb) Constant Spring is an alpha-globin gene variant due to a mutation of the stop codon resulting in the elongation of the encoded polypeptide from 141 to 172 amino acid residues. Patients with homozygous Hb Constant Spring are usually mildly anemic., Methods: We retrospectively describe clinical manifestations, diagnosis, laboratory investigations, treatment, and associated findings in pediatric patients with homozygous Hb Constant Spring followed-up at Srinagarind Hospital., Results: Sixteen pediatric cases (5 males and 11 females) were diagnosed in utero (N=6) or postnatal (n=10). Eleven cases were diagnosed with homozygous Hb Constant Spring, 4 with homozygous Hb Constant Spring with heterozygous Hb E, and 1 with homozygous Hb Constant Spring with homozygous Hb E. Three cases were delivered preterm. Six patients had low birth weights. Clinical manifestations included fetal anemia in 6 cases, hepatomegaly in 1 case, hepatosplenomegaly in 2 cases, splenomegaly in 1 case. Twelve cases exhibited early neonatal jaundice, 9 of which required phototherapy. Six cases received red cell transfusions; 1 (3), >1 (3). After the first few months of life, almost all patients had mild microcytic hypochromic anemia and an increased reticulocyte count with a wide red cell distribution (RDW), but no longer required red cell transfusion. At 1 to 2 years of age, some patients still had mild microcytic hypochromic anemia and some had normocytic hypochromic anemia with Hb around 10 g/dL, increased reticulocyte count and wide RDW. Associated findings included hypothyroidism (2), congenital heart diseases (4), genitourinary abnormalities (3), gastrointestinal abnormalities (2), and developmental delay (1)., Summary: Pediatric patients with homozygous Hb Constant Spring developed severe anemia in utero and up to the age of 2 to 3 months postnatal, requiring blood transfusions. Subsequently, their anemia was mild with no evidence of hepatosplenomegaly. Their Hb level was above 9 g/dL with hypochromic microcytic blood pictures as well as wide RDW. Blood transfusions have not been necessary since then.

The different methods in differentiating biliary atresia (BA) from non-BA-related cholestasis were evaluated in order to provide a practical basis for a rapid, early and accurate differential diagnosis of the diseases. 396 infants with cholestatic jaundice were studied prospectively during the period of May 2007 to June 2011. The liver function in all subjects was tested. All cases underwent abdominal ultrasonography and duodenal fluid examination. Most cases were subjected to hepatobiliary scintigraphy, magnetic resonance cholangiopancreatography (MRCP) and a percutaneous liver biopsy. The diagnosis of BA was finally made by cholangiography or histopathologic examination. The accuracy, sensitivity, specificity and predictive values of these various methods were compared. 178 patients (108 males and 70 females with a mean age of 58±30 days) were diagnosed as having BA. 218 patients (136 males and 82 females with a mean age of 61 ±24 days) were diagnosed as having non-BA etiologies of cholestasis jaundice during the follow-up period in which jaundice faded after treatment with medical therapy. For diagnosis of BA, clinical evaluation, hepatomegaly, stool color, serum gamma-glutamyltranspeptidase (GGT), duodenal juice color, bile acid in duodenal juice, ultrasonography (gallbladder), ultrasonography (griangular cord or strip-apparent hyperechoic foci), hepatobiliary scintigraphy, MRCP, liver biopsy had an accuracy of 76.0%, 51.8%, 84.3%, 70.0%, 92.4%, 98.0%, 90.4%, 67.2%, 85.3%, 83.2% and 96.6%, a sensitivity of 83.1%, 87.6%, 96.1%, 73.7%, 90.4%, 100%, 92.7%, 27.5%, 100%, 89.0% and 97.4%, a specificity of 70.2%, 77.5%, 74.8%, 67.0%, 94.0%, 96.3%, 88.5%, 99.5%, 73.3%, 75.4% and 94.3%, a positive predictive value of 69.0%, 72.6%, 75.7%, 64.6%, 92.5%, 95.7%, 86.8%, 98.0%, 75.4%, 82.6% and 98.0%, and a negative predictive value of 83.6%, 8.5%, 95.9%, 75.7%, 92.3%, 100%, 84.2%, 93.7%, 100%, 84.0% and 92.6%, respectively. It was concluded that all the differential diagnosis methods are useful. The test for duodenal drainage and elements is fast and accurate. It is helpful in the differential diagnosis of BA and non-BA etiologies of cholestasis. It shows good practical value clinically.

Newborns commonly develop physiological hyperbilirubinemia (also known as jaundice). With increased bilirubin levels being observed in breast-fed infants, breast-feeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia. Bilirubin undergoes selective metabolism by UDP-glucuronosyltransferase (UGT) 1A1 and becomes a water soluble glucuronide. Although several factors such as gestational age, dehydration and weight loss, and increased enterohepatic circulation have been associated with breast milk-induced jaundice (BMJ), deficiency in UGT1A1 expression is a known cause of BMJ. It is currently believed that unconjugated bilirubin is metabolized mainly in the liver. However, recent findings support the concept that extrahepatic tissues, such as small intestine and skin, contribute to bilirubin glucuronidation during the neonatal period. We will review the recent advances made towards understanding biological and molecular events impacting BMJ, especially regarding the role of extrahepatic UGT1A1 expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The blood-brain barrier (BBB) is a complex and dynamic structure that plays a key role in central nervous system (CNS) homeostasis. It strictly regulates the entrance of molecules into the brain parenchyma and prevents the access of neurotoxins and pathogens while promoting the efflux of several molecules. The brain microvascular endothelial cells are the anatomical basis of the BBB, which has unique characteristics such as the elaborate junctional complexes that nearly obliterate the intercellular space as well as the presence of influx and efflux transporters. Endothelial cells establish important interactions with glial cells, neurons, and perivascular pericytes as well as with the acellular components of the basement membrane, which together constitute the neurovascular unit. BBB disruption has been reported in a wide range of CNS pathologies, with an emerging role in the onset and disease progression. Accordingly, recent studies revealed vascular dysfunction in neonatal jaundice, a common pathology in the early neonatal period affecting 1/10 children presenting values of total bilirubin>17 mg/dL (291 μM). Here we summarize the clinical aspects of moderate to severe neonatal jaundice and provide a comprehensive review of the literature regarding bilirubin-induced neurotoxicity from a vascular-centered approach. The collected evidence place endothelial dysfunction and pericyte demise as key players in the disruption of CNS homeostasis, mainly in cases of lasting hyperbilirubinemia, thus pointing to novel targets to prevent neurological dysfunction due to severe neonatal jaundice., (Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.)

Aim: To determine the frequencies of diagnoses confirmed by liver biopsy in infants with cholestasis in an Iranian pediatric hospital., Methods: This was a retrospective study conducted in a tertiary referral children's hospital in Iran. We retrieved all pathology reports of liver biopsies from children less than two years of age who had presented for evaluation of cholestatic jaundice from March 2001 to March 2011. Additional specimen samples obtained from archived pathology blocks were reviewed by a pathologist blinded to the final diagnosis. These results were compared with the pathology reports from chart records to ensure consensus and eliminate any inconsistencies in final diagnoses. A structured checklist was used to gather information on multiple variables including age, sex, gestational age at birth, birth weight, age at which hyperbilirubinemia manifested, presence and identification of associated anomalies, clinical manifestations, and histological findings from liver biopsies. The baseline data are reported using descriptive statistics, and differences between groups were assessed by Fisher's exact test and Student's t test when indicated., Results: Fifty-five cases (28 females; 27 males) of infantile cholestasis (IC) were included in this study. The mean serum total bilirubin and direct bilirubin at presentation were 13.6 ± 5.9 and 7.3 ± 3.4, respectively. Forty cases (72.7%) were the product of term pregnancies. Common associated clinical findings were acholic stool in 33 cases (60.0%), hepatomegaly in 30 cases (54.5%), and dark-colored urine in 21 cases (38.2%). Biliary atresia (BA) was the most frequent diagnosis, found in 32 cases (58.2%), followed by intrahepatic bile duct paucity found in 6 cases (10.9%), metabolic disease in 6 cases (10.9%), idiopathic neonatal hepatitis in 5 cases (9.1%), choledochal cyst in 2 cases (3.6%), liver cirrhosis in 2 cases (3.6%), and progressive familial intrahepatic cholestasis and portal fibrosis each in 1 case (1.8%). The mean times for jaundice onset and liver biopsy were 43.8 and 102.0 d, respectively. In BA, the mean age at jaundice presentation was 21 d and for liver biopsy was 87.5 d, representing a mean delay of 66.5 d., Conclusion: A significant delay was found between IC presentation and liver biopsy, which is detrimental in conditions that can cause irreversible liver damage, such as BA.

A 3-days-old infant was seen with jaundice and yellow spots in the oral mucosa . The jaundice was treated with phototherapy, after which the lesions became white. The spots appeared on the mucosa of the lower lip; their diameter was approximately 1 mm. The diagnosis Fordyce's spots was made.

A seven-day-old, mature girl was hospitalized with serum unconjugated bilirubin 420 micromol/l. She was treated with phototherapy, which continued at home until the age of 14 years. Serum total bilirubin was then 250-300 micromol/l and she received a liver transplantation. At the age of 22 years she had no signs of chronic bilirubin encephalopathy. There was no activity of bilirubin UDP-glucuronosyl transferase in the liver, and a mutation was found in one of the coding exons in the gene. The girl suffered from Crigler-Najjar's syndrome type 1. In Denmark the incidence was about 2.7 × 10-6 in the period 1977-2010. The prevalence was about 0.5 × 10-6.

Objectives: The diagnosis of biliary atresia (BA) can be challenging as its histopathologic features overlap with those of other pediatric cholestatic liver diseases. We aimed to study the diagnostic value of hepatic CD56 immunostaining in the differentiation of BA from other causes of neonatal cholestasis., Methods: Hepatic CD56 immunostaining was investigated in 30 infants with BA and compared with that in 30 infants with non-BA cholestatic disorders. The expression of positive cells was interpreted semiquantitatively on the basis of the extent (percentage or number) of positive cells on a scale of 0-3., Results: The occurrence of CD56-positive biliary epithelial cells was significantly higher in the BA (83.3%) than in the non-BA group (6.7%), whereas the occurrence of CD56 natural killer cells in hepatic parenchyma was significantly higher in the non-BA group (76.7%) than in the BA group (6.7%; P<0.0001 for both). In contrast, there was no significant difference between both groups in CD56 natural killer cells in portal tracts (P>0.05). Using this differential expression as a discriminative tool between the BA and the non-BA group, positive biliary epithelial cell staining had high specificity, whereas negative parenchymal staining had high sensitivity (93.3% for both) with an accuracy of 88.3 and 84.65%, respectively. The combination of both parameters improved the accuracy up to 91.65%, with 100% specificity in the diagnosis of BA., Conclusion: CD56 immunostaining of the liver had a diagnostic value; it can be used to differentiate BA from other neonatal cholestatic disorders and might be useful as an additional stain when investigating infants with neonatal cholestasis.

The differentiation between biliary atresia (BA) and idiopathic neonatal hepatitis (INH) is challenging with many histological overlaps especially in the first weeks of life. This study aimed to investigate the role of immunohistochemical staining of CK7, Ki67, CD34, and vimentin in addition to other clinicopathological features in the differentiation between BA and INH. Cases included 30 infants with BA and 30 infants with INH. The diagnosis was based on clinical, laboratory, and liver biopsy examination. Female gender and elevated serum gamma glutamyle transferase were in favor of BA. Portal tract changes, such as bile ductular proliferation documented by CK7, Ki67 immunostaining and angiogenesis documented by CD34 immunostaining, favored the diagnosis of BA. Copper associated protein was positive in 70% of BA cases, but not detected in INH cases. Parenchymatous changes, such as giant cell transformation and positive iron deposition and Kupffer cell proliferation documented by vimentin immunostaining, favored the diagnosis of INH.CK7, Ki67, CD34, and vimentin are helpful adjuvant immunostaining in the differentiation between BA and INH., (© 2012 The Authors. APMIS © 2012 APMIS.)

Neonatal jaundice usually occurs in the transitional period after birth, presenting as an elevation of circulating bilirubin. Bilirubin neurotoxicity can occur if the levels of bilirubin become excessive (hyperbilirubinemia). This pathologic phenotype of newborn jaundice can develop because of excessive bilirubin production or impaired conjugation, with the risk for developing bilirubin-induced neurologic dysfunction, depending on the degree of the resultant bilirubin load. The plasma bilirubin level thus can be used to assess an infant's risk for developing bilirubin neurotoxicity relative to an infant's age in hours. Because all infants have an impaired conjugation ability, infants at greatest risk are those who have increased bilirubin production rates, because of hemolysis, for example. Therefore, developing potential preventive strategies as well as noninvasive technologies to treat and to identify infants with increased bilirubin production rates, respectively, are tantamount to reducing the incidence of bilirubin-induced neurologic dysfunction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We believe that the syndrome of bilirubin-induced neurologic dysfunction [BIND] represents a spectrum of neurologic manifestations among vulnerable infants who have experienced an exposure to bilirubin of lesser degree than generally described in previous publications. Clinical neuro-motor manifestations extend to a range of subtle processing disorders with objective disturbances of visual-motor, auditory, speech, cognition, and language among infants with a previous history of moderate-to-severe hyperbilirubinemia of varied duration. Confounding effects include prematurity, hemolysis, perinatal-neonatal complications, altered bilirubin-albumin binding, severity and duration of bilirubin exposure, and the individual vulnerability of the infant related to genetic, family, social, and educational predilection, regardless of the cause of neonatal jaundice. Tools to better assess BIND specific domains of multisensory processing disorders, identified by pyschometric, audiologic, speech, language and visual-motor, and neuromotor examination would allow for prospective surveillance of infants at risk for the syndrome., (Copyright © 2011. Published by Elsevier Inc.)

Objectives: : The significance of extrahepatic bile duct dilatation on ultrasound examination in jaundiced infants is often uncertain. We wished to clarify the diagnostic and prognostic significance of the present finding in neonatal conjugated hyperbilirubinaemia., Patients and Methods: : We retrospectively enrolled all of the infants younger than 3 months with extrahepatic biliary dilatation > or =1.2 mm (nonfasting ultrasound) who presented during the study period. We reviewed clinical, radiological, and laboratory data to determine mode of presentation, diagnosis, interventions, and long-term outcome., Results: Seventy-six infants (41 male) were identified, all of whom were referred with conjugated hyperbilirubinaemia. Median gestational age was 39 weeks (range 24-42 weeks). Inspissated bile was the most common diagnostic category, whereas congenital choledochal malformation was the diagnosis made in 13% infants. Dilatation was an incidental finding in 9% of the infants. Seventeen percent of infants had required either surgical or radiological intervention by the time of follow-up. Overall, 41% infants had spontaneous resolution of bile duct dilatation, including 8% who had "grown into" an unchanged duct size rather than involution of dilatation. The median size of bile duct at presentation for those who required intervention was 4.7 versus 2 mm for the remainder (P < 0.001). Of those who resolved spontaneously, the median size of duct at presentation was 1.8 mm., Conclusions: : Bile duct dilatation <3 mm (nonfasting ultrasound) with neonatal cholestasis is unlikely to be of significance whereas >4 mm is likely to be associated with choledochal malformation or need for intervention. The intermediate group is likely to be associated with inspissated bile syndrome following resolution of which innocent biliary dilatation may persist.

We report a Caucasian neonate with chronic non-spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work-up failed to reveal other specific factors contributing to cholestasis. Severe hemolytic disease of the newborn may cause cholestasis even in the absence of associated primary hepato-biliary disease.

The uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes the enzyme responsible for bilirubin glucuronidation. To evaluate the contribution of UGT1A1 promoter mutations to neonatal jaundice, we determined the genotypes of c.-3279T>G, c.-3156G>A, and A(TA)7TAA in Malay infants with neonatal jaundice (patients) and in infants without neonatal jaundice (controls). In our population study, only c.-3279T>G was associated with neonatal jaundice. The genotype distributions between both groups were significantly different (p = 0.003): the frequency of homozygosity for c.-3279G was much higher in patients than those in controls. Allele frequency of c.-3279G was significantly higher in patients than those in controls (p = 0.006). We then investigated changes in transcriptional activity because of c.-3279T>G. Luciferase reporter assay in HepG2 cells demonstrated that transcriptional activity of the c.-3279G allele was significantly lower than that of the c.-3279T allele in both the absence and presence of bilirubin. Luciferase reporter assay in COS-7 cells elucidated that c.-3279T>G modified the synergistic effects of the nuclear factors associated with transcriptional machinery. In conclusion, the c.-3279T>G mutation in the UGT1A1 promoter is a genetic risk factor for neonatal jaundice.

Background: Biliary atresia (BA) is the progressive inflammatory obstruction and fibro-obliteration of all or part of the extrahepatic biliary tree and the intrahepatic bile ducts and has its onset exclusively within the first several months of life. This study was undertaken to present the value of diagnostic laparoscopy in infants with prolonged jaundice and technique for laparoscopic cholangiography., Methods: A 5-mm umbilical trocar was introduced to create a port for a 30-degree laparoscope. If the gallbladder was of good size, the fundus was exteriorized through the right subcostal trocar site and a catheter was inserted into the gallbladder for cholangiography, following partial dissection from the liver bed, if required. If the gallbladder was atretic, the fundus was not exteriorized and a laparotomy was performed and cholangiography was abandoned, because the lumen of an atretic gallbladder was usually not fully patent., Results: At laparoscopy, 12 patients had good-sized gallbladders and minimal-to-mild liver fibrosis. They underwent cholangiography via the exteriorized fundus, and infantile hepatitis syndrome (HIS) or cholestatic syndrome (CS) in 8 cases, BA in 2 cases, and biliary hypoplasia (CBDH) in 2 cases were identified. Five patients' gallbladders dissected from the liver bed underwent cholangiography, and BA in 3 cases and CBDH in 2 cases were identified. The remaining 21 had atretic gallbladders and varying degrees of liver fibrosis, so cholangiography via the exteriorized fundus was abandoned and converted to open Kasai portoenterostomy., Conclusions: Laparoscopy-assisted cholangiography is a simple, accurate, and safe method in the diagnosis of prolonged jaundice in infants and allows the anatomic structure of the biliary tree to be obtained accurately with minimal surgical intervention.

Background: Biliary atresia (BA) and idiopathic neonatal hepatitis (NH) account for 50-70% of all cases with neonatal cholestasis. The treatment of the former is early surgical intervention, while the latter requires non-surgical supportive care. Failure to differentiate the two conditions may result in avoidable surgery in NH, which may significantly increase morbidity. The lack of differentiating clinical features, biochemical markers and other specific investigations to distinguish the two is still a major problem., Aim: This study was thus initiated to evaluate electron microscopic changes in the liver in patients with NH and BA, to correlate these with changes on light microscopy and look for specific differentiating features between the two., Methods: Ten patients with neonatal cholestasis whose liver specimens were available for electron microscopic analysis were included in the study. There were 6 patients with BA and 4 patients with NH., Results: Among the biochemical parameters, serum alkaline phosphatase and gamma glutamyl transpeptidase were significantly higher in BA than in patients with NH. On light microscopy, giant cell transformation was seen in 75% patients with NH and 33.3% of patients with BA. Even in BA, intracellular cholestasis was more prominent than ductular cholestasis (100% vs. 50%). Ductular proliferation was seen in 50% of NH patients and all patients of BA. Electron microscopy revealed prominent endoplasmic changes in all patients with NH and to a milder degree in BA. Changes in mitochondria and glycogen content were similar in both groups., Conclusion: Ultrastructural changes in neonatal cholestasis seen through electron microscopy are largely non-specific and do not differentiate BA from NH.

The clinical outcome of nonobstructive neonatal cholestasis (NC) cases varies greatly and the prognosis is generally unpredictable. In this study, we aimed to evaluate the prognostic benefits of qualitative analysis of histopathological changes in nonobstructive NC cases. A total of 28 nonobstructive NC cases (18 neonatal hepatitis; 10 intrahepatic bile duct paucity) were studied. We analyzed the relationship between histopathological and clinical parameters. Hepatic inflammation, bridging necrosis, pericellular fibrosis, giant cell transformation, and extramedullary hematopoiesis were evaluated and scored according to their absence or presence in each case. The sum of the histopathological scores was accepted as "total pathological injury score." The height percentiles, the presence and the degree of hepatomegaly and ascites, and serum alanine aminotransferase (ALT), albumin, and bilirubin levels and prothrombin time were also evaluated and scored. The patients were divided into 2 clinical course groups considered "good" or "bad" according to the total clinical scores. For statistical analysis, Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristic curve were used. We found a statistically significant negative relation between the clinical course and total pathological injury score (P = 0.042) and pericellular fibrosis (P = 0.016). In conclusion, during the interpretation of liver biopsies of nonobstructive NC, scoring of histopathological changes should be done for assessing the clinical prognostic outcome.

Purpose of Review: Published studies during the past year about three topics important to the pediatric clinician-- immunizations, neonatal jaundice, and animal-induced injuries-are concisely reviewed., Recent Findings: Recent updates regarding vaccines including the questionable link with autism, implementation of universal influenza vaccination for young children, the efficacy of pneumococcal vaccine against invasive disease, and new information on pertussis, varicella, hepatitis A, hepatitis B, measles, and rotavirus vaccination are discussed. No association between measles/mumps/rubella vaccine or thimerosal-containing pertussis vaccine and autism is evident. Universal influenza vaccination for children 6 to 23 months of age will be recommended for the 2004-2005 flu season, and this implementation should reduce significant school absenteeism as well as complications seen last year including encephalopathy, seizures, respiratory failure, and pneumonia. Pneumococcal vaccine significantly reduces rates of invasive pneumococcal vaccine in healthy and HIV-infected children, although it does not appear to greatly affect otitis media rates. A reduction in post-vaccine febrile seizures appears to be present since the introduction of acellular pertussis vaccine. Multiple outbreaks in varicella have been reported since the introduction of the varicella vaccine, and a booster vaccination may be necessary in the future. Methods for detecting and preventing severe neonatal hyperbilirubinemia are reviewed, as well as anticipated recommendations from the American Academy of Pediatrics for the detection and management of hyperbilirubinemia. High bilirubin levels in preterm infants may result in hearing dysfunction and developmental impairment. The American Academy of Pediatrics has recommended a higher level of monitoring for newborn jaundice and treatment of hyperbilirubinemia in an effort to prevent kernicterus and sequelae from elevated bilirubin levels, including post-discharge follow-up appointment by day 3 to 5 of age. Dog bites in children with resultant post-traumatic stress disorder, rabies, and salmonellosis from pet reptiles in the home are also addressed. Clinicians need to be aware of the risk for rabies bites, need to recognize that dog bites in children appear to cause post-traumatic stress disorder in more than half of cases, and need to know how to educate patients on how to prevent salmonellosis from pet reptiles and amphibians., Summary: Progress has been made in immunizations, especially immunization for influenza, pneumonia, and pertussis. It is recommended that monitoring for neonatal hyperbilirubinemia be more thorough to prevent the consequences of this condition. Rabies, post-traumatic stress disorder from dog bites, and salmonellosis associated with pet reptiles constitute an important area for patient education.

Background/aims: The clinical presentation of cholestasis in infancy caused by neonatal hepatitis and biliary atresia are very similar. Differential diagnosis is sometimes very difficult. The diagnostic accuracy is very important. The surgical treatment of biliary atresia should be performed as early as possible. If cases of biliary atresia are misdiagnosed, they will become progressive cirrhosis and if cases of neonatal hepatitis are misdiagnosed, they will result in unnecessary laparotomy. The aim of this study is to determine the role of quantitative analysis of ductus proliferation, proliferative activity, Kupffer cell proliferation and angiogenesis in the differential diagnosis of biliary atresia and neonatal hepatitis., Methodology: This study included 60 infants, 30 with neonatal hepatitis and 30 with biliary atresia. Differential diagnosis was done by ultrasonography, cholescintigraphy and liver biopsy. The parafifin-embedded tissue sections of liver biopsies underwent immunohistochemistry with Ki67 to mark proliferation activity, cytokeratin to mark the proliferating ductuli, vimentin to mark Kupffer cells, and CD34 to mark capillary vessels. Number of ductuli per high power field, number of Ki-67 positive cells per ductus, number of Kupffer cells per high power field and number of capillary vessels per high power field were calculated. Independent T test was used for statistical evaluation., Results: Independent sample T test indicated that there is a significant difference for proliferating ductuli and proliferation activity between neonatal hepatitis and biliary atresia. Biliary atresia cases represent more proliferating ductuli and proliferation activity in ductal epithelial cells than neonatal hepatitis cases. There is no statistical significance for Kupffer cell proliferation and vascularization., Conclusions: Our results indicate that, quantitative analysis of proliferating ductuli and proliferation activity of ductal epithelial cells may be helpful in differential diagnosis of neonatal hepatitis and biliary atresia. Besides neither Kupffer cell proliferation nor vascularization are found to be useful in differential diagnosis.

Aim: Hour-specific serum total bilirubin (STB) percentiles have proved useful in predicting which babies will develop significant neonatal hyperbilirubinemia (NHB) requiring intervention. This study investigated whether this assessment could be performed visually instead of by blood test. The aim was to evaluate the ability of experienced clinicians to determine accurately the level of clinical jaundice in neonates by visual means., Methods: Four neonatologists were asked to estimate the level of bilirubin in a group of 283 term clinically jaundiced infants before discharge from the nursery on day 3 of life. Their clinical estimation was compared with actual measurement of STB from samples drawn simultaneously., Results: Clinical estimation of STB had a high correlation to actual serum bilirubin levels (Pearson's correlation coefficient = 0.682, p < 0.001)., Conclusion: Clinical impression of jaundice by the eye of an experienced clinician is a reliable method to assess newborns for significant NHB and may diminish the need for universal serum sampling.

This paper reproduces the introducing talk of the round table conference on current management of neonatal hyperbilirubinemia held during the Journée d'Actualité Lorraine en Néonatologie (JALON 2002, Nancy, october 5th 2002).

The evaluation of hepatic diseases in children is often a multimodality process, requiring multiple imaging tests to determine the cause and extent of an abnormality. Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) have distinct roles to play in the evaluation of hepatic disease in children. This article addresses the hepatic and biliary lesions that are unique or more common in children and describes their cross-sectional imaging characteristics. In addition, the techniques and protocols for US, CT, and MRI are reviewed.

Background: The early diagnosis of surgical jaundice in a neonate is an important step for the surgical success in extrahepatic biliary atresia. Diagnostic laparoscopy, as in many areas in surgery, is included in the conventional diagnostic methods of extrahepatic biliary atresia., Methods: Since 1992, 24 infants with prolonged jaundice, in whom extrahepatic biliary atresia and neonatal hepatitis could not be differentiated with conventional diagnostic interventions, have been evaluated laparoscopically., Results: A coarse, irregular, greenish-brown liver with some degree of fine angiomatous development and an atretic gallbladder are the findings of laparoscopic evaluation in an infant with extrahepatic biliary atresia. However, in neonatal hepatitis, the liver is smooth, sharp-edged, and chocolate brown in color, and simultaneously performed cholangiography should show the passage of the contrast material both into the proximal biliary tracts and the intestinal system. In this series, 10 of 24 cases were proved to be neonatal hepatitis diagnosed by laparoscopy, so unnecessary laparotomy was avoided in 42% of the cases., Conclusion: When the diagnostic laparoscopy, in which the liver and the gallbladder are directly visualized, is combined with the cholangiographic examination, the most accurate and earlier diagnosis in an infant with prolonged jaundice can be achieved, and the important period of time for the surgical success in extrahepatic biliary atresia will be minimally wasted.

Purpose: To evaluate the usefulness of magnetic resonance (MR) cholangiography in excluding biliary atresia as the cause of neonatal cholestasis., Materials and Methods: MR cholangiography was performed on 10 control and 16 jaundiced neonates and infants aged 3 days to 5 months. Diagnosis of biliary atresia (n = 6) was confirmed with surgery and liver biopsy, with or without surgical cholangiography. Diagnosis of neonatal hepatitis (n = 9) was confirmed with clinical follow-up until jaundice resolved. In one infant, paucity of intrahepatic ducts was diagnosed at liver biopsy. MR cholangiography was performed with respiratory-triggered, heavily T2-weighted turbo spin-echo and optional inversion-recovery turbo spin-echo sequences. Diagnosis of biliary atresia was based on nonvisualization of either the common bile duct or common hepatic duct. Cholescintigraphy with technetium 99m disofenin was performed in all 16 jaundiced patients., Results: In the 10 controls, the nine patients with neonatal hepatitis, and the one infant with paucity of intrahepatic ducts, MR cholangiography clearly depicted the gallbladder and common hepatic and common bile ducts. MR cholangiography was 100% accurate in excluding biliary atresia as the cause of neonatal cholestasis, while 99mTc disofenin cholescintigraphic findings were false-positive in four of 10 patients with nonobstructive cholestasis., Conclusion: MR cholangiography can be used to depict the major biliary structures of neonates and small infants and to exclude biliary atresia as the cause of neonatal cholestasis by allowing visualization of the biliary tract.

The histopathology of the liver is fundamental for the differential diagnosis between intra- and extrahepatic causes of neonatal cholestasis. However, histopathological findings may overlap and there is disagreement among authors concerning those which could discriminate between intra- and extrahepatic cholestasis. Forty-six liver biopsies (35 wedge biopsies and 11 percutaneous biopsies) and one specimen from a postmortem examination, all from patients hospitalized for neonatal cholestasis in the Pediatrics Service of Hospital de Clínicas de Porto Alegre, were prospectively studied using a specially designed histopathological protocol. At least 4 of 5 different stains were used, and 46 hepatic histopathological variables related to the differential diagnosis of neonatal cholestasis were studied. The findings were scored for severity on a scale from 0 to 4. Sections which showed less than 3 portal spaces were excluded from the study. Sections were examined by a pathologist who was unaware of the final diagnosis of each case. Bile tract permeability was defined by scintigraphy of the bile ducts and operative cholangiography. The F test and discriminant analysis were used as statistical methods for the study of the hepatic histopathological variables. The chi-square method with Yates correction was used to relate the age of the patients on the date of the histopathological study to the discriminatory variables between intra- and extrahepatic cholestasis selected by the discriminant function test. The most valuable hepatic histopathological variables for the discrimination between intra- and extrahepatic cholestasis, in decreasing order of importance, were periportal ductal proliferation, portal ductal proliferation, portal expansion, cholestasis in neoductules, foci of myeloid metaplasia, and portal-portal bridges. The only variable which pointed to the diagnosis of intrahepatic cholestasis was myeloid metaplasia. Due to the small number of patients who were younger than 60 days on the date of the histopathological study (N = 6), no variable discriminated between intra- and extrahepatic cholestasis before the age of 2 months and all of them, except for the portal expansion, were discriminatory after this age. In infants with cholestasis, foci of myeloid metaplasia, whenever present in the liver biopsy, suggested intrahepatic cholestasis. Periportal ductal proliferation, portal ductal proliferation, portal expansion, cholestasis in neoductules, portal cholestasis and portal-portal bridges suggested extrahepatic obstructive cholestasis.

A neonatal presentation of Caroli's disease with severe cardiac and progressive renal pathology is described. The availability of small paediatric endoscopes ensured early diagnosis. Despite aggressive medical management, the baby died with severe bleeding complications before potentially life saving multiple organ transplantation could take place.

Congenital dyserythropoietic anemia type I is a rare inherited bone marrow disorder characterised by macrocytic anemia with pathognomonic morphological ultrastructural features in erythroid precursors. The disease is usually not diagnosed in the neonatal period. In a retrospective study of 31 patients we found that 17 were first seen in the neonatal age with significant anemia (birth hematocrit 0.34 +/- 0.07); 14 of the 17 infants also had early jaundice. Six infants were small for gestational age and two had syndactyly. Although rare, congenital dyserythropoietic anemia type I should be considered in the differential diagnosis of neonatal anemia.

Hepatocellular carcinoma is an uncommon malignancy in young children associated with a variety of congenital and acquired conditions. It has been generally held that idiopathic neonatal hepatitis is not an antecedent of hepatocellular neoplasia in childhood. We report a 28-month-old girl in whom a diagnosis of neonatal giant cell hepatitis was confirmed by liver biopsy at 4 months of age who was followed up with serial liver biopsies. Hepatitis B and C virus infection and metabolic abnormalities had been excluded by appropriate testing. There was no history of parenteral nutrition. The morphologic criteria for a diagnosis of cirrhosis were satisfied in a liver biopsy undertaken at 23 months of age. At 28 months a laparotomy was performed because of continuing jaundice and the development of an abdominal mass. Biopsy of the mass revealed a hepatocellular carcinoma. Ploidy studies showed an aneuploid tumor and a hyperdiploid karyotype was confirmed by chromosomal analysis. This case demonstrates by sequential biopsy the progression from neonatal hepatitis to cirrhosis and hepatocellular carcinoma in a young child.

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.

Aims: To study the influence of several clinical and paraclinical factors on the association between jaundice meter readings and plasma bilirubin concentration; and to comment on the usefulness of the jaundice meter as a screening device for hyperbilirubinaemia in neonatal intensive care units., Methods: Three hundred and seventy seven newborn babies admitted to the neonatal intensive care unit for various causes were included in the study. When the plasma bilirubin concentration needed to be determined for clinical reasons, the extent of the yellow skin colour was measured transcutaneously, using a jaundice meter. The haemoglobin concentration was also determined. This had no independent influence on the jaundice meter readings. The yellow skin colour was significantly and positively correlated with the bilirubin concentration and the presence of respiratory distress syndrome (RDS), and negatively with gestational age and postnatal ages., Conclusions: These findings were interpreted as being due to variations in the ability of albumin to bind bilirubin, and in the basal yellow skin colour. It was impossible to derive simple criteria for detection of hyperbilirubinemia by jaundice meter readings in this study group.

Idiopathic neonatal hepatitis (INH) is a syndrome characterized clinically and histologically but there is little information concerning the relationship between the clinical features and histological findings. In the present study, sixty-two patients clinically diagnosed as non-familial INH were histologically classified into four groups according to a provisional definition based on predominant lesions and examination of their clinical features. Patients of cholestasis (n = 23) and giant cell hepatitis (GCH, n = 21) were most frequent (37% and 33%, respectively), and patients of fatty liver (n = 10) and hepatitis (n = 8) were less common (16% and 13%). The GCH group showed a dominance of male, low birthweight, older and breast-fed babies. The cholestasis group demonstrated a dominance of male, low birthweight, younger and bottle-fed babies. The hepatitis group had the highest frequencies of high-grade hepatomegaly and splenomegaly. Fifty six cases completely recovered. Two died of hepatic failure in early infancy and four had chronic liver diseases at the age of 12 months. The fatty liver group had the worst outcome. Histological features in non-familial INH were variable and typical giant cell hepatitis was seen in only one-third of patients. Characteristic clinical features in each histologically classified group may suggest heterogenous etiologies underlying non-familial INH.

Asphyxiating thoracic dysplasia (Jeune-syndrome) is an autosomal inherited disease which is characterized by bone dysplasia, renal and hepatic malformations of various expressivity. Newborns who have serious thoracic dysplasia with associated lung hypoplasia normally die during the neonatal period. Patients without signs of pulmonary defects may develop progressive renal failure due to an interstitial fibrosis. In addition, liver- and pancreas fibroses are found. We recently observed the greater variability of clinical manifestation in two patients with Jeune-syndrome. The first patient, a mature male newborn infant, presented early signs of respiratory disease and, more interestingly, had high serum levels of 5.1 mg/dl conjugated bilirubin at day 1; the maximal bilirubin-concentration was 26.5 mg/dl at day 9. Additionally, he developed progressive renal failure (maximal serum creatinin: 2.7 mg/dl at day 13). The patient eventually died of respiratory failure. To our knowledge such an early onset of severe hepato-renal manifestation has not been observed in patients with this disorder. A second term newborn infant with typical radiological signs of Jeune-syndrome and severe lung hypoplasia died within hours after birth. No hepato-renal defects could be documented in this patient.

The authors make a review of paediatric-neonatal cholestasis, a troublesome field in clinical and hepatopathology. They focus the main topics and stress the differential aspects in extrahepatic biliary atresia, "neonatal hepatitis", cholestatic syndromes associated with paucity of interlobular biliary ducts and metabolic diseases. The "overlap" areas and differential diagnosis in these chapters are a challenge for the pathologist. The importance of a close collaboration with clinicians is stressed.

The second step in the pathway for synthesis of bile acids from cholesterol is catalysed by the enzyme 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase. Deficiency of this enzyme has been reported to produce cholestatic liver disease with progressive cirrhosis. Treatment with chenodeoxycholic acid led to clinical and biochemical improvement in one patient. We report a further child with this disorder who presented with prolonged neonatal jaundice followed by symptoms of malabsorption of fat-soluble vitamins. Bile acid replacement therapy resulted in clinical and biochemical improvement; it was also possible to demonstrate improvement in the histological appearance of the liver biopsy 4 months after commencing treatment.

A case of neonatal hemochromatosis in a 3-hour-old male is described. He presented with hypotonia, mild jaundice, and respiratory difficulty immediately after birth. He had no evidence of congenital infection, immune-related hemolysis or exogenous iron uptake. Postmortem examination revealed abnormal facial features. The organs were of normal weight for his age except a small liver and lungs, and a large spleen. The most prominent changes were in the liver and pancreas. The liver was coarsely nodular and fibrotic. The lobular architecture was totally distorted by innumerable multinucleated giant cells, loss or collapse of the hepatocytes, and diffuse fibrosis. A large amount of hemosiderin was seen in the liver, pancreatic acini and thyroid follicular cells. Scanty amount of hemosiderin was also found in the myocardial fibers and renal tubular cells. The pancreas showed hyperplasia and hypertrophy of the islets. The spleen showed severe congestion and a moderate extramedullary hemopoiesis but no deposits of hemosiderin. This patient had three siblings died in neonatal period, one of which had clinical features of neonatal hemochromatosis.

The relationship between cephalocaudal progression of jaundice and bilirubin concentration, reserve albumin concentration and plasma pH was studied in 47 newborn infants. Furthermore, the cephalocaudal progression of the yellow colour of the skin was measured in 131 newborns at birth and on the third postnatal day. The cephalocaudal colour difference correlated positively to the bilirubin concentration (P much less than 0.001), to the reciprocal of the reserve albumin concentration (P less than 0.05) and to the squared hydrogen ion concentration (P = 0.04). The cephalocaudal colour gradient at birth correlated positively to the gradient at the third postnatal day (P less than 0.0004). The results support the hypothesis that the cephalocaudal progression of jaundice in icteric newborn infants may be explained by conformational changes in the young bilirubin-albumin complex.

Hyperbilirubinemia is associated with bilirubin deposition in tissue in the newborn including the liver, kidney, heart, adrenal, lung, and brain. High levels of serum bilirubin will stain the skin and sclera and be called "jaundice" clinically, and similarly high levels of bilirubin will stain tissues internally, preferentially in areas of tissue damage. Whether the bilirubin causes the damage or marks the damage because of other insults or both remains controversial.