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AimPaediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%–60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data.MethodsAll Danish children aged 0–16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data.ResultsA total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p = 0.04.ConclusionFollowing a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances. Aim: Paediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%–60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data. Methods: All Danish children aged 0–16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data. Results: A total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p = 0.04. Conclusion: Following a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances.

Item does not contain fulltext Acute liver failure (ALF) is rare but life-threatening. Common causes include intoxications, infections, and metabolic disorders. Indeterminate etiology is still frequent. No systematic data on incidence, causes, and outcome of ALF across Europe are available. Via an online survey we reached out to European Reference Network Centers on rare liver diseases. Numbers and etiology of ALF cases during 2020 were retrieved and diagnostic and treatment availabilities assessed. In total, 455 cases (306 adult, 149 pediatric) were reported from 36 centers from 20 countries. Intoxication was the most common cause in adult and pediatric care. The number of cases with indeterminate etiology is low. Diagnostic tools and specific treatment options are broadly available within this network. This is the first approach to report on etiology and outcome of ALF in the pediatric and adult population in Europe. High diagnostic yield and standard of care reflects the expert status of involved centers.

Aim: The aim of this study was to conduct a metabolic and nutritional assessment of children with neuromuscular disorders, including the investigation of the liver and bone mineral density. Methods: In this observational study, we included 44 children with neuromuscular disorders. The nutritional status, bone health and liver were assessed by ultrasound, transient elastography, dual X-ray absorptiometry scan, blood samples, anthropometric measurements and 3-day diet registration. Results: Liver involvement was found in 31.0%: liver enlargement in 7.1%, steatosis in 4.8%, fibrosis in 14.3% and liver enlargement together with steatosis or fibrosis was found in 4.8%. These changes were found in 9/23 patients with Duchenne muscular dystrophy, 4/9 patients with spinal muscular atrophy type II and 0/12 patients with other neuromuscular diagnoses. Low bone mineral density was found in 44.0% of the patients, though the majority used daily vitamin D and calcium supplements. Vitamin D insufficiency or deficiency was found in 22.6%. Conclusion: The metabolic assessment in children with neuromuscular disorders shows an increased risk of liver enlargement, steatosis and fibrosis. Possible causes are obesity, decreased mobility, low skeletal muscle mass and for a subgroup the use of glucocorticoids. The findings suggest that monitoring liver function should be part of the nutritional assessment in patients with neuromuscular disorders.

OBJECTIVES Paediatric acute liver failure (P-ALF) is a rare condition and is associated with a high mortality rate. Management of P-ALF aims to stabilise vital organ functions and to remove circulating toxins and provide vital plasma factors that are lacking. High-volume plasmapheresis (HVP) removes protein-bound substances and improves survival in adult ALF. It is unknown if this effect can be extrapolated to P-ALF. The aim of this study is to report the safety and feasibility of HVP in P-ALF. METHODS Children with P-ALF were offered HVP if bilirubin was higher than 200 μmol/L or if the aetiology was toxic hepatitis. HVP was performed with fresh frozen plasma corresponding to 10% of the body weight on a minimum of 3 consecutive days. Diagnostics, biochemical and clinical data during HVP as well as outcome data after 3 months were collected from 2012 to 2019 and retrospectively analysed. RESULTS Sixteen children were treated by HVP and completed at least one series of three treatment sessions with HVP. The only complication seen was an increase in pH > 7.55 in three children within the first 12 hours and was corrected with hydrochloric acid. No bleeding or septic episodes were noted during HVP. Eight children survived without liver transplantation, two survived after successful grafting and a total of six children died. The liver injury unit score between survivors with their own liver and the rest, the two groups was significantly different (P = 0.005). CONCLUSION HVP with fresh frozen plasma is feasible and well tolerated in children with P-ALF. No serious adverse events and no procedure-related mortality were observed.

ObjectivesWe aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID).MethodsThis nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI).ResultsWe included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7–4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0–1.3]), and among females (1.5 [95%CI: 1.4–1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6–0.9]).ConclusionsOur results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID. Objectives: We aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID). Methods: This nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI). Results: We included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7–4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0–1.3]), and among females (1.5 [95%CI: 1.4–1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6–0.9]). Conclusions: Our results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID.

Background: Long-time survivors of pediatric liver transplantation have an increased incidence of the metabolic syndrome. Adult recipients have an increased risk of post-transplantation obesity; however, pediatric data are limited. Methods: The study included 42 recipients of pediatric liver transplantation in Denmark, transplanted between 1990 and 2014. The study participants were examined with anthropometric measures, dual-energy X-ray scans and blood samples. From the anthropometric measures, body mass index (BMI) and BMI standard deviation score (SDS) were calculated. From the dual-energy X-ray scans, fat percent was assessed, and body fat mass index (BFMI) was calculated. Results: The median age was 17.4 years (range 4.1–38.9) at the time of the study, and the median time since transplantation was 8.5 years (range 0.4–23.9). The prevalence of overweight and obesity was 31.0% based on BMI SDS (age below 18) and BMI (age 18 and above). When compared to the participants with normal weight, the participants with overweight and obesity had a higher BFMI (9.29 vs 5.57 kg/m2, p

Congenital portosystemic shunts (CPSS) are rare malformations, which connect the portal venous system and the systemic circulation. The disorder is discovered at prenatal screening, neonatal cholestasis as an incidental finding or by systemic complications such as pulmonary hypertension, encephalopathies or liver nodules. CPSS are associated to cardiac malformations and several syndromes. Intervention radiology plays a key role in treatment by closure of the shunt, which is indicated, if the patient has complications, the shunt is extrahepatic, or it is still persistent at two years of age, using a two-step approach, as summarised and discussed in this review.

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals

Objectives Advances in treatment of cystic fibrosis (CF) have increased survival and thereby prevalence of patients with liver disease, making chronic liver disease one of the major complications of CF. We describe the prevalence of liver fibrosis, portal hypertension, and liver decompensation by extended screening for cystic fibrosis related liver disease (CFLD) including ultrasound, elastography, and an extended panel of biochemical markers. Methods A cross sectional study of CFLD in all pediatric CF patients (1-18 years) from the Copenhagen CF Center. Screening for liver disease included physical examination, biochemical analysis, Vibration-Controlled Transient Elastography (FibroScan), conventional ultrasound, and Real-Time Shear Wave elastography (SWE). Patients were scored according to Williams' ultrasound scoring scale (WUSS) within six months. Results A total of 84 consecutive patients (male sex 46.4%, median age 10.4 years) were included. Eight patients (9.5%) had both ≥ two abnormal results of sonographic methods and ≥ two abnormal biochemical results and were in this study categorized as having manifest CFLD. Manifest CFLD patients were significantly older and had a higher mean value of APRI, but no differences in gender, z-height, z-weight, z-BMI, FEV1% or mean value of bilirubin or albumin were found. Conclusions In total eight patients (9.5%) in this pediatric CF population were categorized as having CFLD according to both biochemical and sonographic tests. Consistency was found among the results of FibroScan and SWE. We suggest WUSS and either FibroScan or SWE, combined with GGT as diagnostic markers for CFLD.

Purpose Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated. Patients and methods In this phase 2, open-label, multicenter study, children received 10‒200 μg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored. Results Twenty patients were enrolled (8 females; 1‒17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26‒564) and were reduced in the majority (−123.1 μmol/L; range, −394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 μg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0−10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0−10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient. Conclusions Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.

This study explored the relationships between suicidal adolescents and their parents, siblings and friends. It examined how much adolescents talked to their parents before suicide attempts, the frequency of self-mutilation, the extent of suicidal ideation, previous suicide attempts and suicide attempts in the adolescent's surroundings.We performed a cross-sectional case-control study that focused on 381 adolescents aged 10-17 years who were admitted to hospitals across Denmark after suicide attempts with acetaminophen and 296 age- and gender-matched controls recruited from schools. The study used questionnaires and medical and child psychiatric records.The study group were ten times more likely to report dissociated parental relationships than the control group (41.5% versus 4%), and there were significant relationships between these reports and feelings of not being heard (p0.0001), dissociated relationships with friends (p0.0001) and siblings (p0.0001) and self-mutilation (p = 0.009). Almost two-thirds (62.5%) of the suicidal adolescents who tried to talk to their parents about their problems felt unheard, and there was a significant relationship between this feeling and the duration of suicidal ideation (p = 0.01) and self-mutilation (p = 0.003).Early risk factors for suicide were dissociated relationships with parents, siblings and friends, feeling unheard, self-mutilation and extended suicidal ideation.

Children with rheumatic diseases often have elevated liver biochemistry. This can be triggered by medical treatment, e.g. methotrexate can induce liver injury ranging from mild to severe. Autoimmune hepatitis and sclerosing cholangitis are also seen in conjunction with rheumatic diseases, and early diagnosis and treatment is crucial to prevent development of cirrhosis and liver transplantation. Macrophage activation syndrome is a rare but important differential diagnosis as it is a potentially fatal complication to systemic rheumatic diseases, causing liver dysfunction and multi-organ failure.

INTRODUCTION: Parenteral nutrition-associated cholestasis (PNAC) is a complication of long-term parenteral nutrition (PN). Removal of lipids may reverse PNAC but compromises the energy to ensure infant growth. The purpose of this study was to test whether a low-fat, high-carbohydrate PN regimen, which prevents and reverses PNAC in adults, could do the same in infants. This regimen could potentially avoid the problem of diminished energy input after removing nutritional lipids.METHODS: Infants developing PNAC over a 2-year period were started on a low-fat PN regimen with calories primarily from carbohydrates. The fat-free PN, containing 314 kJ/ml, was provided 5-6 times a week and fat, including essential fatty acids and fat-soluble vitamins, 1-2 times a week. Enteral feeding was continued according to individual tolerance.RESULTS: The study included 10 infants with short bowel syndrome (six with intestinal failure due to necrotizing enterocolitis, one with gastroschisis, one with complications due to unrecognized anal atresia and two with midgut volvulus). Median duration of PN with fat before initiating the low-fat regime was 69 days (25-75 % percentile: 41-75 days), and mean s-bilirubin was 139 µmol/l (range 87-323 µmol/l). Median duration with low-fat regimen was 69 days (25-75 % percentile: 18-123 days). Bilirubin reversed to normal (CONCLUSIONS: A low-fat, high-carbohydrate PN regimen together with enteral feeding is well tolerated and may be used in reversing liver disease in PN-dependent infants without compromising growth.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (1 year) and smallest (10 kg) children with the highest bilirubin (510 μmol/L), highest INR (1.6), and highest PELD score (20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

BACKGROUND AND OBJECTIVES: Based on a high incidence of Vitamin K deficiency bleeding (VKDB) in breastfed infants with thus far unrecognized cholestasis, such as biliary atresia (BA), the Dutch regimen to prevent VKDB in breastfed infants was changed from a daily oral dosage of 25 µg to 150 µg vitamin K. Infants continued to receive 1 mg of vitamin K orally at birth. We compared the efficacy of the 150-µg regimen with the 25-µg regimen and with the Danish regimen of a single intramuscular (IM) dose of 2 mg vitamin K at birth. METHODS: Data were retrieved from the national BA registries: 25 µg group (Netherlands, January 1991 to February 2011); 150 µg group (Netherlands, March 2011 to January 2015); and IM 2 mg group (Denmark, July 2000 to November 2014). We compared the incidence of VKDB in the groups. RESULTS: VKDB occurred in 45 of 55 (82%) infants of the 25 µg group, in 9 of 11 (82%) of the 150 µg group, but in only 1 of 25 (4%) of the IM 2 mg group (P < .001). Forty percent of all infants of the 25 µg group had an intracranial hemorrhage as presenting symptom, compared with 27% of the infants of the 150 µg group (P = .43). Intracranial hemorrhage was not observed in the IM 2 mg group (0%; P < .001). CONCLUSIONS: A vitamin K prophylactic regimen of 1 mg of vitamin K orally at birth followed by a daily oral dosage of either 25 or 150 µg fails to prevent VKDB in breastfed infants with still unrecognized BA. The data support 2 mg vitamin K IM at birth as prophylaxis against VKDB.

The study evaluated the changes in the prevalence of Helicobacter pylori strains with primary resistance to antibiotics during the last 10 years in Lithuania. H. pylori susceptibilities to antibiotics were tested in 89 patients in 1998, in 81 patients in 2001 and in 90 patients in 2007/2008. Susceptibility to metronidazole, clarithromycin, amoxicillin and tetracycline was tested using E-test or agar dilution method. Susceptibility to ciprofloxacin was only tested in 2007/2008. Data about utilization of all authorized and available on market macrolides and clindamycin in Lithuania during 2003-2007 were evaluated using WHO ATC/DDD methodology. A total of 260 H. pylori strains cultured from untreated adult patients were investigated. Primary resistance rates (1998, 2001 and 2007/2008) for metronidazole were 24.7%, 33.3%, and 35.6%, for clarithromycin 1.1%, 3.7%, and 3.3% and for tetracycline 0%, 2.5% and 0% respectively. No cases of amoxicillin resistance have been detected. The resistance rate for ciprofloxacin was 5.6% in 2007/2008. Data of total macrolides and clarithromycin utilization in Lithuania revealed that despite an increase of consumption of these drugs in Lithuania during 2003-2007 in 1.5 times, the total macrolide consumption remains one of the lowest in Europe. We have not observed any significant changes in the susceptibility of H. pylori to the most widely used antibiotics during the recent 10-year period. The low resistance rate to clarithromycin might be related to the policy to avoid use of macrolides as first-line treatment for pulmonary and other infections.

Autoimmune hepatitis (AIH) in childhood is a progressive chronic inflammatory liver disease. The aim of this study was to compare the clinical and biochemical characteristics of 33 paediatric patients diagnosed as having AIH with earlier described cohorts, and to examine the effect of early treatment strategies on the course of disease.A population-based cohort of patients from January 1993 to September 2009 was identified prospectively, and the patient data were collected by a retrospective examination of the files.Twenty-nine patients had type 1 AIH, 2 had type 2, and 2 could not be categorised. Among the 33 children, 16 (48.5%) were girls and 17 (51.5%) were boys. Twenty-three (69.7%) of the patients had symptoms at presentation indistinguishable from acute viral hepatitis, but in 16 (69.6%) of those the liver biopsy showed cirrhosis. Twenty (60.6%) patients were treated with prednisolone and azathioprine at the time of remission, whereas 8 (24.2%) were treated with prednisolone. One (3%) patient did not experience remission during the observation period.The patients in our study appeared similar to previously published cohorts, although a female predominance was not observed. Our data suggest that early treatment including both prednisolone and azathioprine could be more effective than prednisolone alone, even if randomised controlled paediatric studies comparing these 2 different treatment regimens are needed.

BACKGROUND Increased risk of cardiovascular diseases is well described after adult liver transplantation, whereas the risk in the pediatric population still is discussed. The aim of this study was to investigate the prevalence of metabolic syndrome in pediatric liver transplant recipients and whether measurements of carotid intima media thickness and pulse wave velocity were increased compared to healthy controls. METHODS We included 42 pediatric liver transplantation recipients and examined them for markers of metabolic syndrome, liver fibrosis measured by shear wave velocity, body fat measured by DXA scans and carotid intima-media thickness, and pulse wave velocity (n = 41 for the carotid scans). The ultrasound measurements of carotid intima-media thickness and pulse wave velocity were also conducted on 82 healthy children and adolescents matched on height and age, respectively. RESULTS Participants had a median age of 13.03 years, and median time since transplantation was 8.54 years. Compared to healthy controls, liver-transplanted patients had significantly increased intima-media thickness measurements in both control groups whereas there was no significant difference with regard to pulse wave velocity. Two patients (6.25%) were diagnosed with metabolic syndrome. Within the group of liver-transplanted pediatric patients, only elevated body mass index was associated with elevated carotid intima-media thickness measurement. Elevated pulse wave velocity was only associated with abdominal obesity. Factors not significantly correlated with either were age, sex, metabolic syndrome, hyperglycemia, triglycerides, years since transplantation, fibrosis of the liver, body fat content, smoking habits, HDL cholesterol levels, hypertension, and mono-drug versus multi-drug therapies. CONCLUSION Pediatric liver transplant recipients do have an increased risk of increased carotid intima-media thickness.

Studies on formula-fed infants indicate a beneficial effect of dietary DHA on visual acuity. Cross-sectional studies have shown an association between breast-milk DHA levels and visual acuity in breast-fed infants. The objective in this study was to evaluate the biochemical and functional effects of fish oil (FO) supplements in lactating mothers. In this double-blinded randomized trial, Danish mothers with habitual fish intake below the 50th percentile of the Danish National Birth Cohort were randomized to microencapsulated FO [1.3 g/d long-chain n-3 FA (n-3 LCPUFA)] or olive oil (OO). The intervention started within a week after delivery and lasted 4 mon. Mothers with habitual high fish intake and their infants were included as a reference group. Ninety-seven infants completed the trial (44 OO-group, 53 FO-group) and 47 reference infants were followed up. The primary outcome measures were: DHA content of milk samples (0, 2, and 4 mon postnatal) and of infant red blood cell (RBC) membranes (4 mon postnatal), and infant visual acuity (measured by swept visual evoked potential at 2 and 4 mon of age). FO supplementation gave rise to a threefold increase in the DHA content of the 4-mon milk samples (P < 0.001). DHA in infant RBC reflected milk contents (r = 0.564, P < 0.001) and was increased by almost 50% (P < 0.001). Infant visual acuity was not significantly different in the randomized groups but was positively associated at 4 mon with infant RBC-DHA (P = 0.004, multiple regression). We concluded that maternal FO supplementation during lactation did not enhance visual acuity of the infants who completed the intervention. However, the results showed that infants with higher RBC levels of n-3 LCPUFA had a better visual acuity at 4 mon of age, suggesting that n-3 LCPUFA may influence visual maturation.

Objective It is assumed that early feeding can affect liver biochemistry because breast-fed infants have a higher risk of hyperbilirubinemia than formula-fed infants. The authors sought to determine how feeding mode affected liver biochemistry in healthy term infants. Methods Healthy term infants were followed up during infancy with a monthly questionnaire about feeding mode. Blood samples were obtained at 2, 6, and 9 months. Liver biochemistry (serum albumin, alkaline phosphatase, lactic dehydrogenase, aspartate aminotransferase [AST], and bilirubin), total insulin-like growth factor 1 (IGF-I), and insulin growth factor binding protein 3 (IGFBP-3) were determined at all ages. Results Mean AST and bilirubin were significantly higher in breast-fed infants at 2 and 6 months. In addition, mean albumin levels were higher in breast-fed infants at 2 months. Alkaline phosphatase, IGF-I, IGFBP-3, and lactic dehydrogenase levels did not differ between the feeding groups. AST levels did not correlate significantly with bilirubin, albumin, alkaline phosphatase, or lactic dehydrogenase values. There was a strong positive association between AST and IGF-I at 2 months (r = 0.47, P = 0.004). Conclusion Cytomegalovirus infection, vitamin K deficiency, and macromolecular forms of AST could be an explanation for a higher AST level among breast-fed infants. However, no other clinical or paraclinical sign of liver disease was seen, all infants were given oral vitamin K, and the AST did not rise to levels comparable to those seen in individuals with macromolecular AST. The authors speculate the most likely explanation of the elevated AST is induction of hepatocytes by factors in human milk. This is supported by the higher albumin levels in breast-fed infants and the positive association between AST and IGF-I.

The effect of breast-feeding on brain development, especially cognitive and visual, has been examined in many studies. The aim of this article is to summarize this group’s studies and relate them to results from reviews and meta-analyses. In two separate studies of visual development in term infants, visual acuity was better in breast-fed than in formula-fed infants, which is in accordance with the results from a meta-analysis. Among studies examining the association between breast-feeding and cognitive development most find a positive association, even when controlling for relevant confounding factors. A positive effect was found in two different samples of young adults using two different intelligence quotient tests. The most plausible explanation for this effect is the differences in composition between human milk and infant formula (e.g. docosahexaenoic acid). It could also be because mothers who choose to breast-feed on average stimulate and support their i nfants better. Further, unidentified factors may also correlate with both infant feeding and development of cognitive and intellectual ability, so-called residual confounding. Keywords: breast-feeding; cognitive ability; docosahexaenoic acid; infant feeding; intelligence quotient (IQ); LCPUFA; mental development; visual acuity; visual evoked potentials

Chronic hepatitis C (HCV) infection has a prevalence of 2-3% worldwide. The vertical transmission rate is approximately 5%. There is no evidence to recommend abstinence from breastfeeding or elective C-section to prevent transmission. In children, the natural history of HCV infection is typically benign, but liver cirrhosis and hepatocellulary carcinoma are later complications. Children with HCV infection may benefit from early treatment with pegylated interferon and ribavirin with duration depending on genotype. Overall, response to antiviral treatment of HCV infected children is comparable to results in adults.

Chronic hepatitis B (HBV) infection is seen in 400 million persons worldwide. HBV is transmitted vertically or horizontally by infected blood and body fluids. An effective vaccine exists. Most children develop a chronic HBV infection if infected early in life. They are often in an immune-tolerant phase with no indication for antiviral treatment. Antiviral treatment with interferon or a nucleotide analogue is a possibility if the HBV infected child develops into a phase of immune activation. HBV infection can lead to liver cirrhosis and hepatocellular carcinoma.

We have compared the oestrogenic potency of the synthetic oestrogen Zeranol, used as a growth promoter in meat production, and five related compounds, with the potency of 17beta-oestradiol, diethylstilboestrol (DES), genistein, and Bisphenol-A. The potency was assayed by analysing differences in expression levels of endogenous oestrogen-regulated genes in human MCF7 cells, treated with different concentrations of the compounds. Zeranol, 17beta-oestradiol and DES were about equally potent, genistein was four to six orders of magnitude less potent than 17beta-oestradiol but an order of magnitude more potent than Bisphenol-A. There were gene specific differences, the PS2 and TGFbeta3 genes were about equally sensitive to Zeranol, 17beta-oestradiol and DES whereas a down-regulation of MRG1/p35srj could be detected at fmol/l concentrations of Zeranol whereas 17beta-oestradiol was several orders of magnitude less potent. GST mu3 was sensitive to fmol/l concentrations of 17beta-oestradiol but much less sensitive to Zeranol and DES. The very high potency of Zeranol compared with other potential endocrine disrupters suggests that Zeranol intake from beef products could have greater impact on consumers than the amounts of the known or suspected endocrine disrupters that have been found in food. Since little data is available in man, there is an urgent need for reliable measurements of the concentration of Zeranol in human serum after ingestion of meat products from treated animals.

Gene discovery, i.e. detection of genes whose expression is affected in diseases or by different treatments of cells or animals, has become the focus of much genetic research. The technologies that are used to detect changes in expression level include polymerase chain reaction (PCR)-based subtraction methods, arrays of cDNA clones on chips or filters, serial analysis of gene expression, and differential display. In this paper we show that differential display can be used to investigate global gene expression in situations where a few genes change expression levels such as exposure of MCF7 cells to estradiol, and in more complex situations such as neuronal differentiation of human NTERA2 cells which affects a large number of genes. Furthermore, we show that differential display can replace Northern blotting and RNase protection as a tool to study the expression level of a specific gene in many samples. Results obtained by differential display can be stored in databases, where the identity of a band (gene or mRNA name) can be linked with information about the primer combination displaying the band and a gel image showing the band pattern, which is all the information that is needed to compare the expression level of this gene in other samples.

Liver involvement during the early toxicity phase after hematopoietic stem cell transplantation (HSCT) is well documented, with reports of mild to moderate elevation in liver enzymes and bilirubin in up to 80% of the patients.1, 2, 3 In contrast, our knowledge regarding liver impairment at long-term follow-up is limited. The primary aim of this study was to describe liver parameters at 1-year follow-up after HSCT and to identify risk factors. The secondary aim was to analyze the impact of liver affection at 1-year follow-up on long-term survival beyond 1 year.

A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA.

BACKGROUND AND AIM Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance regulator protein (CFTR)-regulated tissues such as granulocytes, monocytes, and lymphocytes. The aim of the present study was to investigate whether patients with CF-related liver disease have lower n-3 LCPUFA level than patients with CF without liver disease. METHODS Twenty patients with known CF-related liver disease were matched with 20 CF patients without. Blood samples were analysed for liver biochemistry and haematology. Granulocytes, mononuclear cells, and RBC were separated by density gradient centrifugation, and fatty acid composition was measured by gas chromatography. Hepatic ultrasound was scored according to Williams et al. Hepatic transit time (HTT) was measured with the ultrasound contrast agent SonoVue. RESULTS No significant differences were seen in either n-6 or n-3 LCPUFAs in any cell line when the 2 groups were compared. In a multiple regression analysis including HTT, age, Pseudomonas aeruginosa infection, diabetes mellitus, treatment with ursodeoxycholic acid, forced expiratory volume in 1 second (% of predicted value), and Williams' ultrasound scoring scale, only n-3 LCPUFA docosahexaenoic acid in mononuclear cell membranes was positively associated with HTT (P = 0.02). The arachidonic acid/docosahexaenoic acid ratio within the mononuclear cells was negatively associated with both HTT (P = 0.003) and Williams' ultrasound scoring scale (P = 0.03). For RBC-LCPUFAs, no significant associations were seen. CONCLUSIONS These findings indicate that in patients with CF, the degree of liver disease was negatively associated with LCPUFA n-3 levels in CFTR-expressing white blood cells but unrelated to those levels in CFTR-negative RBC.

Docosahexaenoic acid (DHA) accumulates in the brain during the 1st and 2nd years of life. The objective of this study was to see if an increased content of DHA in breast-milk via maternal fish oil (FO)-supplementation affects mental development in term infants. one hundred twenty-two Danish mothers with a habitual fish intake below the population median were randomized to 4.5 g.d(-1) of FO or olive oil (OO) for the first four months of lactation. Fifty-three mothers with habitual fish intake in the highest quartile were included as reference group. The effect of the resulting increase in infant DHA-intake and RBC-DHA level was assessed on problem solving ability at nine months and language at one and two years of age. Infants in the three groups performed equally well on the problem test and no association was observed between problem solving and erythrocyte-DHA at four months. Passive vocabulary at one year was lower in the children of the FO- compared with the OO-group (P < 0.05), but no differences were found at two years of age. Word comprehension at one year was inversely associated with erythrocyte-DHA at four months. The trial indicate a small effect of DHA levels in breast-milk on early language development of breast-fed infants.

The aim of the study was to describe variations in swept visual evoked potential (SWEEP-VEP) assessment of visual acuity and contrast sensitivity in infants and to evaluate the best way to estimate visual performance from obtained SWEEP-VEP data. The visual performance of 92 infants (6-40 wk of age) was measured in two separate visits. Results were verified with repeated tests in seven adults. There was a strong association between the two measurements of infant visual acuity (r = 0.91, p < 0.001), with no constant bias and an inter-assay coefficient of variation of 8.4%. The intra-assay coefficient of variation was 17% and in repeated sessions all obtained acuity measures were normally distributed, indicating that the mean and not the maximum threshold best estimates visual acuity. This estimate of visual acuity also had lower test-retest variability than those calculated from the maximum threshold or threshold from the average EEG signals (p = 0.001). Test-retest measures of infant contrast sensitivity had a correlation coefficient of 0.72 (p < 0.001) and an inter-assay coefficient of variation of 23%. With the observed test-retest variability, SWEEP-VEP is less valid for estimating the visual performance of individual subjects, but it can give reliable group means. This method was well suited to describe visual development in the infants, which for acuity as well as contrast sensitivity increased by 0.64 octave per doubling in age. However, the variability of the SWEEP-VEP method can be a limiting factor, for example, in the assessment of the potential effect of dietary docosahexaenoic acid in a homogeneous group of infants.

Objective. To characterize early risk factors of moderate/severe hepatotoxicity in a pediatric population with acetaminophen overdose, due to suicide attempt, admitted to a general secondary-level pediatric department. Methods. A retrospective case study of 107 patients, 11 to 15 years old. Results. There was a highly significant relationship between the number of episodes of prehospital vomiting and several elevated hepatologically relevant biochemical parameters, for example, maximum aspartate aminotransferase ( P = .0001). The duration of the latency time before initiation of N-acetylcysteine treatment was significantly related to the elevation of several hepatologically relevant biochemical parameters (eg, maximum γ-glutamyl transferase; P = .0001). Patients suffering from illness prior to their suicide attempt had significantly greater elevations of their hepatologically relevant biochemical parameters, for example, maximum alanine aminotransferase ( P = .01) levels than healthy patients. Conclusion. By use of risk factors, it is possible to identify pediatric patients at increased risk of moderate/severe hepatotoxicity at an early stage of admission.

Background Docosahexaenoic acid (DHA), present in high concentrations in the brain and retina, has a role in visual development. DHA is present in human milk, but not in most infant formulas. It is, however, under discussion whether DHA should be added to formulas intended for term infants. The concentration of DHA in human milk, which is influenced by maternal diet, varies considerably, but it is unknown whether this variation affects visual development in term infants. Methods The authors investigated 39 4-month-old fully breast-fed term infants in a cross-sectional study. Visual acuity was measured by swept visual evoked potentials, milk DHA was determined by gas chromatography, and maternal fish intake was assessed by a frequency questionnaire. Results Frequency of fish intake correlated positively to the DHA level in breast-milk (P = 0.001). Mothers who ate fish the day before sampling had a milk DHA level higher than expected from habitual fish intake (P = 0.002). If this was taken into account, 57% of the variation in milk DHA could be explained by fish intake. Multiple linear regression analysis revealed a significant association between visual acuity and milk DHA (P = 0.02, R2 = 0.09). Conclusion This finding suggests a cause-and-effect relationship between infant milk DHA intake and visual acuity. If these data are confirmed, there is a need to consider the optimal intake of DHA for the lactating mother.

Scientific evidence suggests that humans and wildlife species may experience adverse health consequences from exposure to environmental chemicals that interact with the endocrine system. Reliable short-term assays are needed to identify hormone-disrupting chemicals. In this study we demonstrate that the estrogenic activity of a chemical can be evaluated by assaying induction or repression of endogenous estrogen-regulated "marker genes" in human breast cancer MCF-7 cells. We included four marker genes in the assay--pS2, transforming growth factor beta3 (TGFbeta3), monoamine oxidase A, and [alpha]1-antichymotrypsin--and we evaluated estrogenic activity for 17beta-estradiol (E(2)), diethylstilbestrol, [alpha]-zearalanol, nonylphenol, genistein, methoxychlor, endosulphan, o,p-DDE, bisphenol A, dibutylphthalate, 4-hydroxy tamoxifen, and ICI 182.780. All four marker genes responded strongly to the three high-potency estrogens (E(2), diethylstilbestrol, and [alpha]-zearalanol), whereas the potency of the other chemicals was 10(3)- to 10(6)-fold lower than that of E(2). There were some marker gene-dependent differences in the relative potencies of the tested chemicals. TGFbeta3 was equally sensitive to the three high-potency estrogens, whereas the sensitivity to [alpha]-zearalanol was approximately 10-fold lower than the sensitivity to E(2) and diethylstilbestrol when assayed with the other three marker genes. The potency of nonylphenol was equal to that of genistein when assayed with pS2 and TGFbeta3, but 10- to 100-fold higher/lower with monoamine oxidase A and [alpha]1-antichymotrypsin, respectively. The results are in agreement with results obtained by other methods and suggest that an assay based on endogenous gene expression may offer an attractive alternative to other E-SCREEN methods. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9

BACKGROUND Docosahexaenoic acid is present in high concentration in retina and does not influence visual development in preterm infants. It is still under discussion whether docosahexaenoic acid is important for visual development in term infants. METHODS Thirty-seven infants fed formula for a median of 14 days were randomized at median age of 25 days to three formulas: a) DHAGF: 0.3 wt% docosahexaenoic acid and 0.5 wt% gamma-linolenic acid; b) DHAF 0.3 wt% docosahexaenoic acid; or c) STF: standard formula without long-chain polyunsaturated fatty acids and 17 breast-fed infants were observed, using blood samples and anthropometric measurements from 1 to 4 months of age. At 4 months, visual acuity was measured by swept steady-state visual evoked potential. A cross-sectional study on 25 breast-fed infants was carried out as a reference group for the analyses. RESULTS Infants fed the two docosahexaenoic acid-supplemented formula had relative docosahexaenoic acid concentrations in red blood cell phospholipids almost as high as those in breast-fed infants, whereas infants in the standard formula group had significantly lower levels. The addition of gamma-linolenic acid to the formula had a positive effect on red blood cell arachidonic acid levels, compared with levels obtained using fish oil only. Visual acuity was significantly different among all feeding groups (analysis of variance; p = 0.05, means +/- standard deviation: breast-fed, 0.37+/-0.06 logMAR; DHAF and DHAGF combined, 0.40+/-0.07 logMAR; and standard formula 0.44+/-0.07 logMAR. However, there was no statistical difference among the formula groups. In a multiple regression analysis including all formula-fed infants, weight at delivery (p = 0.002), but not type of formula, was significantly associated with visual acuity at 4 months of age. CONCLUSIONS The addition of docosahexaenoic acid resulted in concentrations in red blood cells at similar levels as those in breast-fed infants, whereas the increase in visual acuity did not reach significance. The addition of gamma-linolenic acid resulted in higher arachidonic acid concentrations in red blood cells.