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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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Aim: To investigate whether the increase in adult stature in European countries is continuing.Methods: The secular trend in growth after 1990 for various European countries was assessed by national conscript data. Results: In Scandinavia and the Netherlands, the height has reached a plateau at 179–181 cm, and in Italy a plateau at 174 cm. In Belgium, Portugal and Spain, height continued to increase. Conclusion: Only in the northern European countries and Italy height has ceased to increase.

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.