Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020.

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group.

Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10-20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.

Gastrointestinal Toxicity, Systemic Inflammation, and Liver Biochemistry in Allogeneic Hematopoietic Stem Cell Transplantation.

Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-regulating cytokines during the early post-transplantation period. We prospectively included 81 children and adults undergoing HSCT after myeloablative conditioning. Alanine aminotransferase (ALT), total bilirubin levels, and international normalized ratio were measured longitudinally until 3 months after the transplantation and related to levels of inflammatory markers (C-reactive protein [CRP], IL-6, and IL-10) and to plasma citrulline as a marker of intestinal toxicity during the first 3 weeks after HSCT. The majority of patients experienced ALT levels above the normal range (45 U/L) with significant increases at 3 months after HSCT. Increased levels of total bilirubin were observed in 26% during the 3-month period. Citrulline levels decreased significantly to a nadir at day 7 (B = .23; 95% confidence interval [CI], .12 to .35; P < .0001), but citrulline levels at nadir were not associated with parameters of liver toxicity. However, a faster reconstitution of mucosa with higher citrulline levels at day +21 correlated with lower bilirubin levels 3 months after HSCT (r = -.26, P = .034) and increased overall survival (hazard ratio, .88; 95% CI, .79 to .97; P = .008) . Increased levels of CRP and IL-6 at day 7 after HSCT correlated positively with ALT and bilirubin, and in the multivariate analysis, IL-6 at day 7 appeared to be the only predicting risk factor for increased mean bilirubin during the early post-transplantation phase (B = .01; 95% CI, .01 to .02; P = .001) as well as maximum levels of bilirubin (B = .3; 95% CI, .12 to .48; P= .001) and occurrence of sinusoidal obstruction syndrome during the first 3 months after HSCT (odds ratio, 1.003; 95% CI, 1.001 to 1.005; P = .002). The results of this study indicate that liver toxicity after HSCT is associated with an increased inflammatory response mounted during the phase of maximal gastrointestinal toxicity in the early phase after transplantation.

Childhood suicide attempts with acetaminophen in Denmark: characteristics, social behaviour, trends and risk factors.

AIMS: To explore: (1) The relationship between children admitted to our paediatric department as a result of suicide attempts with acetaminophen and their parents and friends. (2) The extent to which the children had attempted to speak to their parents about their problems before their suicide attempts. (3) The frequency of self-mutilation among children with suicidal behaviour. (4) The purposes and reasons for childhood suicide attempts. METHODS: A retrospective case-control study based on medical records and in-hospital child psychiatric assessments at the Paediatric Department, Hillerød Hospital, Denmark, 2006-2011. STUDY GROUP: 107 children, 11 to 15 years old. CONTROL GROUP: 59 age- and gender-matched children. RESULTS: 43.5% experienced a dissociated parental relationship characterized by the inability to speak to their parents about any problems, compared with 2% in the control group. There was a significant association between a dissociated parental relationship and 'the feeling of not being heard' (p = 0.004), the discovery of the suicide attempt (p = 0.008), the reasons for the suicide attempt (p = 0.006), academic school problems (p = 0.03), and the child's relationships with friends (p = 0.02). Prior to their suicide attempts, 41.5% of the children had attempted to speak to their parents about their problems but felt that they were not heard. There was a significant association among 'the feeling of not being heard' and the purpose of the suicide attempt (p = 0.002) and self-mutilation (p = 0.002). Forty percent mutilated themselves repeatedly. CONCLUSIONS: A consistently impaired parent-child relationship, 'the feeling of not being heard', and self-mutilation are identifiable early risk factors that require increased concern and attention among professionals who work with children.

Long-chain PUFA in granulocytes, mononuclear cells, and RBC in patients with cystic fibrosis: relation to liver disease.

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.

Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis.

Alpha-1-antitrypsin (A1AT) is an important inhibitor of neutrophil proteases including elastase, cathepsin G, and proteinase 3. Transcription profiling data suggest that A1AT is expressed by human neutrophil granulocytes during all developmental stages. A1AT has hitherto only been found associated with azurophile granules in neutrophils indicative of A1AT expression being restricted to the promyelocyte stage. We examined the localization and production of A1AT in healthy donor neutrophils and found A1AT to be a constituent of all granule subtypes and to be released from neutrophils following stimulation. A1AT is produced at all stages of myeloid maturation in the bone marrow. The production increases as neutrophils enter circulation and increases further upon migration to tissues as observed in skin windows and when blood neutrophils are incubated with granulocyte colony-stimulating factor. Neutrophils from patients with A1AT-deficiency carrying the (PI)ZZ mutation in the A1AT gene appeared structurally and functionally normal, but A1AT produced in leukocytes of these patients lacked the ability to bind proteases efficiently. We conclude that A1AT generation and release from neutrophils add significantly to the antiprotease levels in tissues during inflammation. Impaired binding of neutrophil A1AT to serine proteases in patients with (PI)ZZ mutations may enhance their susceptibility to the development of emphysema.

Maternal fish oil supplementation in lactation: effect on developmental outcome in breast-fed infants.

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.

Maternal fish oil supplementation in lactation: effect on visual acuity and n-3 fatty acid content of infant erythrocytes.

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.

Fluctuations in human milk long-chain PUFA levels in relation to dietary fish intake.

Within the Danish population, milk DHA (22:6n-3) levels vary by more than a factor of 10. This paper deals with fluctuations in the milk content of 22:6n-3 and other long-chain PUFA (LCPUFA) and the acute effects of fish meals and fish oil supplements on milk levels of LCPUFA. Twelve fish-eating mothers with 4-mon-old infants provided one blood and one adipose tissue sample, and seven consecutive morning hind-milk samples with dietary records from the previous days. Another 12 lactating women were given fish oil (2-8 g) for breakfast and delivered 6-12 milk samples during the following 24 h. The mean milk 22:6n-3 content of the fish-eating mothers was 0.57+/-0.28 FA% (= percentage of total area of FAME peaks in GLC) and the day-to-day variation (SD/mean) within the individual was 35+/-17%. Mean milk 22:6n-3 content on mornings with no fish the day before was 0.42+/-0.15 FA%; this was increased by 82+/-17% (n = 9, P = 0.05) if the mother had eaten fatty fish. Fish oil resulted in a twofold increase in milk 22:6n-3 levels, which peaked after 10 h and lasted for 24 h. The EPA content of milk was also increased by fish meals and fish oil supplements, but these had no effect on the level of arachidonic acid. The study showed that diurnal and day-to-day fluctuations in levels of milk n-3 LCPUFA are large, which makes it difficult to assess the 22:6n-3 intake of breast-fed infants from a single milk sample. In studies of the functional outcome of dietary 22:6n-3 in breast-fed infants it is suggested also to use a measure of maternal 22:6n-3 status.