Paediatric-onset immune-mediated inflammatory disease is associated with an increased mortality risk-A nationwide study.

BACKGROUND: Paediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes than when diagnosed in adults. However, data on mortality are often extrapolated from adult studies. AIM: To estimate the effect of pIMID on mortality. METHODS: In a population-based cohort study using the nationwide Danish healthcare registers, we included all patients diagnosed with pIMID in Denmark from 1980 to 2018. PIMID were defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, lupus erythematosus, or vasculitis registered before age 18 years. All-cause mortality was the primary outcome; cause-specific mortality was the secondary outcome. We used Cox survival analysis to estimate hazard ratios (HR), and Aalen survival analysis to estimate rate differences. RESULTS: We included 11,581 individuals diagnosed with pIMID and 99,665 reference individuals, accounting for 1,371,994 person-years of follow-up. Median and interquartile (IQR) age at diagnosis was 12.6 (7.9-15.9) years. During follow-up, 152 patients with pIMID and 316 reference individuals died; adjusted HR (aHR) was 3.8 (95% confidence interval [CI] 3.1-4.7). This corresponded to 6.9 (95% CI: 5.3-8.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal diseases (aHR 22.8; 95% CI 9.6-64.1), gastrointestinal cancers (aHR 19.2; 95% CI 5.0-74.2) and lymphoproliferative disorders (aHR 6.8; 95% CI 2.8-16.8). CONCLUSION: Patients diagnosed with pIMID have a fourfold higher risk of mortality when followed into early adulthood compared with reference individuals. This underlines the severe disease course of pIMID and highlights the need for multidisciplinary care.

Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD).

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.

Low skeletal muscle mass and liver fibrosis in children with cerebral palsy.

The purpose of the study was to conduct a nutritional and metabolic assessment of children with cerebral palsy, including an investigation of liver status, body composition, and bone mineral density. In this cross-sectional study we included 22 children with cerebral palsy. By using ultrasound, transient elastography, dual x-ray absorptiometry (DXA) scan, blood samples, anthropometric measurements, and a three-day diet registration, the nutritional and metabolic status was evaluated. Liver fibrosis and steatosis were found in four patients (18.2%), all with severe motor impairments, low skeletal muscle mass, and epilepsy. All patients with liver involvement had normal liver-related blood samples. Decreased bone mineral density was found in 26.3%, and 91.0% had low skeletal muscle mass. Fat mass and muscle mass were significantly lower in the patients with severe motor impairments compared to the patients with less severe motor impairments. Within the children classified as 'underweight' or 'normal' according to body mass index, body fat determined by DXA scan was normal or high in 50% of these patients. CONCLUSIONS: This study is the first to report liver fibrosis and steatosis in children with cerebral palsy. Possible causes of liver fibrosis and/or steatosis are altered body composition with low skeletal muscle mass, decreased mobility and medical drug intake. Further investigations of liver involvement and risk factors are needed. WHAT IS KNOWN: • Children and adolescents with cerebral palsy are at risk of malnutrition and altered body composition, both of which can lead to fatty liver disease. • It is unknown whether children with cerebral palsy are at increased risk of metabolic disturbances such as fatty liver disease. WHAT IS NEW: • Altered body composition and low skeletal muscle mass, regardless of ambulation is present in 91% of the children with cerebral palsy. • Liver fibrosis and/or steatosis were found in 18.2% of the patients. Possible causes are altered body composition, decreased mobility and medical drug intake.

Psychiatric disorders in paediatric-onset immune-mediated inflammatory diseases: a nationwide Danish study.

OBJECTIVES: To investigate the frequency of psychiatric disorders before and after onset of paediatric-onset immune-mediated inflammatory diseases (pIMID). STUDY DESIGN: In a nationwide study from 1996 to 2018, we investigated psychiatric disorders in patients with paediatric-onset inflammatory bowel diseases, autoimmune liver diseases and rheumatic diseases, using Danish national healthcare and population registers. Each case was matched with up to 10 controls from the background population. The cumulative incidence for psychiatric disorders prior to pIMID onset in patients was compared with controls. Cox proportional regression was used to estimate adjusted HRs (aHR) with a 95% CI between cases and controls after the index date. RESULTS: We included 11 208 cases (57% female) and 98 387 controls. The median age at disease onset was 12.5 years (IQR 8-15) and follow-up time 9.8 years (IQR 5-15). We found an association between psychiatric disorders before index date and a diagnosis of subsequent pIMID (OR 1.3, 95% CI 1.2 to 1.4). Notably, after index date, cases also had an increased risk (aHR 1.6, 95% CI 1.5 to 1.7) of psychiatric disorders compared with controls. This risk was increased for all groups of psychiatric disorders. Female patients had an increased risk of suicide attempt after index date (aHR 1.4, 95% CI 1.1 to 1.8). CONCLUSION: Patients with pIMID are at increased risk for a broad spectrum of psychiatric disorders both before and after onset of pIMID. The results support the need for awareness of psychiatric morbidity in this young patient group and the need for coordinated healthcare for those with comorbid states.

Microvillus Inclusion Disease Caused by MYO5B: Different Presentation and Phenotypes Despite Same Mutation.

Microvillus inclusion disease (MVID) is associated with specific variants in the MYO5B gene causing disrupt epithelial cell polarity. MVID may present at birth with intestinal symptoms or with extraintestinal symptoms later in childhood. We present 3 patients, of whom 2 are siblings, with MYO5B variants and different clinical manifestations, ranging from isolated intestinal disease to intestinal disease combined with cholestatic liver disease, predominant cholestatic liver disease clinically similar to low-gamma-glutamyl transferase PFIC, seizures, and fractures. We identified 1 previously unreported MYO5B variant and 2 known pathogenic variants and discuss genotype-phenotype correlations of these variants. We conclude that MVID may present phenotypically different and mimic other severe diseases. We suggest that genetic testing is included early during diagnostic investigations of children with gastrointestinal and cholestatic presentation.

High yield on aetiology using a systematic diagnostic approach to paediatric acute liver failure, analysis of a nationwide cohort.

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.

Pre- and perinatal exposures associated with developing pediatric-onset immune-mediated inflammatory disease: A Danish nation-wide cohort study.

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.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Metabolic assessment in children with neuromuscular disorders shows risk of liver enlargement, steatosis and fibrosis.

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.

[Diagnosis and treatment of a multisystemic disorder in children called congenital portosystemic shunts].

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.

Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: Phase 2 study.

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.

Safety of High-Volume Plasmapheresis in Children With Acute Liver Failure.

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.

Extended Screening for Cystic Fibrosis-related Liver Disease Including Elastography in Children and Adolescents.

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 6 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 ≥2 abnormal results of sonographic methods and ≥2 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, 8 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.

Risk markers for later cardiovascular diseases in liver-transplanted children and adolescents.

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.

[Affected liver biochemistry in children with rheumatic diseases].

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.

[Liver failure in neonatal children is a diagnostic challenge].

This case report presents a newborn boy with hypoglycaemia, anaemia, jaundice and severe coagulopathy during the first day of his life, imitating sepsis and disseminated intravascular coagulation. One week after the birth he was diagnosed with acute liver failure due to gestational alloimmune liver disease (GALD). Despite the fact that GALD is rare, it must be suspected in all unexplained stillborn children and infants with severe liver disease. If diagnosed, it is possible to prevent death and severe liver failure in future newborns by treating the affected women with immunoglobulin during pregnancy.

Prophylactic Dosing of Vitamin K to Prevent Bleeding.

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.