Outbreak of severe community-acquired bacterial infections among children in North Rhine-Westphalia (Germany), October to December 2022.

PURPOSE: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences. METHODS: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics. RESULTS: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9). DISCUSSION: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks.

Transient elastography correlated to four different histological fibrosis scores in children with liver disease.

Currently, liver histology is the gold standard for the detection of liver fibrosis. In recent years, new methods such as transient elastography (TE) have been introduced into clinical practice, which allow a non-invasive assessment of liver fibrosis. The aim of the present study was to investigate the predictive value of TE for higher grade fibrosis and whether there is any relevance which histologic score is used for matching. For this purpose, we compared TE with 4 different histologic scores in pediatric patients with hepatopathies. Furthermore, we also determined the aspartate aminotransferase-to-platelet ratio (APRI) score, another non-invasive method, to investigate whether it is equally informative. Therefore, liver fibrosis in 75 children was evaluated by liver biopsy, TE and laboratory values. Liver biopsies were evaluated using four common histological scoring systems (Desmet, Metavir, Ishak and Chevalier's semi-quantitative scoring system). The median age of the patients was 12.3 years. TE showed a good correlation to the degree of fibrosis severity independent of the histological scoring system used. The accuracy of the TE to distinguish between no/minimal fibrosis and severe fibrosis/cirrhosis was good (p = 0.001, AUC-ROCs > 0.81). The optimal cut-off value for the prediction of severe fibrosis was 10.6 kPa. In contrast, the APRI score in our collective showed no correlation to fibrosis.Conclusion: TE shows a good correlation to the histological findings in children with hepatopathy, independent of the used histological scoring system. What is Known: • The current gold standard for detecting liver fibrosis is liver biopsy. Novel non-invasive ultrasound-based methods are introduced to clinical diagnostics. • Most histological scores have been developed and evaluated in adult populations and for only one specific liver disease. What is New: • Transient elastography (TE) in children showed a good correlation to fibrosis severity irrespective of the utilized histological scoring system. • The aspartate aminotransferase-to-platelet ratio (APRI) showed no correlation with different stages of liver fibrosis in children.

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

BACKGROUND & AIMS: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency.

UNLABELLED: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. CONCLUSIONS: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis.

[Tardive movement disorders with antipsychotics ­ a case of aripirazole-induced tardive dystonia and review of the literature]. / Antipsychotika-induzierte tardive Bewegungsstörungen ­ Fallbeispiel einer tardiven Dystonie unter Aripiprazol und Literaturübersicht.

Extrapyramidal adverse events (EPS) occur less frequently with second-generation antipsychotics (SGAs) than with first-generation antipsychotics (FGAs). Tardive dyskinesia (TD), but not tardive dystonia (TDt), also seems to occur less often in adults. TD was found to occur less frequently in children and adolescents treated with FGAs than in adults. No data are available on TDt, and the data pertaining to SGAs are limited and conflicting. SGAs differ in their profile of adverse events. Aripiprazole is less frequently associated with adverse metabolic or cardiac events, but more often with EPS, at least in children and adolescents. To date, there are several case reports of TD or TDt with aripiprazole in adults. Symptomatology, differential diagnosis, pathophysiology, prevalence, and therapy of TDt are presented here based on a case report of TDt during aripiprazole therapy in a 13-year-old girl. During medication with SGAs, the occurrence of EPS, including tardive movement disorders, should be considered and regularly monitored.

High affinity anti-BSEP antibodies after liver transplantation for PFIC-2 - Successful treatment with immunoadsorption and B-cell depletion.

PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized that some PFIC-2 patients develop phenotypic disease recurrence post-OLT due to the appearance of anti-BSEP antibodies. Here, we describe a boy who became cholestatic four yr after OLT during modification of immunosuppression. Canalicular antibody deposits were detected in biopsies of the transplant and antibodies specifically reacting with BSEP were identified at high titers in his serum. These antibodies bound extracellular epitopes of BSEP and inhibited BS transport and were assumed to cause disease recurrence. Consequently, anti-BSEP antibody depletion was pursued by IA and B-cell depletion by anti-CD20 antibodies (rituximab) along with a switch of immunosuppression. This treatment resulted in prolonged relief of symptoms. Depletion of pathogenic anti-BSEP antibodies causing AIBD after OLT in PFIC-2 patients should be considered as a central therapeutic goal.

Antibiotic prophylaxis in the management of percutaneous endoscopic gastrostomy in infants and children.

BACKGROUND: In randomized controlled trials in adult patients the use of prophylactic broad-spectrum antibiotic reduces the number of insertion site and systemic infections, associated with placement of percutaneous endoscopic gastrostomy (PEG) tubes. For pediatric patients no such trials exist. The aim of this study was to assess the value of antibiotic prophylaxis in PEG placement in pediatric patients. METHODS: In a retrospective chart review PEG placement in infants and children performed in a tertiary care center was analyzed. All PEG procedures were performed by an experienced pediatric gastroenterologist using the pull-through technique under general anesthesia. RESULTS: A total of 103 procedures were analyzed; 33 patients received antibiotic prophylaxis and 70 did not. Two (6%) of the patients receiving prophylaxis developed local or systemic infections after PEG placement, whereas seven (10%) without prophylaxis suffered from a PEG-related infection. This difference was not significant on chi-squared test (P = 0.5). Sixty patients had a body temperature >38°C within the first 3 days after the PEG procedure. A total of 77% of these patients had no antibiotic prophylaxis. Mean body temperature differed significantly between patients with and without prophylaxis (37.9°C vs. 38.3°C, respectively; P = 0.02). CONCLUSIONS: The incidence of PEG-related local or systemic infection after PEG-placement was not significantly different between patients with and without antibiotic prophylaxis, but the latter had a significantly higher mean body temperature after the PEG procedure. Taking elevated mean body temperature as a marker for putative bacteremia it is suggested that antibiotic prophylaxis is indicated in all pediatric patients after PEG placement.

Normal values of liver elasticity measured by real-time tissue elastography (RTE) in healthy infants and children.

PURPOSE: To define normal values of liver elasticity measured by real-time tissue elastography (RTE) in healthy infants and children. METHODS: RTE was performed on 91 children and adolescents by two experienced observers (female, n = 43; male, n = 48) and in two age groups (0-10 years, n = 45; 11-20 years, n = 46). Hepatopathies were excluded clinically by extensive laboratory testing and by ultrasound. RTE provides a histogram from a region of interest (ROI) in the liver representing the degree of stiffness of the liver. The distribution of the colors in the histogram corresponds to organ elasticity. By calculating the mean of stiffness values, a numerical value is expressed in arbitrary units (a.u.) representing the mean elasticity of the liver (MEAN). Additionally, the percentage values of relatively stiffer areas (color coded in blue) in the ROI can be calculated (%AREA). A Mann-Whitney U test was performed for these two parameters according to gender. The reproducibility of these values was determined with an intraclass correlation coefficient (ICC) test on another group of 18 healthy volunteers. RESULTS: The median elasticity was 106 a.u. Gender did not have an influence on the parameters (MEAN: p = 0.052; %AREA: p = 0.051). Age-specific analyses did not yield any significant difference between the two age groups for either of the two analyzed parameters (MEAN: p = 0.059; %AREA: p = 0.058). The ICC test demonstrated a moderate agreement for MEAN (ICC = 0.582) and %AREA (ICC = 0.659). CONCLUSION: Real-time elastography is a new sonography-based method and may be used as a supportive analysis to assess liver parenchyma elasticity in children, especially when fibrosis is suspected. We measured RTE normal values in children as reference data.

Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients.

Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparable CNI blood concentrations frequency and severity of adverse effects vary considerably among individual patients. Determining the RGE of NFAT-regulated genes in leukocytes is a new pharmacodynamic approach to measure directly the functional consequences of calcineurin inhibition in T-lymphocytes. We compared clinical outcome parameters and RGE of activated T-cells after pLtx. We measured prospectively RGE of NFAT regulated genes in 33 pLTX recipients in the maintenance period after pLTX. CsA-treated patients with recurrent infections had significantly lower RGE rates (27%) than children without recurrent infections (50%; p = 0.04), whereas pharmacokinetic parameters of CsA and the concomitant immunosuppressive therapy were comparable between both groups. In patients on tacrolimus-based IS therapy NFAT RGE was only slightly reduced (90%). Pharmacodynamic monitoring of CsA by measurement of RGE in T-lymphocytes has the potential to identify over-immunosuppressed pediatric liver transplant recipients on a CsA-based IS therapy, while in children on low-dose tacrolimus therapy, RGE measurement does not provide additional clinically useful information.

Molecular Adsorbents Recirculating System dialysis in children with cholestatic pruritus.

BACKGROUND: Cholestatic pruritus may severely compromise quality of life. The Molecular Adsorbents Recirculating System (MARS) allows removal of pruritogenic substances without exposure to foreign proteins. Pediatric data, however, are scant. METHODS: We retrospectively analyzed the efficacy of MARS in three boys with severe cholestatic pruritus. They received a total of 135 MARS sessions during 8, 4, and 13 months prior to liver transplantation. Total serum bilirubin and bile acids were monitored, and pruritus was assessed by a numerical rating scale (NRS 0 = no pruritus, 10 = maximal pruritus). RESULTS: MARS sessions were initially performed three times weekly at a mean duration of 6.3 ± 1.4 h. Sessions could be reduced to once weekly and once every other week in two patients. Pre-MARS plasma bile acid concentrations averaged 207 ± 67 µmol/l. They declined to 67 ± 9%, 48 ± 3%, 38 ± 14%, and 37 ± 5% of baseline within 2, 4, 6 and 8 h of therapy, respectively (all p < 0.05). The average interdialytic increase of plasma bile acids was 34 ± 33 µmol/l per day. Mean NRS score decreased from 6.5 ± 2.3 to 3.3 ± 2.9 (p < 0.01). Skin lesions from itching disappeared. All MARS treatments were well tolerated. CONCLUSION: MARS dialysis substantially reduces cholestatic pruritus in children refractory to pharmacological treatment.

Feasibility study and control values of transient elastography in healthy children.

Transient elastography (TE) is a new technique for the non-invasive assessment of liver fibrosis. The degree of fibrosis is equivalent to the liver stiffness measured in kilopascal (kPa). It is frequently used in adult patients with a mean normal stiffness of 4.4-5.5 kPa. Since 2008, liver stiffness can be measured even in small children and infants following the availability of a new probe with a smaller diameter (S-probe 5 mm) than the regular probe (M-probe 7 mm). We report control values for healthy children between 0 and 18 years and investigated the feasibility of this technique in a pediatric population. For control values, TE was performed in infants and children after exclusion of liver disease by medical history, clinical examination, blood investigation, and abdominal ultrasound. For feasibility analyses the results of all TE performed in our clinic were analyzed irrespective of the underlying disease. Liver stiffness was measured with the S-probe (thorax diameter <45 cm (S1) or 45-75 cm (S2)) and the M-probe (thorax diameter >75 cm) according to the manufacturer's recommendations. A total of 240 healthy children were analyzed to establish control values. The median liver stiffness was 4.7 kPa resulting in an upper limit of normal of 6.47 kPa. Median values of stiffness were significantly age dependent with 4.40, 4.73, and 5.1 kPa in children 0-5, 6-11, and 12-18 years (p = 0.001) while the interquartile range decreased with age (0.8, 0.7, and 0.6 kPa). The resulting upper limit of normal (median plus 1.64 times standard deviation) was 5.96, 6.65, and 6.82 kPa. Girls between 11 and 18 years showed a significantly lower median stiffness than boys of the same age (4.7 vs. 5.6 kPa; p < 0.005). Feasibility was tested in 975 consecutive liver stiffness measurements (LSM) in children 0-18 years of age. Patients with invalid LSM were significantly younger than those with valid LSM (5.8 vs. 9.7 years, p < 0.0001), showed a significantly higher stiffness (10.2 vs. 6.17, p < 0.0001), and examinations took significantly longer (202 vs. 160 s, p < 0.0001). TE is technically possible in children of all age groups. The upper limit of normal increases significantly with age. Due to movement artifacts the measurement is reliable from the age of 6 without sedation. In younger children the number of invalid measurements increases significantly. Further studies are needed to asses the value of TE in the diagnosis and follow-up of liver disease in pediatric hepatology.

Comparison of Molecular Adsorbents Recirculating System (MARS) dialysis with combined plasma exchange and haemodialysis in children with acute liver failure.

BACKGROUND: Molecular Adsorbents Recirculating System (MARS) is an extracorporeal liver support system eliminating albumin-bound and water-soluble substances. While it is increasingly applied in patients with acute liver failure (ALF), no comparison with standard dialysis methods has yet been performed. METHODS: This is an analysis of ten children (0.1-18 years) with ALF, who underwent a total of 22 MARS sessions. Standard adult MARS sets were used in seven (23.5-72 kg) and MARS Mini in three children (2.8-13 kg). In eight children, MARS was alternated with combined plasma exchange (PE) and haemodialysis (HD) treatments. Mean treatment duration was 7.2 (6-10) h for MARS and 5.7 (4.5-6.6) h for PE/HD. RESULTS: Standard MARS treatment only slightly decreased serum bilirubin (16.3 ± 6.5-13.8 ± 5.9 mg/dL) and ammonia (113 ± 62-99 ± 68 µmol/L) and international normalized ratio (INR) tended to increase (1.5 ± 0.3 and 2 ± 1.1). Mini-MARS did not reduce serum bilirubin (19.7 ± 3-20.5 ± 3.2 mg/dL), ammonia slightly decreased (70 ± 24-56 ± 9 µmol/L) and INR increased (2.5 ± 0.7-2.9 ± 1.1, all P = n.s.). In contrast, PE/HD reduced serum bilirubin (23 ± 8.4-14.7 ± 7 mg/dL), ammonia (120 ± 60-70 ± 40 µmol/L) and INR (2.4 ± 0.8-1.4 ± 0.1, all P < 0.05). Intraindividual comparison showed a slight increase in bilirubin by 2 ± 22% with MARS and a reduction by 37 ± 11% with PE/HD (P < 0.001 versus MARS) and a decrease in ammonia of 18 ± 27 and 39 ± 23% (P < 0.05). INR increased during MARS by 26 ± 41% and decreased with PE/HD by 37 ± 20% (P < 0.01). All treatment sessions were well tolerated. Five children died, including the three children treated with Mini-MARS. CONCLUSION: Our experience suggests superior efficacy of combined PE/HD as compared to intermittent MARS therapy for treating ALF.

High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure.

OTCD can present with ALF at any age. Under adequate therapy symptoms resolve quickly. We report a three-yr-old girl with the manifestation of an OTCD as ALF. Despite adequate pharmacotherapy and protein restriction, the patient deteriorated and developed hepatic encephalopathy. A high urgency liver transplantation was performed and the patient recovered completely. We conclude that in patients with ALF urea cycle defects in general and OTCD in particular should be considered as differential diagnosis. Patients should be managed in a center that has the capacity for an emergency liver transplantation.

One life ends, another begins: Management of a brain-dead pregnant mother-A systematic review-.

BACKGROUND: An accident or a catastrophic disease may occasionally lead to brain death (BD) during pregnancy. Management of brain-dead pregnant patients needs to follow special strategies to support the mother in a way that she can deliver a viable and healthy child and, whenever possible, also be an organ donor. This review discusses the management of brain-dead mothers and gives an overview of recommendations concerning the organ supporting therapy. METHODS: To obtain information on brain-dead pregnant women, we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included the age of the mother, the cause of brain death, maternal medical complications, gestational age at BD, duration of extended life support, gestational age at delivery, indication of delivery, neonatal outcome, organ donation of the mothers and patient and graft outcome. RESULTS: In our search of the literature, we found 30 cases reported between 1982 and 2010. A nontraumatic brain injury was the cause of BD in 26 of 30 mothers. The maternal mean age at the time of BD was 26.5 years. The mean gestational age at the time of BD and the mean gestational age at delivery were 22 and 29.5 weeks, respectively. Twelve viable infants were born and survived the neonatal period. CONCLUSION: The management of a brain-dead pregnant woman requires a multidisciplinary team which should follow available standards, guidelines and recommendations both for a nontraumatic therapy of the fetus and for an organ-preserving treatment of the potential donor.

Rapamycin inhibits proliferation and migration of hepatoma cells in vitro.

BACKGROUND: Systemic immunosuppression represents the major factor for cancer recurrence after orthotopic liver transplantation for hepatocellular carcinoma (HCC). Rapamycin is an immunosuppressant with unique antitumoral properties. Although rapamycin has been successfully used in HCC patients after liver transplantation, the detailed mechanisms of rapamycin action on tumor cells are poorly understood. METHODS: Two HCC cell lines (PLC5 and HuH7) were used to evaluate the effect of rapamycin. Tumor cell proliferation was analyzed using cell counting and BrdU incorporation assay. Expression of phosphorylated Akt was studied using enzyme linked immunosorbent assay. Digital time-lapse microscopy was utilized to measure tumor cell migration in vitro. RESULTS: Rapamycin induced a strongly dose-dependent inhibition of tumor cell proliferation in both HCC cell lines. Additionally, rapamycin inhibited activation of Akt phosphorylation and tumor cell migration after prolonged treatment. CONCLUSIONS: Rapamycin suppresses tumor progression due to inhibition of phosphorylated Akt, cell proliferation, and migration. The data of the present study strengthen clinical implications of rapamycin after liver transplantation with HCC.

A new pediatric liver transplantation program in Southern Germany. The Heidelberg experience.

pLTx is a highly complex procedure. It can only be performed safely by experienced teams. Starting a new pLTx program in a country with established centers must therefore avoid a learning curve. We have initiated a liver transplantation program for children in 2003. Medical standards were defined by a team of surgeons, pediatricians, radiologists, anesthesiologists, and pathologists before the first transplantation. An external expert in the field of pLTx supervised the whole process. In a pilot phase, six children weighing more than 20 kg were successfully transplanted. Following this series, the clinical pathways were re-evaluated, and the program was opened for children of all age groups. Between 2003 and 2008, 32 children received 34 organs. Sixty-eight percent of patients received a split-liver, 26% a full size organ, and 6% a reduced size graft. Four LRLTx were performed. Patient survival rate was 91%. We conclude that a new pLTx program can be established without a significant learning curve regarding mortality if a strict strategy of team-building is followed. In the pilot phase, small children and infants have to be referred and transplanted in an established center. An interdisciplinary team of specialists closely working together is the key for sustained success.

Adenovirus infection and treatment with cidofovir in children after liver transplantation.

In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real-time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life-threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow-up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 x 10(9 )copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 x 10(4) copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset.

Genetic variants in the adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid-associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4-associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504-514).

Limitations and opportunities of non-invasive liver stiffness measurement in children.

Changes in liver structure are an important issue in chronic hepatopathies. Until the end of the 20th century, these changes could only be determined by histological analyses of a liver specimen obtained via biopsy. The well-known limitations of this technique (i.e., pain, bleeding and the need for sedation) have precluded its routine use in follow-up of patients with liver diseases. However, the introduction of non-invasive technologies, such as ultrasound and magnetic resonance imaging, for measurement of liver stiffness as an indirect marker of fibroses has changed this situation. Today, several non-invasive tools are available to physicians to estimate the degree of liver fibrosis by analysing liver stiffness. This review describes the currently available tools for liver stiffness determination that are applicable to follow-up of liver fibrosis/cirrhosis with established clinical use in children, and discusses their features in comparison to the "historical" tools.