Background
Although fibrosis is the main determinant of liver stiffness, other disease-related factors usually disregarded in studies on liver elastography, such as inflammation and cholestasis, may ...influence liver stiffness.
Objective
To evaluate the accuracy of two-dimensional (2-D) shear wave elastography in assessing liver fibrosis in children with chronic liver disease by controlling for the confounding role of several disease- and patient-related factors.
Materials and methods
Three disease groups were studied: 1) various chronic liver diseases, 2) autoimmune hepatitis and 3) biliary atresia. The METAVIR (meta-analysis of histological data in viral hepatitis) score was used for fibrosis staging and grading of necroinflammatory activity. Multiple linear regression was used to evaluate the relationship between liver stiffness measurements and disease-related factors. The diagnostic accuracy of elastography for predicting fibrosis stages was assessed by calculating the area under the receiver operating characteristic curves.
Results
The various chronic liver diseases group (
n
=32; 7.1±4.9 mean±standard deviation years) showed liver stiffness of 8.9±5.0 (mean±standard deviation) kPa, the autoimmune hepatitis group (
n
=33; 8.1±4.4 years) of 7.1±2.7 kPa, and the biliary atresia group (
n
=19; 0.2±0.1 years) of 19.7±15.2 kPa. Liver stiffness measurements differed across METAVIR fibrosis categories in all disease groups. The highest values were found in biliary atresia, at fibrosis stages ≥F2 (F2: 12.4±1.6 kPa, F3: 17.8±2 kPa, F4: 41.5±12.4 kPa). Liver stiffness was strongly associated only with fibrosis (
P
<0.0001) in various chronic liver diseases, but with necroinflammatory activity (
P
<0.0001) and fibrosis (
P
=0.002) in autoimmune hepatitis, and with age (
P
<0.0001), fibrosis (
P
<0.0001) and cholestasis (
P
=0.009) in biliary atresia. Optimal cutoffs for detecting advanced fibrosis (≥F3) were 16 kPa (area under curve: 0.98; sensitivity: 87.5%; specificity: 96.7%) in biliary atresia and 8.7 kPa (area under curve: 0.98; sensitivity: 93.8%; specificity: 96.1%) in other chronic liver diseases.
Conclusion
Two-dimensional shear wave elastography is reliable in assessing liver fibrosis in children with chronic liver diseases.
Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN). Here, using Chinese hamster ovary (CHO) ...Niemann-Pick type C1 (NPC1) mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6) accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs). This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.
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•Late endosomes determine TGN cholesterol levels to regulate Stx6 location•Cholesterol regulates Stx6 complex formation with VAMP3 and VAMP4•Stx6 mislocation in recycling endosomes (REs) inhibits the recycling of integrins•Stx6 accumulation in REs reduces cell migration and invasion
Cell migration is fundamental to many physiological and pathological settings such as wound healing and cancer cell metastasis. Here, Reverter et al. show that the intracellular cholesterol levels determine the capacity of cells to initiate cell migration, adhere, and/or invade. Fine-tuning of cholesterol levels at Golgi/endosome boundaries is critical for regulating the trafficking and function of specific SNARE proteins that eventually regulate integrin recycling and cell behavior.
Atopy patch testing with allergen extracts (Stallergenes, Antony, France) resulted in eczematous skin lesions for cat dander and house dust mite, suggesting a clinical relevance of the allergic ...sensitization (Fig 1, C). ...within 1 week after testing, progressive exacerbation of the erythema was noted (Fig 1, D). The precise role of ichthyin has not been elucidated; it has homologies to G protein-coupled receptors and magnesium transporter proteins and is proposed to be a receptor for trioxilins.3NIPAL4 mutations have been associated with generalized scaling and palmoplantar keratoderma and distinct ultrastructural features4; by contrast, erythema and atopy were observed only in some patients (see Table E4). ...we hypothesized that in our case additional genetic variants could contribute to and superimpose the clinical and morphologic picture.
We report the use of FilmArray Blood Culture Identification (BCID) multiplex PCR system for pathogen detection from a child with septic arthritis that Streptococcus pyogenes was identified directly ...from synovial fluid and a child with complicated pneumonia with pleural effusion that Streptococcus pneumoniae was identified from pleural fluid.
A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia.
A thorough workup for infections, ...congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal COVID-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered. The clinical condition of the neonate deteriorated and due to laboratory evidence of hyperinflammation, hemophagocytic lymphohistiocytosis was suspected, and treatment with etoposide and dexamethasone was initiated with temporary stabilization. Gaucher disease type 2 was eventually diagnosed.
Gaucher disease can rarely present in neonates as hemophagocytic lymphohistiocytosis.
Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from ...internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system.
The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D.
Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients.
LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels.
The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype.
This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.
•Clinical and genetic study of 14 patients with childhood-onset LAL-D.•Four patients were homozygous for the common c.894G > A variant of LIPA gene.•In six patients c.894G > A was associated with other pathogenic variants.•A novel missense and a novel splicing pathogenic variant were identified.•The putative geographical origin of three variants is suggested.
This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A ...encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine β-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities.
The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence.
The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 μM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.
Niemann–Pick type C (NPC) disease is an autosomal recessive lysosomal disorder characterised by the accumulation of a complex pattern of lipids in the lysosomal-late endosomal system. More than 300 ...disease-causing mutations have been identified so far in the NPC1 and NPC2 genes, including indel, missense, nonsense and splicing mutations. Only one genomic deletion, of more than 23kb, has been previously reported. We describe two larger structural variants, encompassing NPC1 and flanking genes, as a cause of the disease. QMPSF, SNP inheritance and CytoScan® HD Array were used to confirm and further characterise the presence of hemizygous deletions in two patients. One of the patients (NPC-57) bore a previously described missense mutation (p.T1066N) and an inherited deletion that included NPC1, C18orf8 and part of ANKRD29 gene. The second patient (NPC-G1) had a 1-bp deletion (c.852delT; p.F284Lfs*26) and a deletion encompassing the promoter region and exons 1–10 of NPC1 and the adjacent ANKRD29 and LAMA3. This study characterised two novel chromosomal microdeletions at 18q11–q12 that cause NPC disease and provide insight into missing NPC1 mutant alleles.
► Deletions including the NPC1 and flanking regions gene as cause of Niemann–Pick C. ► Deletions have been characterised by QMPSF, SNP segregation analysis and array-CGH. ► This information was used for prenatal diagnosis in one of the cases.
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