ABSTRACT
Background and study aims: Liver abscesses are rare in the Western pediatric population and data on predisposing factors and etiology are scarce. We aimed to describe predisposing factors, microbiological characteristics, and treatment. Patients and methods: Retrospective analysis of children admitted to two tertiary care hospitals in Belgium from 1 January 1996 to 31 December 2019. We analyzed clinical features, predisposing factors, imaging characteristics, microbiological data, treatment, and outcome in children with a liver abscess and compared these data with the literature. Results: We collected 24 cases with a male to female ratio of 1.4 and a median age of 3.2 years at time of diagnosis. Survival was 95.8%. Invasive culture specimens were obtained in 83.3% and showed growth of bacteria in 55%. Parenteral antibiotics were administered before invasive culture sampling in 80%. Liver abscesses were cryptogenic in four (16.7%) patients. Hepatobiliary disease was the most prevalent predisposing factor (n = 6; 25%), followed by recent antineoplastic therapy for malignancies (n = 5; 20.8%), intra-abdominal surgical pathology (n = 4; 16.7%) and umbilical venous catheters (n = 2; 8.3%). In two patients there was a parasitic origin (n = 2; 8.3%) and in one it was caused by Bartonellosis. There was no diagnosis of chronic granulomatous disease (CGD) in our cohort. Conclusions: Pediatric liver abscesses have a favorable outcome in the developed world. Whenever feasible, invasive abscess culture specimens should be obtained. In patients presenting with a cryptogenic liver abscess or atypical disease course, immunological workup should be ensured.
Subject(s)
Liver Abscess , Anti-Bacterial Agents/therapeutic use , Belgium/epidemiology , Child , Child, Preschool , Female , Hospitalization , Humans , Liver Abscess/diagnosis , Liver Abscess/epidemiology , Liver Abscess/therapy , Male , Retrospective StudiesABSTRACT
Since January 2020, the Novel Coronavirus Disease 2019 (COVID-19) pandemic has dramatically impacted the world. In March 2020, the COVID-19 epidemic reached Belgium creating uncertainty towards all aspects of life. There has been an impressive capacity and solidarity of all healthcare professionals to acutely reconvert facilities to treat these patients. In the context of liver transplantation (LTx), concerns are raised about organ donation shortage and safety, the ethics of using limited healthcare resources for LTx, selection criteria for LTx during the epidemic and the risk of de novo COVID-19 infection on the waiting list and after LTx. BeLIAC makes several recommendations to try to mitigate the deleterious effect that this epidemic has/will have on donation and LTx, taking into account the available resources, and trying to maximize patients and healthcare professionals' safety.
Subject(s)
Coronavirus Infections , End Stage Liver Disease/surgery , Infection Control/methods , Liver Transplantation/methods , Pandemics , Pneumonia, Viral , Belgium , Betacoronavirus , COVID-19 , Coronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , End Stage Liver Disease/epidemiology , Humans , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , SARS-CoV-2ABSTRACT
Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by hypercalcemia associated with inappropriate hypocalciuria and normal parathyroid hormone levels. Acute recurrent pancreatitis (ARP) is rare in children. Predisposing factors include hypercalcemia and mutations in the serine protease inhibitor Kazal-type 1 (SPINK1) gene. The disease carries a heavy morbidity and preventive treatment options are scant. Here, we report a child with a novel genetic/metabolic form of ARP associated with compound heterozygous SPINK1/AP2S1 (adaptor protein-2 σ1-subunit) mutations, recurrence of which was completely abrogated for 6 years by cinacalcet treatment.
Subject(s)
Adaptor Protein Complex 2/genetics , Adaptor Protein Complex sigma Subunits/genetics , Calcium-Regulating Hormones and Agents/therapeutic use , Cinacalcet/therapeutic use , Pancreatitis/genetics , Pancreatitis/prevention & control , Trypsin Inhibitor, Kazal Pancreatic/genetics , Acute Disease , Adolescent , Female , Humans , Hypercalcemia/complications , Hypercalcemia/congenital , Hypercalcemia/genetics , Mutation/genetics , RecurrenceABSTRACT
Cyclosporine A, a potent calcineurin inhibitor, has been widely used in organ transplantation and in the treatment of autoimmune diseases. It has, however, been shown to induce serious renal and hepatic side effects. The drug is also used in preclinical studies, but with little published information on the optimal dose and route of administration in rodents. Objectives of this study were to identify efficient and safe doses of cyclosporine A in rodent and to assess its effects on hepatic and renal functions. For this purpose, we tested the effects of different doses and administration routes of cyclosporine A (5, 2.5 and 1 mg/kg) administered during 28 days intraperitoneally, or by gastric feeding on Wistar rats. Our data indicate that rats injected intraperitoneally with 5 mg/kg/2d (every two days) exhibited trough cyclosporine A levels within known therapeutic range in human, but were subject to blood cyclosporine A accumulation, whereas the 5 mg/kg/d gavage resulted in only a small cyclosporine A accumulation over time. In both cases this accumulation was not deleterious to renal and hepatic functions, as shown by transaminase, urea, creatinine and bilirubin measurements.
ABSTRACT
AIM: To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. BACKGROUND: Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis. PATIENTS AND METHODS: This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed. FINDINGS: HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies. INTERPRETATION: We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis. FUNDING: None.
Subject(s)
Inflammation/pathology , Liver Transplantation , Liver/pathology , Age Factors , Alleles , Biopsy , Child , Child, Preschool , Female , Fibrosis , Genetic Predisposition to Disease , Genotype , HLA Antigens/immunology , HLA-DRB1 Chains/genetics , Humans , Immune System/metabolism , Liver/metabolism , Liver Diseases/genetics , Liver Diseases/pathology , Liver Diseases/therapy , Logistic Models , Male , Multivariate Analysis , Odds Ratio , Sex Factors , Transplantation, HomologousABSTRACT
Hemophilia remains a non-curative disease, and patients are constrained to undergo repeated injections of clotting factors. In contrast, the sustained production of endogenous factors VIII (FVIII) or IX (FIX) by the patient's own cells could represent a curative treatment. Gene therapy has thus provided new hope for these patients. However, the issues surrounding the durability of expression and immune responses against gene transfer vectors remain. Cell therapy, involving stem cells expanded in vitro, can provide de novo protein synthesis and, if implanted successfully, could induce a steady-state production of low quantities of factors, which may keep the patient above the level required to prevent spontaneous bleeding. Liver-derived stem cells are already being assessed in clinical trials for inborn errors of metabolism and, in view of their capacity to produce FVIII and FIX in cell culture, they are now also being considered for clinical application in hemophilia patients.
Subject(s)
Factor IX/biosynthesis , Factor VIII/biosynthesis , Genetic Therapy/methods , Hemophilia A/surgery , Hemorrhage/prevention & control , Liver/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Animals , Extracellular Vesicles/metabolism , Factor IX/genetics , Factor VIII/genetics , Hemophilia A/blood , Hemophilia A/diagnosis , Hemophilia A/genetics , Hemostasis , Humans , Treatment OutcomeABSTRACT
INTRODUCTION: Chest physiotherapy is regularly prescribed for children, particularly in cystic fibrosis. Gastro-oesophageal reflux is common in this disease and is associated with certain chest physiotherapy manoeuvres. AIM OF THE STUDY: To evaluate the influence of two chest physiotherapy techniques on gastro-oesophageal reflux in children. MATERIAL AND METHOD: Twenty-nine children were investigated by routine pHmetry. During the examination, they performed two chest physiotherapy manoeuvres in a seated position for 10 minutes each with a 5 minutes rest between them. The two manoeuvres used were a slow expiration technique (ELPr) and positive expiratory pressure (PEP). It was a prospective study and the order of manoeuvres was randomised. The pH traces were analysed blindly when all the studies had been completed. RESULTS: In the sample, 21% of children had gastro-oesophageal reflux during the physiotherapy session. No relationship was found between reflux during physiotherapy and pathological reflux (P=0.411) nor the physiotherapy technique used (P=0.219). CONCLUSION: The use of these two chest physiotherapy techniques in children in a seated position can produce gastro-oesophageal reflux.
Subject(s)
Gastroesophageal Reflux/etiology , Physical Therapy Modalities/adverse effects , Adolescent , Child , Child, Preschool , Exhalation , Female , Gastric Acidity Determination/instrumentation , Humans , Infant , Male , Positive-Pressure Respiration/adverse effects , Posture , Prospective StudiesABSTRACT
BACKGROUND: Post-transplant food allergy (LTFA) is increasingly observed after paediatric liver transplantation (LT). Although the immunopathology of LTFA remains unclear, immunoglobulin (Ig) E seems to be implicated. OBJECTIVE: To study humoral and cellular immunity in paediatric LT patients in search for factors associated with LTFA, and compare with healthy controls (HC) and non-transplant food-allergic children (FA). METHODS: We studied serum Ig levels in 29 LTFA, 43 non-food-allergic LT patients (LTnoFA), 21 FA patients and 36 HC. Serum-specific IgA and IgE against common food allergens in LTFA, IgA1 , IgA2 and joining-chain-containing polymeric IgA (pIgA) were measured. Peripheral blood mononuclear cells were analysed by flow cytometry for B and T cell populations of interest. RESULTS: Serum IgA and specific IgA were higher in LTFA compared to LTnoFA. LTFA patients had the highest proportion of circulating T follicular helper cells (cTfh). The percentage of cTfh correlated positively with serum IgA. Unique in LTFA was also the significant increase in serum markers of mucosal IgA and the decrease in the Th17 subset of CXCR5(-) CD4(+) cells compared to HC. Both LT patients exhibited a rise in IgA(+) memory B cells and plasmablasts compared to HC and FA. CONCLUSIONS: LT has an impact on humoral immunity, remarkably in those patients developing FA. The increase in serum markers of mucosal IgA, food allergen-specific IgA and cTfh cells observed in LTFA, point towards a disturbance in intestinal immune homoeostasis in this patient group.
Subject(s)
Food Hypersensitivity/blood , Food Hypersensitivity/immunology , Immunoglobulin A/immunology , Liver Transplantation , T-Lymphocytes, Helper-Inducer/immunology , Adolescent , Age Factors , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Biomarkers , CD4 Lymphocyte Count , Child , Child, Preschool , Female , Food Hypersensitivity/diagnosis , Humans , Immunoglobulin A/blood , Immunoglobulin A, Secretory/immunology , Immunoglobulin E/blood , Immunoglobulin E/immunology , Immunologic Memory , Immunophenotyping , Infant , Liver Transplantation/adverse effects , Male , T-Lymphocytes, Helper-Inducer/metabolismABSTRACT
Progressive liver allograft fibrosis (LAF) is well known to occur long term, as shown by its high prevalence in late posttransplant liver biopsies (LBs). To evaluate the influence of clinical variables and immunosuppression on LAF progression, LAF dynamic was assessed in 54 pediatric liver transplantation (LT) recipients at 6 months, 3 and 7 years post-LT, reviewing clinical, biochemical data and protocol LBs using METAVIR and the liver allograft fibrosis score, previously designed and validated specifically for LAF assessment. Scoring evaluations were correlated with fibrosis quantification by morphometric analysis. Progressive LAF was found in 74% of long-term patients, 70% of whom had unaltered liver enzymes. Deceased grafts showed more fibrosis than living-related grafts (p = 0.0001). Portal fibrosis was observed in correlation with prolonged ischemia time, deceased grafts and lymphoproliferative disease (p = 0.001, 0.006 and 0.012, respectively). Sinusoidal fibrosis was correlated with biliary complications (p = 0.01). Centrilobular fibrosis was associated with vascular complications (p = 0.044), positive autoantibodies (p = 0.017) and high gamma-globulins levels (p = 0.028). Steroid therapy was not associated with reduced fibrosis (p = 0.83). LAF could be viewed as a dynamic process with mostly progression along the time. Peri- and post-LT-associated factors may condition fibrosis development in a specific area of the liver parenchyma.
Subject(s)
Graft Rejection/etiology , Liver Cirrhosis/etiology , Liver Transplantation , Adolescent , Allografts , Child , Child, Preschool , Disease Progression , Female , Fibrosis/pathology , Follow-Up Studies , Graft Rejection/pathology , Graft Survival , Humans , Immunosuppression Therapy , Infant , Liver Cirrhosis/pathology , Liver Function Tests , Male , Prognosis , Transplantation ToleranceABSTRACT
Hepatic stellate cells (HSCs) play an important role in several (patho)physiologic conditions in the liver. In response to chronic injury, HSCs are activated and change from quiescent to myofibroblast-like cells with contractile properties. This shift in phenotype is accompanied by a change in expression of intermediate filament (IF) proteins. HSCs express a broad, but variable spectrum of IF proteins. In muscle, syncoilin was identified as an alpha-dystrobrevin binding protein with sequence homology to IF proteins. We investigated the expression of syncoilin in mouse and human HSCs. Syncoilin expression in isolated and cultured HSCs was studied by qPCR, Western blotting, and fluorescence immunocytochemistry. Syncoilin expression was also evaluated in other primary liver cell types and in in vivo-activated HSCs as well as total liver samples from fibrotic mice and cirrhotic patients. Syncoilin mRNA was present in human and mouse HSCs and was highly expressed in in vitro- and in vivo-activated HSCs. Syncoilin protein was strongly upregulated during in vitro activation of HSCs and undetectable in hepatocytes and liver sinusoidal endothelial cells. Syncoilin mRNA levels were elevated in both CCl4- and common bile duct ligation-treated mice. Syncoilin immunocytochemistry revealed filamentous staining in activated mouse HSCs that partially colocalized with α-smooth muscle actin, ß-actin, desmin, and α-tubulin. We show that in the liver, syncoilin is predominantly expressed by activated HSCs and displays very low-expression levels in other liver cell types, making it a good marker of activated HSCs. During in vitro activation of mouse HSCs, syncoilin is able to form filamentous structures or at least to closely interact with existing cellular filaments.
Subject(s)
Hepatic Stellate Cells/metabolism , Intermediate Filament Proteins/metabolism , Liver/pathology , Muscle Proteins/metabolism , Actins/pharmacokinetics , Animals , Carbon Tetrachloride/pharmacology , Cell Differentiation , Cell Line , Desmin/pharmacology , Fibrosis/pathology , HEK293 Cells , Hepatic Stellate Cells/cytology , Hepatocytes/pathology , Humans , Intermediate Filament Proteins/genetics , Intermediate Filament Proteins/pharmacokinetics , Liver/cytology , Male , Mice , Mice, Inbred BALB C , Muscle Proteins/genetics , Muscle Proteins/pharmacokinetics , RNA Interference , RNA, Messenger/biosynthesis , RNA, Small Interfering , Tubulin/pharmacokineticsABSTRACT
UNLABELLED: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that encompasses a wide spectrum of liver abnormalities ranging from simple liver steatosis to steatohepatitis (non-alcoholic steatohepatitis), which may be associated with fibrosis and progress to cirrhosis and end-stage liver disease. NAFLD has recently become the most common cause of chronic liver disease in children and adolescents. NAFLD prevalence, alongside obesity, continues to increase among pediatric patients. Obesity is believed to represent a major risk factor for NAFLD, which is considered to be the liver presentation of the metabolic syndrome. Although the pathogenesis of NAFLD is not fully understood, the notion that multiple factors affect disease development and progression is widely accepted. Both genetic background and environmental factors contribute to NAFLD development. A more complete understanding of the pathogenesis may aid in developing non-invasive diagnostic tools and identifying new therapeutic targets. Liver biopsy currently remains the gold standard for NAFLD diagnosis and staging. Although lifestyle and diet modifications are key in NAFLD treatment, the development of new pharmacological therapies is crucial for patients who are unresponsive to first-line therapy. CONCLUSION: Pediatric NAFLD is an increasing public health issue that remains underdiagnosed. A large-scale screening in the high-risk population, especially among the overweight pediatric patients, should be considered, including measurement of serum transaminases and liver ultrasound. It is crucial to treat this condition as soon as possible in order to avoid the progression to end-stage liver disease.
Subject(s)
End Stage Liver Disease/epidemiology , Fatty Liver/epidemiology , Adolescent , Biopsy , Child , Combined Modality Therapy , Diet, Reducing , Disease Progression , Drugs, Investigational/therapeutic use , End Stage Liver Disease/diagnosis , End Stage Liver Disease/therapy , Fatty Liver/diagnosis , Fatty Liver/therapy , Female , Humans , Life Style , Liver/pathology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Liver Cirrhosis/therapy , Male , Non-alcoholic Fatty Liver Disease , Obesity/complications , Obesity/epidemiology , Obesity/therapy , Overweight/complications , Overweight/epidemiology , Overweight/therapy , Risk Factors , UltrasonographyABSTRACT
BACKGROUND: Although the liver is the major site of coagulation factor VIII (FVIII) synthesis, the type of cells producing FVIII within the liver is still unclear. OBJECTIVES: To measure FVIII in extracts of primary liver sinusoidal endothelial cells (LSECs) and hepatocytes, thereby preventing potential bias resulting from the modifications of the cell phenotype that can take place during in vitro culture. METHODS: LSECs were purified by flow cytometry cell sorting on the basis of their coexpression of Tie2 and CD32b. The purity of the cells was controlled by RNA sequencing. FVIII activity (FVIII:C) in extracts of purified cells was measured with a sensitive FVIII chromogenic assay, in which the specificity of the reaction is controlled by neutralization of FVIII activity with specific inhibitor antibodies. RESULTS: The FVIII:C concentration in purified LSECs ranged from 0.3 to 2.8 nU per cell. In contrast, FVIII:C was undetectable in hepatocytes. The intracellular FVIII:C concentrations are therefore at least 10-100-fold higher in LSECs than in hepatocytes. CONCLUSIONS: Our data demonstrate that LSECs, but not hepatocytes, contain measurable amounts of FVIII:C, and suggest that the former are the main cells producing FVIII in the human liver.
Subject(s)
Endothelial Cells/metabolism , Factor VIII/metabolism , Hepatocytes/metabolism , Liver/metabolism , Humans , Liver/cytology , Sequence Analysis, RNAABSTRACT
Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are nonresponders. We performed liver cell transplantation in a 6-year-old boy with severe tetrahydrobiopterin nonresponsive phenylketonuria who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 to 19 h. However, 3 months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell-based therapy is a promising therapeutic option in phenylketonuria, and the domino concept may solve the issue of cell sources for hepatocyte transplantation.
Subject(s)
Hepatocytes/transplantation , Phenylketonurias/therapy , Cell- and Tissue-Based Therapy , Child , Female , Glycogen Storage Disease Type I/therapy , Half-Life , Hepatocytes/cytology , Humans , Infant , Liver Function Tests , Male , Phenylalanine/blood , Phenylalanine Hydroxylase/genetics , Phenylalanine Hydroxylase/metabolism , Phenylketonurias/diagnosisABSTRACT
A 3-year-old girl with multifocal hepatoblastoma was referred to our clinic for living-donor liver transplantation, the patient's father being the donor. Pretransplant evaluation revealed that the father presented partial asymptomatic antithrombin (AT) deficiency, with no inherited AT deficiency found in the girl. The genetic testing showed an AT type IIb deficiency responsible for a defect in the heparin-binding region of AT which is less thrombogenic but more common than the other AT qualitative defects. Her mother was ABO incompatible. Despite the thrombophilia on the father's side, transplantation was successfully performed under replacement therapy with intravenous AT concentrate and low-molecular-weight heparin thromboprophylaxis given to both the recipient and the donor. No thrombotic complications occurred. In the posttransplantation course, acquired partial AT deficiency was detected in the recipient, who received adjuvant chemotherapy without thrombotic complications. This case report highlights the relevance of full thrombophilic work-up before liver transplantation from a living donor, while illustrating that the procedure can be successfully performed in the case of AT deficiency on the donor's side provided that appropriate AT supplementation and thromboprophylaxis are administered to both the recipient and the donor.
Subject(s)
Antithrombin III Deficiency/etiology , Genetic Predisposition to Disease , Hepatoblastoma/surgery , Liver Neoplasms/surgery , Liver Transplantation/adverse effects , Living Donors , Anticoagulants/therapeutic use , Antithrombin III Deficiency/drug therapy , Child, Preschool , Female , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Male , Thrombophilia/prevention & controlABSTRACT
We report long-term (seven yr) immunological tolerance in a 16-yr-old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post-transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression-free solid organ transplantation from the same donor.
Subject(s)
Bone Marrow Transplantation/methods , Liver Transplantation/methods , Adolescent , Adult , Alleles , Biopsy , Child, Preschool , Family Health , Humans , Immune Tolerance , Immunosuppression Therapy/adverse effects , Immunosuppressive Agents/therapeutic use , Liver/pathology , Living Donors , Male , Treatment OutcomeABSTRACT
AIM/HYPOTHESIS: The glucose-lowering drug metformin has been shown to activate hepatic AMP-activated protein kinase (AMPK), a master kinase regulating cellular energy homeostasis. However, the underlying mechanisms remain controversial and have never been investigated in primary human hepatocytes. METHODS: Hepatocytes isolated from rat, mouse and human livers were treated with various concentrations of metformin. Isoform-specific AMPKα abundance and activity, as well as intracellular adenine nucleotide levels and mitochondrial oxygen consumption rates were determined at different time points. RESULTS: Metformin dose- and time-dependently increased AMPK activity in rat and human hepatocytes, an effect associated with a significant rise in cellular AMP:ATP ratio. Surprisingly, we found that AMPKα2 activity was undetectable in human compared with rat hepatocytes, while AMPKα1 activities were comparable. Accordingly, metformin only increased AMPKα1 activity in human hepatocytes, although both AMPKα isoforms were activated in rat hepatocytes. Analysis of mRNA expression and protein levels confirmed that only AMPKα1 is present in human hepatocytes; it also showed that the distribution of ß and γ regulatory subunits differed between species. Finally, we demonstrated that the increase in AMP:ATP ratio in hepatocytes from liver-specific Ampkα1/2 (also known as Prkaa1/2) knockout mice and humans is due to a similar and specific inhibition of the mitochondrial respiratory-chain complex 1 by metformin. CONCLUSIONS/INTERPRETATION: Activation of hepatic AMPK by metformin results from a decrease in cellular energy status owing to metformin's AMPK-independent inhibition of the mitochondrial respiratory-chain complex 1. The unique profile of AMPK subunits found in human hepatocytes should be considered when developing new pharmacological agents to target the kinase.
Subject(s)
AMP-Activated Protein Kinases/drug effects , Hepatocytes/drug effects , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , AMP-Activated Protein Kinases/analysis , Adenine Nucleotides/analysis , Animals , Cells, Cultured , Hepatocytes/enzymology , Humans , Isoenzymes/metabolism , Male , Mice , Mice, Knockout , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Oxygen Consumption/drug effects , RatsABSTRACT
UNLABELLED: Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) levelabove 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). CONCLUSION: The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.
Subject(s)
Hyperlipoproteinemia Type II/therapy , Adult , Cardiology/methods , Child , Consensus Development Conferences as Topic , Decision Making , Female , Gastroenterology/methods , General Practice/methods , Guidelines as Topic , Heterozygote , Humans , Hyperlipoproteinemia Type II/diet therapy , Hyperlipoproteinemia Type II/genetics , Lipids/chemistry , Male , Nutritional Sciences , Pediatrics/methods , Young AdultABSTRACT
BACKGROUND: The efficacy of infliximab (IFX) in inducing and maintaining remission in pediatric Crohn disease is currently well documented. However, the optimal treatment strategy beyond 1 year has not been established. In particular, systematic continuation of maintenance therapy and its association with immunomodulators have not yet been analyzed. OBJECTIVE: The aim of this study was to describe the long-term outcome of pediatric Crohn disease patients on IFX therapy and to evaluate the clinical response to the therapy and the effect on growth. METHODS: A single-center and retrospective chart review was conducted. The clinical maintenance response to treatment, effect on the linear growth, and long-term outcome were examined. These parameters were analyzed according to the age of the patients, duration and localization of the disease, as well as associated therapies. RESULTS: We identified 52 children with Crohn disease younger than 16 years of age at the time of diagnosis. Of these patients, 20 (38%) received a biologic therapy at a mean age of 13.9±2 years. Fifteen patients received IFX therapy and 13 (86%) were in clinical remission 10 weeks after the first infusion. Among the responders, 82% were still in remission after 1 year of therapy and 66% after 2 years. Among patients treated for more than 1 year, we observed IFX dependency in 89%. Thirty-eight percent of patients with initial IFX response showed a loss of response after a median of 30 months (range, 3-42 months). At 2 years, the median Z score for height among patients with presumed growth potential had improved slightly, from -0.7 to -0.55 DS. No serious adverse events were observed. CONCLUSION: Our results confirm the continuous efficacy of IFX in pediatric Crohn disease patients after 1 year of treatment. However, a high level of dependency was observed (89 %). A slight beneficial effect on growth was observed after 2 years of treatment.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Crohn Disease/drug therapy , Adolescent , Child , Female , Humans , Infliximab , Male , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
The parenchymal liver cell is a unique fully functional metabolic unit that can be used for liver regenerative medicine to restore function of the diseased organ; the aim of the procedure is to prevent progression of end-stage disease. The alternative, orthotopic liver transplantation, is highly intrusive, irreversible and limited by general organ shortage. Mature liver cell - hepatocyte - transplantation has been shown to have short- to medium-term efficacy for correction of miscellaneous inborn errors of metabolism. However, although proof of concept has been established, the procedure has not yet achieved full success, due to limited durability of functional benefit. Hepatocyte procurement is also restricted by organ shortage, and their storage is difficult due to poor tolerance of cryopreservation. Alternative cell sources are therefore needed for development and wider accessibility of cell-based liver regenerative medicine. Besides safety, the main challenge for these alternative cells is to acquire similar levels of functionality once implanted into the target organ. In this respect, liver derived progenitor cells may have some advantages over stem cells derived from other tissues.
Subject(s)
Hepatocytes/transplantation , Liver Regeneration , Regenerative Medicine/trends , Stem Cell Transplantation/trends , Animals , Bone Marrow Transplantation/trends , Humans , Mesenchymal Stem Cell Transplantation/trendsABSTRACT
Previous studies have suggested that the susceptibility of newborns to infections is linked to the immaturity of their immune system, but very few data are available on the early stages of maturation of the immune response. Therefore, we decided to investigate the evolution of the interferon (IFN)-α and interleukin (IL)-10 responses in neonatal mononuclear cells. To this end, mononuclear cells isolated from cord blood and peripheral blood of 2-, 6- and 18-month-old children and adults were stimulated with unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) 2216 (IFN-α response) or lipopolysaccharide (LPS) (IL-10 response) for 24 h. The production of IFN-α and IL-10 was then measured in culture supernatants using enzyme-linked immunosorbent assay (ELISA) or a 6-plex cytokine array, respectively. Compared to adults, we found a significant impairment in both the IFN-α and IL-10 responses of neonatal mononuclear cells. Interestingly, both responses had increased significantly after 2 months, but remained lower than the adult responses throughout the first 18 months of life. This study shows that although the immune response of neonates tends to mature fairly quickly, it remains different when compared to the adult immune response throughout the first 18 months of life. This could have important consequences on children's ability to mount an appropriate immune response to various challenges and to establish tolerance and immune homeostasis.