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1.
J Pediatr Gastroenterol Nutr ; 78(1): 27-35, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38291699

RESUMO

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Criança , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Contagem de Plaquetas , Aspartato Aminotransferases , Alanina Transaminase , Índice de Gravidade de Doença , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Curva ROC , Biópsia , Fígado/patologia
2.
Cureus ; 15(10): e46515, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37927648

RESUMO

Physicians regularly use corticosteroids to treat various conditions, attributing their anti-inflammatory and immunosuppressive properties. Cases of allergic sensitivity reactions and dermatitis induced by corticosteroids are relatively uncommon. We present a case regarding an 81-year-old male with a history of actinic keratosis, atopic dermatitis, and psoriasis, who experienced a Type I hypersensitivity reaction with facial angioedema and urticaria on his axilla, torso, and popliteal fossa that developed after treatment with oral prednisolone. This episode also exacerbated his previously diagnosed psoriasis. To treat psoriasis, a dermatologist prescribed clobetasol topical ointment, which did not alleviate the symptoms; instead, it only exacerbated the rash, and he was subsequently referred for corticosteroid allergy testing. North American 85 Comprehensive Series patch testing revealed a positive test for various classes of steroids, including clobetasol-17-propionate, budesonide, and dexamethasone, thus proving a T cell-mediated allergy to corticosteroids.

4.
Elife ; 122023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36722855

RESUMO

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.


Assuntos
Resistência à Insulina , Lipodistrofia , Humanos , Animais , Camundongos , Leptina/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Obesidade/metabolismo , Hidrolases/metabolismo , Lipodistrofia/genética , Lipodistrofia/metabolismo , Mitocôndrias/metabolismo
5.
Trends Mol Med ; 29(3): 228-240, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36496278

RESUMO

Acute liver failure (ALF) is a rare but potentially fatal disease in children. The etiology is multifactorial, including infection, autoimmune, and genetic disorders, as well as indeterminate hepatitis, which has a higher requirement for liver transplantation. Activation of the innate and adaptive immune systems leads to hepatocyte-specific injury which is mitigated by T regulatory cell activation. Recovery of the native liver depends on activation of apoptotic and regenerative pathways, including the integrated stress response (ISR; e.g., PERK), p53, and HNF4α. Loss-of-function mutations in these pathways cause recurrent ALF in response to non-hepatotropic viruses. Deeper understanding of these mechanisms will lead to improved diagnosis, management, and outcomes for pediatric ALF.


Assuntos
Falência Hepática Aguda , Humanos , Criança , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/terapia , Hepatócitos , Mutação
7.
Cureus ; 14(8): e27920, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36110455

RESUMO

Adult growth hormone (GH) deficiency is rare and requires replacement with extrinsic/synthetic injection. GH hypersensitivity has been reported; specifically, atopic patients may develop rashes from somatotropin therapy. Allergic and non-allergic skin reactions to recombinant human GH are uncommon and infrequently reported. We describe a graded-dose challenge with intravenous Norditropin® in a 65-year-old atopic adult woman who developed a severe whole-body rash with Norditropin FlexPro® administration on several occasions but was negative on skin-prick testing to Norditropin® percutaneously and intradermally, but the patch testing was positive for gold and nickel. The patient was registered as a direct admission to the emergency room at a university hospital for a rapid antigen coronavirus disease 2019 (COVID-19) testing after having received two COVID-19 vaccinations and re-testing four months after vaccination. She was then directly admitted to a non-COVID-19 intensive care unit with direct bedside supervision by a registered nurse and a physician board certified in internal medicine, allergy/immunology, and pulmonary diseases. The patient brought a Norditropin® pen which our pharmacy team attached to a compatible syringe for dilutions. A graded dose challenge at a final dosage of 0.1 mL was performed and the patient was monitored for allergic and other adverse drug reactions, which did not occur. At the time of writing this case report, the patient has been maintained on Norditropin FlexPro® 0.1 mL and has not experienced any adverse reactions, including recurrent skin eruptions. The case presented is the first to describe a patient who successfully tolerated a graded dose challenge of an adult patient to GH replacement therapy (as Norditropin®) under supervision in an intensive care unit, whereas prior to reporting of this case, a graded dose challenge to GH replacement therapy had only been successfully performed in a child using another formulation of somatotropin (Humatrope®). Hence, this case lends support that graded dose challenge with somatotropin analogs may be considered for patients with isolated GH deficiency such as in the case presented here.

8.
Hepatol Commun ; 6(11): 3279, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35593156
9.
Liver Int ; 42(8): 1823-1835, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35474605

RESUMO

BACKGROUND: Understanding the genetics of liver disease has the potential to facilitate clinical risk stratification. We recently identified acquired somatic mutations in six genes and one lncRNA in pre-existing fatty liver disease. We hypothesised that germline variation in these genes might be associated with the risk of developing steatosis and contribute to the prediction of disease severity. METHODS: Genome-wide association study (GWAS) summary statistics were extracted from seven studies (>1.7 million participants) for variants near ACVR2A, ALB, CIDEB, FOXO1, GPAM, NEAT1 and TNRC6B for: aminotransferases, liver fat, HbA1c, diagnosis of NAFLD, ARLD and cirrhosis. Findings were replicated using GWAS data from multiple independent cohorts. A phenome-wide association study was performed to examine for related metabolic traits, using both common and rare variants, including gene-burden testing. RESULTS: There was no evidence of association between rare germline variants or SNPs near five genes (ACVR2A, ALB, CIDEB, FOXO1 and TNRC6B) and risk or severity of liver disease. Variants in GPAM (proxies for p.Ile43Val) were associated with liver fat (p = 3.6 × 10-13 ), ALT (p = 2.8 × 10-39 ) and serum lipid concentrations. Variants in NEAT1 demonstrated borderline significant associations with ALT (p = 1.9 × 10-11 ) and HbA1c, but not with liver fat, as well as influencing waist-to-hip ratio, adjusted for BMI. CONCLUSIONS: Despite the acquisition of somatic mutations at these loci during progressive fatty liver disease, we did not find associations between germline variation and markers of liver disease, except in GPAM. In the future, larger sample sizes may identify associations. Currently, germline polygenic risk scores will not capture data from genes affected by somatic mutations.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hemoglobinas Glicadas/metabolismo , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
10.
Hepatol Commun ; 6(8): 1934-1948, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35411667

RESUMO

Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.


Assuntos
17-Hidroxiesteroide Desidrogenases , Proteínas Mitocondriais , Hepatopatia Gordurosa não Alcoólica , Oxirredutases , 17-Hidroxiesteroide Desidrogenases/genética , Criança , Estudo de Associação Genômica Ampla , Humanos , Hidroxiesteroides , Proteínas Mitocondriais/genética , Hepatopatia Gordurosa não Alcoólica/genética , Oxirredutases/genética , Oximas
11.
J Pediatr Gastroenterol Nutr ; 74(6): 734-741, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35185113

RESUMO

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. METHODS: We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping. RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants. CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.


Assuntos
Doenças Cardiovasculares , Hepatopatia Gordurosa não Alcoólica , Adulto , Doenças Cardiovasculares/etiologia , Criança , Estudos Transversais , Humanos , Lipidômica , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos
12.
Lancet Gastroenterol Hepatol ; 6(10): 864-873, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364544

RESUMO

The term non-alcoholic fatty liver disease (NAFLD), and its definition, have limitations for both adults and children. The definition is most problematic for children, for whom alcohol consumption is usually not a concern. This problematic definition has prompted a consensus to rename and redefine adult NAFLD associated with metabolic dysregulation to metabolic (dysfunction)-associated fatty liver disease (MAFLD). Similarities, distinctions, and differences exist in the causes, natural history, and prognosis of fatty liver diseases in children compared with adults. In this Viewpoint we, an international panel, propose an overarching framework for paediatric fatty liver diseases and an age-appropriate MAFLD definition based on sex and age percentiles. The framework recognises the possibility of other coexisting systemic fatty liver diseases in children. The new MAFLD diagnostic criteria provide paediatricians with a conceptual scaffold for disease diagnosis, risk stratification, and improved clinical and multidisciplinary care, and they align with a definition that is valid across the lifespan.


Assuntos
Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Adolescente , Adulto , Criança , Consenso , Progressão da Doença , Feminino , Humanos , Resistência à Insulina/fisiologia , Comunicação Interdisciplinar , Masculino , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/epidemiologia , Prevalência , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Índice de Gravidade de Doença
13.
J Pediatr ; 238: 50-56.e3, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34303727

RESUMO

OBJECTIVE: To describe the characteristics and clinical course of children and young persons with inflammatory bowel disease (IBD) and sclerosing cholangitis (SC). STUDY DESIGN: Retrospective analysis of clinical characteristics, management, and outcome of two separate cohorts of children and young persons with IBD-SC managed in a tertiary pediatric gastroenterology center and in a tertiary pediatric hepatology center in the UK. RESULTS: Eighty-two pediatric patients (31% female) with IBD-SC and a mean age at diagnosis of 11.9 ± 2.8 years were followed up for a mean of 6.8 ± 3.3 years. The most common type of IBD was ulcerative colitis (55%), followed by unclassified IBD (30%) and Crohn's disease (15%). Autoimmune SC (ASC) was diagnosed in 72%, and small duct SC was diagnosed in 28%. Complication-free and native liver survival were 96% and 100%, respectively, at 5 years after diagnosis and 75% and 88%, respectively, at 10 years after diagnosis. Patients in the gastroenterology center, who were diagnosed with liver disease sooner after diagnosis of IBD compared with the hepatology center cohort (mean, 2.7 ± 6.1 months vs 9.3 ± 19.4 months; P = .03), did not develop liver-related complications during follow-up. CONCLUSIONS: Our data suggest that children with IBD-SC have better clinical outcomes than have been reported previously, particularly if diagnosed early. We recommend prompt assessment for SC, including liver biopsy and biliary imaging, when liver function abnormalities are detected in a children diagnosed with IBD.


Assuntos
Colangite Esclerosante/diagnóstico , Doenças Inflamatórias Intestinais/complicações , Adolescente , Criança , Colangite Esclerosante/etiologia , Colangite Esclerosante/terapia , Diagnóstico Precoce , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Estudos Retrospectivos
14.
Hepatology ; 74(4): 1884-1901, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33973269

RESUMO

BACKGROUND AND AIMS: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. APPROACH AND RESULTS: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. CONCLUSIONS: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.


Assuntos
Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose , Síndrome Metabólica/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Animais , Animais Geneticamente Modificados , Colesterol na Dieta , Dieta , Sacarose Alimentar , Açúcares da Dieta , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Humanos , Fígado/patologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Reprodutibilidade dos Testes
15.
Elife ; 92020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33063664

RESUMO

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.


Obesity and diabetes are increasingly common diseases that can lead to other complications such as fatty liver disease. Fatty liver disease affects one in five people and is caused by a built-up of fat in the liver, which can result in scarring of the liver tissue and other serious complications. There is currently no cure for fatty liver disease. Drugs that have been effective in treating the condition in mice, lack efficacy in humans. To better understand why this is the case, Hunter, de Gracia Hahn, Duret, Im et al. conducted a review of over 5,000 published studies, analysing over 600 experiments. Hunter et al. asked which drugs improved fatty liver in mice the most and if they had the same effect in humans. They also tested whether the age of the mice affected the outcome of the experiments. The analyses revealed that the drugs that work best in mice are different to the ones that show some effect in humans. In mice, many of the drugs reduced their weight or lowered their blood sugar levels, which also improved the fatty liver condition. Moreover, drugs appeared to be less effective the older the mice were. However, most of these drugs do not cause weight loss or lower blood sugar levels in humans, suggesting that factors other than the intended action of these drug could affect the outcome of a mouse study. These findings will help shape future research into obesity, diabetes and fatty liver disease using mice. They highlight that results obtained from studies with mice so far do not predict if a drug will work in humans to treat fatty liver disease. Moreover, weight loss seems to be the most important factor linked to how efficiently a drug treats fatty liver disease.


Assuntos
Modelos Animais de Doenças , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Animais , Fígado/efeitos dos fármacos , Camundongos , Ratos , Resultado do Tratamento , Triglicerídeos/metabolismo
16.
PLoS One ; 15(10): e0241357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33108366

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a 'real world' cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1-1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0-4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0-1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8-4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD.


Assuntos
Doenças Cardiovasculares/complicações , Hospitalização , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/mortalidade , Estudos de Casos e Controles , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
17.
Hum Mol Genet ; 29(20): 3451-3463, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-32720691

RESUMO

Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.


Assuntos
Predisposição Genética para Doença , Cirrose Hepática/patologia , Metaboloma , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Prognóstico , Estudos Prospectivos
18.
J Clin Invest ; 129(10): 4009-4021, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31380809

RESUMO

Lipodystrophies are the result of a range of inherited and acquired causes, but all are characterized by perturbations in white adipose tissue function and, in many instances, its mass or distribution. Though patients are often nonobese, they typically manifest a severe form of the metabolic syndrome, highlighting the importance of white fat in the "safe" storage of surplus energy. Understanding the molecular pathophysiology of congenital lipodystrophies has yielded useful insights into the biology of adipocytes and informed therapeutic strategies. More recently, genome-wide association studies focused on insulin resistance have linked common variants to genes implicated in adipose biology and suggested that subtle forms of lipodystrophy contribute to cardiometabolic disease risk at a population level. These observations underpin the use of aligned treatment strategies in insulin-resistant obese and lipodystrophic patients, the major goal being to alleviate the energetic burden on adipose tissue.


Assuntos
Adipócitos , Tecido Adiposo Branco , Lipodistrofia , Síndrome Metabólica , Obesidade , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Humanos , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia
19.
Am J Clin Nutr ; 110(2): 430-436, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31172170

RESUMO

BACKGROUND: Intestinal failure (IF) is associated with significant morbidity and mortality, yet specific parameters that determine medium- and long-term outcomes remain ill defined. OBJECTIVE: The aim of this study was to determine the long-term outcomes in childhood IF and identify patient characteristics associated with clinical endpoints. DESIGN: MEDLINE and EMBASE were searched for cohorts of >10 pediatric-onset IF patients with >12 mo follow-up. Random-effects meta-analysis and meta-regression weighted by follow-up duration were used to calculate clinical outcome rates and patient factors associated with outcomes. Primary outcome was mortality rate; secondary outcomes included neurodevelopmental status, transplantation, IF-associated liver disease (IFALD), enteral autonomy, and sepsis. RESULTS: In total, 175 cohorts (9318 patients and 34,549 y follow-up) were included in the meta-analysis. Overall mortality was 5.2% per y (95% CI: 4.3, 6.0) and was associated with sepsis and IFALD on meta-regression. Mortality rate improved with time from 5.9% per y pre-2000 to 4.5% per y post-2005. Sepsis rate was also predictive of IFALD and liver failure. Enteral autonomy was associated with small bowel length but not presence of ileo-cecal valve. There was a relative lack of data on neurodevelopmental outcomes. CONCLUSIONS: Sepsis is the primary modifiable factor associated with mortality and liver failure, whereas enteral autonomy correlates with small-bowel length. No clear parameters have been identified that accurately predict neurodevelopmental outcomes, and hence further research is needed. Together, our findings are helpful for parental counseling and resource planning, and support targeting reduction in sepsis.


Assuntos
Enteropatias/patologia , Enteropatias/terapia , Criança , Humanos , Enteropatias/complicações , Hepatopatias/etiologia , Modelos Logísticos , Transtornos do Neurodesenvolvimento/etiologia
20.
Am J Gastroenterol ; 114(4): 556-559, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951517

RESUMO

Nonalcoholic fatty liver disease and hypertension are closely related but there has been little genetic evidence to link them. In this issue, Musso et al. provide evidence that a common variant in AGTR1 (A1166C) is associated with both incident hypertension and nonalcoholic fatty liver disease, as well as nonalcoholic steatohepatitis, fibrosis, dyslipidemia, and insulin resistance. AGTR1 is strongly expressed in adipose, liver, and arteries. The mechanism of this gain-of-function variant is unclear but may include adipose or endothelial dysfunction and immune activation. Despite previous unsuccessful clinical trials of angiotensin receptor blockers in nonalcoholic steatohepatitis, individuals with the rs5186A>C variant may have greater benefit from this therapy.


Assuntos
Hipertensão , Resistência à Insulina , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Gorduras na Dieta , Humanos , Receptor Tipo 1 de Angiotensina
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