RESUMO
Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.
Assuntos
Lipodistrofia Generalizada Congênita , Proteínas de Ligação a RNA , Humanos , Masculino , Feminino , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/patologia , Adolescente , Criança , Lactente , Pré-Escolar , Adulto , Adulto Jovem , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologiaRESUMO
OBJECTIVES: To investigate laboratory and bone marrow findings that can help predict a diagnosis of hemophagocytic lymphohistiocytosis (HLH) for patients who have demonstrated hemophagocytes (HPCs) in the bone marrow. METHODS: A total of 57 cases from 48 patients with HPCs present on bone marrow examination were included. The numbers and morphologic characteristics of HPCs with ingested nucleated cells (nHPC) were counted. Pertinent medical history, relevant laboratory values, and flow cytometry data at the time of bone marrow biopsy were collected. RESULTS: A total of 24 patients fulfilled diagnostic criteria for HLH, and the remaining 24 patients did not. By using HLH-2004 cutoffs, only hypertriglyceridemia (≥265 mg/dL) was significantly associated with HLH diagnosis. The HLH cases more frequently had nHPC-ingesting granulocytic cells (gHPC) (75.9% vs 24.1%, P = .009). The percentage of gHPC to all nHPC was also significantly higher in HLH cases (median, 15.4% vs 0%; P = .0002). Both triglyceride level (area under the curve [AUC] = 0.88, P < .0001) and gHPC percentage (AUC = 0.81, P = .0005) were significant in predicting HLH diagnosis. Finally, no overt immunophenotypic abnormality was noted for 19 HLH cases with available flow cytometry data. CONCLUSIONS: The presence of hypertriglyceridemia and more frequent gHPC has predictive value for HLH diagnosis in patients with bone marrow HPC.
Assuntos
Hipertrigliceridemia , Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/patologia , Medula Óssea/patologia , Exame de Medula Óssea , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/patologia , BiópsiaRESUMO
Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM_052968: c.579_592delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM_000237.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease.
Assuntos
Hipertrigliceridemia , Pancreatite , Apolipoproteína A-V/genética , Pré-Escolar , Heterozigoto , Homozigoto , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/patologia , Masculino , Pancreatite/genética , Deleção de SequênciaAssuntos
Benzoxazóis/uso terapêutico , Butiratos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertrigliceridemia/complicações , Transtornos do Metabolismo dos Lipídeos/patologia , Doenças Retinianas/etiologia , Adulto , Glicemia/efeitos dos fármacos , Dieta com Restrição de Gorduras , Humanos , Hiperlipidemias , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/patologia , Hipolipemiantes/uso terapêutico , Insulina/uso terapêutico , Transtornos do Metabolismo dos Lipídeos/terapia , Masculino , XantomatoseRESUMO
Hexosaminidase A (HexA), a heterodimer consisting of HEXA and HEXB, converts the ganglioside sphingolipid GM2 to GM3 by removing a terminal N-acetyl-d-galactosamine. HexA enzyme deficiency in humans leads to GM2 accumulation in cells, particularly in neurons, and is associated with neurodegeneration. While HexA and sphingolipid metabolism have been extensively investigated in the context of neuronal lipid metabolism, little is known about the metabolic impact of HexA and ganglioside degradation in other tissues. Here, we focussed on the role of HexA in the liver, which is a major regulator of systemic lipid metabolism. We find that hepatic Hexa expression is induced by lipid availability and increased in the presence of hepatic steatosis, which is associated with increased hepatic GM3 content. To assess the impact of HEXA on hepatic lipid metabolism, we used an adeno-associated virus to overexpress HEXA in the livers of high-fat diet fed mice. HEXA overexpression was associated with increased hepatic GM3 content and increased expression of enzymes involved in the degradation of glycated sphingolipids, ultimately driving sphingomyelin accumulation in the liver. In addition, HEXA overexpression led to substantial proteome remodeling in cell surface lipid rafts, which was associated with increased VLDL processing and secretion, hypertriglyceridemia and ectopic lipid accumulation in peripheral tissues. This study established an important role of HEXA in modulating hepatic sphingolipid and lipoprotein metabolism.
Assuntos
Fígado Gorduroso/patologia , Hexosaminidase A/metabolismo , Hipertrigliceridemia/patologia , Lipídeos/análise , Lipoproteínas VLDL/metabolismo , Microdomínios da Membrana/patologia , Esfingolipídeos/metabolismo , Animais , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hexosaminidase A/genética , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.
Assuntos
Glicemia/metabolismo , Células da Medula Óssea/enzimologia , Senescência Celular , Metilação de DNA , Diabetes Mellitus Tipo 2/sangue , Células Progenitoras Endoteliais/enzimologia , Epigênese Genética , Hiperglicemia/sangue , Hipertrigliceridemia/sangue , Histona Desmetilases com o Domínio Jumonji/metabolismo , Triglicerídeos/sangue , Adulto , Idoso , Animais , Células da Medula Óssea/patologia , Estudos de Casos e Controles , Linhagem da Célula , Células Cultivadas , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Células Progenitoras Endoteliais/patologia , Feminino , Hemoglobinas Glicadas , Humanos , Hiperglicemia/enzimologia , Hiperglicemia/genética , Hiperglicemia/patologia , Hipertrigliceridemia/enzimologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/patologia , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: Tamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it. CASE PRESENTATION: 47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically. CONCLUSIONS: From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipertrigliceridemia/patologia , Lipoproteínas/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Tamoxifeno/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/complicações , Dislipidemias/patologia , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Prognóstico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologiaRESUMO
Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1-9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.
Assuntos
Aterosclerose/genética , Doença das Coronárias/genética , Diabetes Mellitus/genética , Fígado Gorduroso/genética , Hipertrigliceridemia/genética , Lipodistrofia/genética , Aciltransferases/deficiência , Aciltransferases/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Distribuição da Gordura Corporal , Doença das Coronárias/etiologia , Doença das Coronárias/metabolismo , Doença das Coronárias/patologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Resistência à Insulina , Lamina Tipo A/deficiência , Lamina Tipo A/genética , Metabolismo dos Lipídeos/genética , Lipodistrofia/complicações , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Pancreatite/etiologia , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Xantomatose/etiologia , Xantomatose/genética , Xantomatose/metabolismo , Xantomatose/patologiaRESUMO
OBJECTIVES: Although smoking is known to have a negative impact in patients with metabolic syndrome (MetS), only a few studies have examined the association between electronic cigarette (e-cig) use and MetS. METHODS: Among 22,948 participants in the 6th Korea National Health and Nutrition Examination Survey, 14,738 (13,459 [91.3%] never, 954 [6.5%] ever, and 325 [2.2%] current e-cig users) were selected. The relationship between e-cig exposure and MetS (based on the National Cholesterol Education Program Adult Treatment Panel [NCEP-ATP] III criteria) was evaluated using a multivariable logistic regression analysis. An unweighted analysis was performed to evaluate this association without a sampling weight. A subgroup analysis was performed among active smokers to compare dual users with never e-cig users. RESULTS: Among current e-cig users, 85.0% were dual users, 12.7% were former cigarette users, and 2.2% were only e-cig users. After adjustment for covariates, abdominal obesity and hypertriglyceridemia were significantly associated with current e-cig exposure (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 1.41-2.50 and OR: 1.32, 95% CI: 1.00-1.74 respectively [compared with the never e-cig users group]). Compared with never e-cig users, current e-cig users showed an OR of 1.27 (95% CI: 0.96-1.70, Ptrend = 0.01) for MetS. In the unweighted analysis, the OR for MetS in current e-cig users was 1.40 (95% CI: 1.08-1.81, Ptrend <0.01). Compared with never e-cig users, dual users showed a higher OR for abdominal obesity (OR: 1.71, 95% CI: 1.25-2.34, Ptrend <0.001). CONCLUSIONS: Current e-cig exposure was associated with an increased risk of MetS. Dual use of e-cigs and cigarettes was associated with abdominal obesity. Further longitudinal studies and better assessment of e-cig use and type are needed to clarify this relationship.
Assuntos
Síndrome Metabólica/patologia , Vaping , Adulto , HDL-Colesterol/sangue , Fumar Cigarros , Feminino , Humanos , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/patologia , Modelos Logísticos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/epidemiologia , Obesidade/patologia , Razão de Chances , República da Coreia/epidemiologia , Triglicerídeos/sangueRESUMO
PURPOSE OF REVIEW: Apolipoprotein C-II (apoC-II) is a critical cofactor for the activation of lipoprotein lipase (LPL), a plasma enzyme that hydrolyzes triglycerides (TG) on TG-rich lipoproteins (TRL). Although apoC-II was first discovered nearly 50 years ago, there is renewed interest in it because of the recent efforts to develop new drugs for the treatment of hypertriglyceridemia (HTG). The main topic of this review will be the development of apoC-II mimetic peptides as a possible new therapy for cardiovascular disease. RECENT FINDINGS: We first describe the biochemistry of apoC-II and its role in TRL metabolism. We then review the clinical findings of HTG, particularly those related to apoC-II deficiency, and how TG metabolism relates to the development of atherosclerosis. We next summarize the current efforts to develop new drugs for HTG. Finally, we describe recent efforts to make small synthetic apoC-II mimetic peptides for activation of LPL and how these peptides unexpectedly have other mechanisms of action mostly related to the antagonism of the TG-raising effects of apoC-III. SUMMARY: The role of apoC-II in TG metabolism is reviewed, as well as recent efforts to develop apoC-II mimetic peptides into a novel therapy for HTG.
Assuntos
Apolipoproteína C-II/genética , Aterosclerose/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Lipase Lipoproteica/genética , Apolipoproteína C-III/genética , Aterosclerose/genética , Aterosclerose/patologia , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/patologia , Lipoproteínas , Lipoproteínas HDL/genética , Peptídeos/uso terapêutico , Triglicerídeos/genética , Triglicerídeos/metabolismoRESUMO
Numerous benefits are attributed to omega-3 fatty acids (OM3) especially in cardiovascular health. However, bioavailability and clinical efficacy depend on numerous factors, including OM3 form, food matrix effects (especially the lipid content of the diet), and metabolic capacity. Here, we show in humans that a "pre-digested" OM3-sn-1(3)-monoacylglycerol lipid structure (OM3-MAG) has a significantly greater absorption at high therapeutic doses (2.9 g/day) than the most commonly OM3-ethyl ester (3.1 g/day) form (used for the treatment of hypertriglyceridemia), and a comparable profile to other pre-digested OM3 free fatty acids (OM3-FFA) structure (3.2 g/day). Nutritional supplement doses of MAG resulted in similar increases in OM3 blood level, compared to OM3 triacylglycerols (OM3-TAG) supplements in obese subjects (1.2 g/day) under low fat diet, and in children with cystic fibrosis (1.0 g/day). These results suggest that both forms of pre-digested OM3-MAG and OM3-FFA are effectively absorbed and re-incorporated effectively into triacylglycerols inside the enterocytes, before being exported into the chylomicrons lipid transport system. The pre-digested OM3-MAG might provide a more effective therapy in severe cardiovascular conditions where high doses of OM3 are required and a low-fat diet is indicated, which limited digestive lipase activity.
Assuntos
Fibrose Cística/tratamento farmacológico , Suplementos Nutricionais , Ácidos Graxos Ômega-3 , Hipertrigliceridemia/tratamento farmacológico , Monoglicerídeos , Obesidade/tratamento farmacológico , Adulto , Disponibilidade Biológica , Quilomícrons/metabolismo , Fibrose Cística/sangue , Fibrose Cística/patologia , Enterócitos/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacocinética , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/patologia , Masculino , Pessoa de Meia-Idade , Monoglicerídeos/administração & dosagem , Monoglicerídeos/farmacocinética , Obesidade/sangue , Obesidade/patologia , Triglicerídeos/sangueRESUMO
A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.
Assuntos
Hipertrigliceridemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Índice de Massa Corporal , Colesterol/sangue , Feminino , Homeostase/genética , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Insulina/metabolismo , Resistência à Insulina/genética , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de RiscoRESUMO
Soluble low-density lipoprotein receptor (sLDLR) is the circulating ectodomain of transmembrane LDLR. Its blood level strongly correlates with that of triglycerides (TG). This correlation has eluded satisfactory explanation. Hypertriglyceridemia and shedding of the ectodomain of many transmembrane receptors often accompany inflammatory states. The shedding mostly occurs through cleavage by a disintegrin-and-metalloproteinase-17 (ADAM-17), an enzyme activated by inflammation. It reduces the cellular uptake of TG-loaded lipoproteins, causing their accumulation in circulation; hence the correlation between plasma sLDLR and TG. Soluble LDLR could become a new surrogate marker of inflammation.
Assuntos
Inflamação/sangue , Receptores de LDL/sangue , Proteína ADAM17/metabolismo , Animais , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Inflamação/metabolismo , Inflamação/patologia , Receptores de LDL/metabolismo , Triglicerídeos/sangueRESUMO
BACKGROUND: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI). PROCEDURE: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. RESULTS: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). CONCLUSION: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.
Assuntos
Asparaginase/efeitos adversos , Asparaginase/química , Composição de Medicamentos , Hipertrigliceridemia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipertrigliceridemia/induzido quimicamente , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , PrognósticoAssuntos
Adenocarcinoma/sangue , Hipertrigliceridemia/induzido quimicamente , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/sangue , Tegafur/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Combinação de Medicamentos , Feminino , Humanos , Hipertrigliceridemia/patologia , Pessoa de Meia-Idade , Ácido Oxônico/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Tegafur/farmacologia , Neoplasias PancreáticasAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Remoção de Componentes Sanguíneos/métodos , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hipertrigliceridemia/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática , Neoplasias do Mediastino/secundário , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Gender-related factors might play an important role in the development of reflux esophagitis (RE) and symptomatic gastro-esophageal reflux disease (GERD). We aimed to evaluate the prevalence and risk factors for RE and symptomatic GERD and determine whether gender specific differences exist. METHODS: This study was conducted on a health cohort consisting of 10,158 participants who underwent comprehensive health screening. Lifestyles and gastrointestinal symptoms were investigated using a self-reported structured questionnaire. Questionnaires about menstrual status were added for the women. RESULTS: The prevalence of RE in men was significantly higher than that in women (10.6% vs. 2.0%, P < 0.001); however, symptomatic GERD showed predominance in women (6.2% vs. 2.5%, P < 0.001). Although the prevalence of RE gradually increased with the duration of menopause stratified by decade (P = 0.007), that of symptomatic GERD rapidly increased across the menopausal transit in women. Apart from common risk factors of obesity and current smoking for RE, over 70 years of age in women and hiatal hernia and hypertriglyceridemia in men were significant risk factors. In symptomatic GERD, high somatization was a common risk factor. Excessive alcohol drinking was a significant risk factor in men, but not in women. CONCLUSION: This study showed a predominance of RE in men, but a predominance of symptomatic GERD in women. In women, dynamic increase in the prevalence of GERD is closely related to the menopause conditions and its duration. There are specific risk factors for RE and symptomatic GERD according to gender differences.
Assuntos
Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/epidemiologia , Nível de Saúde , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos Transversais , Feminino , Hérnia Hiatal/patologia , Humanos , Hipertrigliceridemia/patologia , Estilo de Vida , Masculino , Menopausa/fisiologia , Pessoa de Meia-Idade , Obesidade/patologia , Qualidade de Vida , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Fumar/efeitos adversos , Inquéritos e QuestionáriosRESUMO
Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.
Assuntos
Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertrigliceridemia/etiologia , Leucemia Mieloide Aguda/terapia , Lipodistrofia/etiologia , Doenças Metabólicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Fígado Gorduroso/patologia , Feminino , Intolerância à Glucose/patologia , Humanos , Hipertrigliceridemia/patologia , Lactente , Leucemia Mieloide Aguda/patologia , Lipodistrofia/patologia , Doenças Metabólicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , PrognósticoRESUMO
BACKGROUND: Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial. METHODS: Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and managed by investigators. Key strategies for preventing and managing the most common adverse events included patient education, supportive care, and dose modification. RESULTS: Between February 2015 and August 2016, 294 patients received anlotinib. A total of 170 (57.8%) patients received antihypertensive medications for hypertension, 53 (18.0%) patients received levothyroxine for hypothyroidism, 24 (8.2%) patients received fibrates for hypertriglyceridemia, 11 (3.7%) patients took cortisone cream for hand-foot syndrome, and 38 (12.9%) patients received anti-diarrheal medications for diarrhea. Dose reduction and drug discontinuation were required in 24 (8.16%) and 31 (10.54%) patients in the anlotinib group, respectively. CONCLUSION: Anlotinb-related adverse events could be controlled by patient education, prophylactic measures, early and active intervention, and dose modification.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Indóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Síndrome Mão-Pé/tratamento farmacológico , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/patologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/patologia , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/patologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Tiroxina/administração & dosagemRESUMO
BACKGROUND: Overexpression of apolipoprotein CIII (ApoCIII) leads to hypertriglyceridemia (HTG) which promotes atherosclerosis development. However, it remains unclear whether ApoCIII affects the atherosclerosis alone by promoting the inflammation and endoplasmic reticulum (ER) stress, or in combination with HTG. METHODS: Transgenic (ApoCIIItg) mouse models were used to investigate the atherogenic role of ApoCIII. Since endothelial cells and macrophages play crucial roles in atherosclerosis, we examined whether triglyceride-rich lipoproteins (TRLs), the major lipoproteins, in plasma of ApoCIIItg mice affect inflammation and ER stress levels in these cells. To further investigate the role of ApoCIII and triglyceride, we incubated HUVECs cells and peritoneal macrophages with TRLs with or without ApoCIII. RESULTS: Increased inflammation and ER stress were found in the aorta of ApoCIIItg mice. TRLs increased ER stress and oxidative stress in HUVECs and macrophages in a dose dependent. Moreover, TRLs together with ApoCIII could induce a higher inflammation level than TRLs alone in these cells. CONCLUSIONS: Both TRLs and ApoCIII contribute to the progression of atherosclerosis, and the modulation of TRLs and ApoCIII may represent a novel therapeutic approach against HTG induced atherosclerosis.