RESUMO
Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.
Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ezetimiba , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Colômbia , Fitosteróis/efeitos adversos , Fitosteróis/genética , Enteropatias/genética , Enteropatias/diagnóstico , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/genética , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/diagnóstico , Ezetimiba/uso terapêutico , Xantomatose/genética , Xantomatose/patologia , Xantomatose/diagnóstico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Mutação , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Homozigoto , Criança , Heterozigoto , Lipoproteínas/genéticaRESUMO
Alopecia areata (AA) is an autoimmune disease that grows in the scalp or in other parts of the body. Alopecia universalis, which is a rare form of alopecia areata, is characterized by a loss of hair that affects the entire body. In the two patients presented in this study, atorvastatin treatment was implemented, with the diagnosis of hypercholesterolemia; however, when the target values were not reached, a combination of simvastatin and ezetimibe was implemented. After a period of simvastatin/ezetimibe treatment, the AA disorder, which began with hair loss on the scalp, spread to the entire body and turned into Alopecia Universalis. Although statins can cause alopecia with autoimmune reactions, they are generally used in the treatment of alopecia due to their immunomodulatory effects.
A alopecia areata (AA) é uma doença autoimune que se desenvolve no couro cabeludo ou em outras partes do corpo. A alopecia universal, que é uma forma rara de alopecia areata, é caracterizada pela perda de pelos que afeta todo o corpo. Nos dois pacientes apresentados, o tratamento com atorvastatina foi iniciado com o diagnóstico de hipercolesterolemia, mas, quando as metas de valores não foram alcançadas, foi iniciado o tratamento com uma combinação de sinvastatina e ezetimiba. Depois de um período de tratamento com sinvastatina e ezetimiba, o distúrbio de AA, o qual começou com a perda de cabelo no couro cabeludo, espalhou pelo corpo todo e se transformou em alopecia universal. Embora as estatinas possam causar alopecia com reações autoimunes, elas geralmente são utilizadas no tratamento da alopecia, por seus efeitos imunomoduladores.
Assuntos
Alopecia em Áreas , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Sinvastatina/efeitos adversos , Ezetimiba/uso terapêutico , Atorvastatina/efeitos adversosRESUMO
BACKGROUND: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks. METHODS: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed. FINDINGS: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0). INTERPRETATION: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients. FUNDING: Amgen. TRANSLATIONS: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.
Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Criança , LDL-Colesterol , Método Duplo-Cego , Ezetimiba/uso terapêutico , Cefaleia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9 , Subtilisinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Despite lipid-lowering and antiplatelet therapy, the pattern of residual lipoproteins seems relevant to long-term cardiovascular outcomes. This study aims to evaluate the effects of combined therapies, commonly used in subjects with acute myocardial infarction, in the quality of low-density lipoprotein (LDL) particles. METHODS: Prospective, open-label trial, included patients with acute myocardial infarction. Patients were randomized to antiplatelet treatment (ticagrelor or clopidogrel) and subsequently to lipid-lowering therapy (rosuvastatin or simvastatin/ezetimibe) and were followed up for six months. Nonlinear optical properties of LDL samples were examined by Gaussian laser beam (Z-scan) to verify the oxidative state of these lipoproteins, small angle X-ray scattering (SAXS) to analyze structural changes on these particles, dynamic light scattering (DLS) to estimate the particle size distribution, ultra violet (UV)-visible spectroscopy to evaluate the absorbance at wavelength 484 nm (typical from carotenoids), and polyacrylamide gel electrophoresis (Lipoprint) to analyze the LDL subfractions. RESULTS: Simvastatin/ezetimibe with either clopidogrel or ticagrelor was associated with less oxidized LDL, and simvastatin/ezetimibe with ticagrelor to lower cholesterol content in the atherogenic subfractions of LDL, while rosuvastatin with ticagrelor was the only combination associated with increase in LDL size. CONCLUSIONS: The quality of LDL particles was influenced by the antiplatelet/lipid-lowering strategy, with ticagrelor being associated with the best performance with both lipid-lowering therapies. Trial registration: NCT02428374.
Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Infarto do Miocárdio , Anticolesterolemiantes/efeitos adversos , Clopidogrel , Ezetimiba/uso terapêutico , Humanos , Lipoproteínas , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Estudos Prospectivos , Rosuvastatina Cálcica/uso terapêutico , Espalhamento a Baixo Ângulo , Sinvastatina/uso terapêutico , Ticagrelor , Difração de Raios XRESUMO
For cardiovascular disease prevention, statins alone or combined with ezetimibe have been recommended to achieve low-density lipoprotein cholesterol targets, but their effects on other lipids are less reported. This study was designed to examine lipid changes in subjects with ST-segment elevation myocardial infarction (STEMI) after two highly effective lipid-lowering therapies. Twenty patients with STEMI were randomized to be treated with rosuvastatin 20 mg QD or simvastatin 40 mg combined with ezetimibe 10 mg QD for 30 days. Fasting blood samples were collected on the first day (D1) and after 30 days (D30). Lipidomic analysis was performed using the Lipidyzer platform. Similar classic lipid profile was obtained in both groups of lipid-lowering therapies. However, differences with the lipidomic analysis were observed between D30 and D1 for most of the analyzed classes. Differences were noted with lipid-lowering therapies for lipids such as FA, LPC, PC, PE, CE, Cer, and SM, notably in patients treated with rosuvastatin. Correlation studies between classic lipid profiles and lipidomic results showed different information. These findings seem relevant, due to the involvement of these lipid classes in crucial mechanisms of atherosclerosis, and may account for residual cardiovascular risk.Randomized clinical trial: ClinicalTrials.gov, NCT02428374, registered on 28/09/2014.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Quimioterapia Combinada/métodos , Ezetimiba/uso terapêutico , Feminino , Humanos , Hipercolesterolemia/tratamento farmacológico , Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Rosuvastatina Cálcica/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Sinvastatina/uso terapêuticoRESUMO
Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.
Assuntos
Aspirina/uso terapêutico , Quimioprevenção , Ezetimiba/uso terapêutico , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/prevenção & controle , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/prevenção & controle , Animais , Colecistolitíase/complicações , Colesterol/metabolismo , Colesterol na Dieta , Doença Crônica , Dieta , Modelos Animais de Doenças , Progressão da Doença , Fígado Gorduroso/patologia , Comportamento Alimentar , Neoplasias da Vesícula Biliar/patologia , Cálculos Biliares/etiologia , Cálculos Biliares/patologia , Inflamação/patologia , Masculino , Metaplasia , Camundongos Endogâmicos C57BL , Lesões Pré-Cancerosas/patologia , Baço/patologiaRESUMO
Alopecia areata is a common type of non-scarring alo¬pecia. Although the exact pathogenesis remains elusive, alopecia areata is thought to have a multifactorial etiology described as an interplay of genetic predisposition and environmental exposures. In patients with genetic susceptibility, stress, infection, and microtrauma have been documented to decrease immunosuppressive cytokines that generally maintain the hair follicle's immune privilege. There is currently no curative therapy for alopecia areata, although some treatments can induce hair growth in a percentage of patients. It has been postulated that simvastatin reestablishes the immune privilege, and ezetimibe would provide an immunomodulatory and anti-inflammatory effect. We report a case of a 23 years-old woman with alopecia areata successfully treated with simvastatin/ezetimibe.
La alopecia areata es un tipo común de alopecia no cicatricial. Aunque la patogénesis exacta permanece sin dilucidar, se piensa que la alopecia areata tiene una etiología multifactorial en donde se interrelacionan predisposición genética y factores ambientales. En pacientes susceptibles, se han documentado que el estrés, infecciones y microtraumas disminuyen las citoquinas inmunosupresoras que normalmente mantienen el privilegio inmune del folículo piloso. Actualmente no hay terapia curativa para la alopecia areata, aunque ciertos tratamientos pueden inducir el crecimiento del cabello en un porcentaje de pacientes. Se postula que la simvastatina restablece el privilegio inmune y ezetimibe aportaría un efecto inmunomodulador y antiinflamatorio. Se presenta el caso de una mujer de 23 años con alopecia areata, exitosamente tratada con simvastatina y ezetimibe.
Assuntos
Alopecia em Áreas , Ezetimiba , Imunossupressores , Sinvastatina , Adulto , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/genética , Ezetimiba/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Sinvastatina/uso terapêutico , Adulto JovemRESUMO
La alopecia areata es un tipo común de alopecia no cicatricial. Aunque la patogénesis exacta permanece sin dilucidar, se piensa que la alopecia areata tiene una etiología multifactorial en donde se interrelacionan predisposición genética y factores ambientales. En pacientes susceptibles, se han documentado que el estrés, infecciones y microtraumas disminuyen las citoquinas inmunosupresoras que normalmente mantienen el privilegio inmune del folículo piloso. Actualmente no hay terapia curativa para la alopecia areata, aunque ciertos tratamientos pueden inducir el crecimiento del cabello en un porcentaje de pacientes. Se postula que la simvastatina restablece el privilegio inmune y ezetimibe aportaría un efecto inmunomodulador y antiinflamatorio. Se presenta el caso de una mujer de 23 años con alopecia areata, exitosamente tratada con simvastatina y ezetimibe.
Alopecia areata is a common type of non-scarring alo¬pecia. Although the exact pathogenesis remains elusive, alopecia areata is thought to have a multifactorial etiology described as an interplay of genetic predisposition and environmental exposures. In patients with genetic susceptibility, stress, infection, and microtrauma have been documented to decrease immunosuppressive cytokines that generally maintain the hair follicle's immune privilege. There is currently no curative therapy for alopecia areata, although some treatments can induce hair growth in a percentage of patients. It has been postulated that simvastatin reestablishes the immune privilege, and ezetimibe would provide an immunomodulatory and anti-inflammatory effect. We report a case of a 23 years-old woman with alopecia areata successfully treated with simvastatin/ezetimibe.
Assuntos
Humanos , Feminino , Adulto , Adulto Jovem , Sinvastatina/uso terapêutico , Alopecia em Áreas/genética , Alopecia em Áreas/tratamento farmacológico , Ezetimiba/uso terapêutico , Imunossupressores/uso terapêutico , Predisposição Genética para DoençaRESUMO
PURPOSE OF REVIEW: The causal association of LDL-cholesterol (LDL-C) with atherosclerotic cardiovascular disease (ASCVD) has been demonstrated in robust experimental, epidemiological, genetic, and interventional randomized controlled trials (RCTs). The goal of this review is to show how the knowledge acquired from statin RCTs influenced and was recommended on guidelines for prevention of ASCVD during the last three decades. RECENT FINDINGS: Guideline recommendations have evolved with accruing information derived mostly from statin RCTs, and as decades passed, more intensive LDL-C lowering was recommended according to a given ASCVD risk. Recent guidelines are unanimous in recommending intensive LDL-C lowering for the highest-risk individuals; however, they differ regarding risk stratification tools, use of specific LDL-C targets, management of primary prevention individuals, and thresholds to start non-statin lipid-lowering therapies. Even considering the advent of non-statin therapies like ezetimibe and PCSK9 inhibitors, due to their efficacy, safety, and low cost, guidelines state that statins persist as the main component of ASCVD preventive strategies and should be prescribed in adequate doses to attain evidence-based LDL-C lowering.
Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Guias de Prática Clínica como Assunto , Prevenção Primária/métodos , Aterosclerose/sangue , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Humanos , Inibidores de PCSK9 , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêuticoRESUMO
BACKGROUND: Several studies have investigated the association between non-statin lipid-lowering therapy and regression of atherosclerosis. However, these studies were mostly small and their results were not always robust. The objectives were: (1) to define if a dual lipid-lowering therapy (statin + non-statin drugs) is associated with coronary atherosclerosis regression, estimated by intravascular ultrasound (IVUS); (2) to assess the association between dual lipid-lowering-induced changes in low density lipoprotein cholesterol (LDL-C) and non-high-density-lipoprotein cholesterol (non-HDL-C) levels and atherosclerosis regression. METHODS: A meta-analysis including trials of non-statin lipid-lowering therapy, reporting LDL-C, non-HDL-C and total atheroma volume (TAV) with a minimum of 6 months of follow-up was performed. The primary endpoint was defined as the change in TAV measured from baseline to follow-up, comparing groups of subjects on statins alone versus combination of statin and non-statin drugs. The random-effects model and meta-regression were performed. RESULTS: Eight eligible trials of non-statin lipid-lowering drugs (1759 patients) were included. Overall, the dual lipid-lowering therapy was associated with a significant reduction in TAV [- 4.0 mm3 (CI 95% -5.4 to - 2.6)]; I2 = 0%]. The findings were similar in the stratified analysis according to the lipid-lowering drug class (ezetimibe or PCSK9 inhibitors). In the meta-regression, a 10% decrease in LDL-C or non-HDL-C levels, was associated, respectively, with 1.0 mm3 and 1.1 mm3 regressions in TAV. CONCLUSION: These data suggests the addition of ezetimibe or PCSK9 inhibitors to statin therapy results in a significant regression of TAV. Reduction of coronary atherosclerosis observed with non-statin lipid-lowering therapy is associated to the degree of LDL-C and non-HDL-C lowering. Therefore, it seems reasonable to achieve lipid goals according to cardiovascular risk and regardless of the lipid-lowering strategy used (statin monotherapy or dual treatment).