OLIVEIRA,V. O. Disfunção endotelial precoce em pacientes com lipodistrofia generalizada congênita (síndrome de berardinelli-seip) avaliada por dilatação fluxo-mediada da artéria braquial e tonomeria arterial periférica. 2015. 172 f. Tese (Doutorado em Ciências Medicas) - Faculdade de Medicina, Universidade Federal do Ceará, 2015 / Submitted by Ivone Sousa (ppgcm.ufc@gmail.com) on 2017-10-25T15:59:23Z
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Previous issue date: 2015-08-31 / Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive disease, characterized by total or almost total absence of adipose tissue since birth. Mutations in the BSCL1/AGPAT2 and BSCL2/Seipin genes account for 95% of cases. CGL courses with severe insulin resistance (IR), diabetes mellitus (DM) and dyslipidemia, which may culminate in atherosclerosis and premature cardiovascular mortality. However, there is a lack of studies evaluating early vascular damage in this condition. This study aimed to determine the prevalence of endothelial dysfunction (ED), through assessment of flow-mediated dilation (FMD) of the brachial artery and peripheral arterial tonometry (PAT), and its association with genotypic and phenotypic characteristics in population with CGL. We evaluated 11 patients with CGL, 11 with metabolic syndrome (MS) and 22 healthy controls, matched for sex and age. We performed clinical and laboratory evaluation, abdominal ultrasonography, echocardiography, molecular study of AGPAT2 and BSCL2 genes and evaluation of endothelial function by FMD (by the % of the brachial artery dilation -%FMD) and PAT (by reactive hyperemia index - RHI). In the CGL, MS and control groups, age (years) was, respectively, 10 (5-30), 13 (11-19) and 12 (10-19) and were female, 63.5%, 68.2% and 54.1%. There was a higher prevalence of hypertriglyceridemia, hypercholesterolemia, DM, BP above the 95 percentile (p<0.001) and low HDL-c (p=0.013). The MS group differed from the CGL group by the absence of DM and higher BMI (p=0.001). Among the CGL, 45.5% were BSCL2 mutants and 18.2% AGPAT2 (36.3% without genetic study). Of these, all had hypoleptinemia (1.1ng/ml, 0.8-1.7), hypertriglyceridemia and low HDL-c; 63.6% had DM, 54.5% hypercholesterolemia, 45.5% hepatic steatosis, 45.5% nephropathy and 36.4% hypertrophy of the left ventricle. In the CGL group, 81.9% had FMD<10% and 63.6% RHI<1.67, featuring ED. The % FMD in this group was lower compared with the MS, 8.0% (2.9-10.3) vs. 13.0% (6.9-28.1; p=0.003) and controls, 16.0% (10.0-30.0, p=<0.001). The basal brachial artery diameter (BBD) was higher in the CGL group compared to the MS (p=0.041) and control (p=0.015) (suggesting more severe ED). The %FMD was also lower among individuals with CGL and DM (7.1%; 8.9% vs. 2.9-10.3; 5.2-10.3) and BSCL2 mutants vs. AGPAT2 (5.3%; 2.9-10.3 vs.
7.9%; 7.1-8.7). CGL and control groups assessed PAT. The CGL group showed less reactive hyperemia index (RHI), 1.7 (0.8-2.3) vs. control group, 2.1 (1.7-3.0; p <0.001) and greater PAT- AIx than the control (p=0.023) (suggesting increased arterial stiffness). The ED was more prevalent among BSCL2 mutants and those with DM. There was a negative correlation between
%FMD and BBD; %FMD and triglycerides; RHI and triglycerides and positive between %FMD and RHI with HDL-c. The concordance of the results of FMD and PAT was 63.6%. In conclusion, ED, evaluated by both FMD, and PAT was condition of very high prevalence in the CGL, observed in most subjects from this significant Brazilian series. In this condition, ED is presented earlier and with more severe characteristics,. The hyperglycemia, dyslipidemia (low HDL-c and hypertriglyceridemia) were strongly associated with ED. These factors, as well as severe IR and hipoleptinemia, quite prevalent in this syndrome and that typically affect early on individuals with CGL, could justify the greater impairment of endothelial function in this disease. It is noteworthy that ED was more prevalent in patients BSCL2 mutants, which typically have more severe forms of the disease. The agreement between diagnosis in ED by FMD and PAT suggests that both methods are valid in the investigation of endothelial dysfunction, but possibly complementary. / A lipodistrofia generalizada congênita (LGC) é uma doença rara, autossômica recessiva, caracterizada por ausência total ou quase total de tecido adiposo desde o nascimento. Mutações nos genes BSCL1/AGPAT2 e BSCL2/Seipin são responsáveis por 95% dos casos. A LGC cursa com grave resistência à insulina (RI), diabetes mellitus (DM) e dislipidemia, que podem evoluir com aterosclerose e mortalidade cardiovascular prematura. Contudo, faltam estudos avaliando dano vascular precoce nessa condição. Este trabalho objetivou determinar a prevalência de disfunção endotelial (DE), por avaliação da dilatação fluxo-mediada (FMD) da artéria braquial e por tonometria arterial periférica (PAT), e sua associação com características genotípicas e fenotípicas em população com LGC. Participaram do estudo 11 indivíduos com LGC, 11 com síndrome metabólica (SM) e 22 controles saudáveis, pareados para sexo e idade. Foram realizadas avaliação clínico-laboratorial, ultrassonografia abdominal, ecocardiograma, estudo molecular dos genes AGPAT2 e BSCL2 e avaliação da função endotelial pela DMF (pela da obtenção da % de dilatação da artéria braquial - %DMF) e PAT (pela obtenção do índice de hiperemia reativa – RHI). Nos grupos LGC, SM e controle, a idade (anos) foi 10 (5-30), 13 (11-17) e 12 (10-19), sendo do sexo feminino, 63,5%, 54,5% e 68,2%. Houve maior prevalência de hipertrigliceridemia, hipercolesterolemia, DM, PA>percentil 95 (p<0,001) e HDL-c baixo (p=0,013) no grupo LGC. O grupo SM diferia do grupo LGC pela ausência de DM e maior IMC (p=0,001). No grupo LGC, 45,5% eram BSCL2 mutantes e 18,2% AGPAT2 mutantes e 36,3% não tinham estudo genético. Todos tinham hipoleptinemia (1,1ng/mL; 0,8-1,7), hipertrigliceridemia e HDL-c baixo; 63,6% tinham DM, 54,5% hipercolesterolemia, 45,5% esteatose hepática, 45,5% nefropatia e 36,4% hipertrofia de ventrículo esquerdo. No grupo LGC, 81,9% apresentaram FMD<10% e 63,6% RHI<1,67, caracterizando DE. Foi observada menor %DMF entre os indivíduos com LGC, 8,0% (2,9-10,3) vs. grupo SM, 13,0% (6,9-28,1; p=0,003) e vs. controle, 16,0% (10,0-30,0; p=<0,001). Observou-se menor %FMD entre indivíduos com DM (7,1%; 2,9-10,3 vs. 8,9%; 5,2-10,3) e nos BSCL2 mutantes vs. AGPAT2 mutantes (5,3%; 2,9-10,3 vs. 7,9%; 7,1-8,7). O diâmetro basal da artéria braquial (DBB) foi maior no grupo LGC em relação ao SM (p=0,041) e controle (p=0,015) (sugerindo DE mais grave). Foram avaliados por PAT os grupos LGC e controle. Os portadores de LGC apresentaram menores valores de RHI, 1,7 (0,8-2,3) vs. controle, 2,1 (1,7-3,0; p<0,001) e maiores valores do índice de aumento derivado da onda de pulso da PAT (PAT-Aix), p=0,0023(sugerindo maior rigidez da parede arterial). Observou-se correlação negativa entre %FMD e DBB; %FMD e triglicerídeos; RHI e triglicerídeos e correlação positiva entre %DMF e HDL-c e entre RHI e HDL-c. A concordância dos resultados da FMD e PAT foi 63.6%. Conclui-se que a DE, avaliada tanto por FMD, quanto por PAT, é condição de elevada prevalência nessa significativa casuística brasileira de LGC, apresentando-se precocemente e com maior gravidade. A hiperglicemia e a dislipidemia (HDL-c baixo e a hipertrigliceridemia) estiveram associadas à DE e, especula-se que a grave RI e a hipoleptinemia características dessa condição poderiam justificar o maior comprometimento da função endotelial desses pacientes. Ressalta-se ainda que a DE foi mais prevalente nos pacientes BSCL2 mutantes, que tipicamente apresentam formas mais graves da doença. A concordância diagnóstica para DE por FMD e PAT sugere que ambos os métodos são válidos e possivelmente complementares na investigação da DE.
| Identifer | oai:union.ndltd.org:IBICT/oai:www.repositorio.ufc.br:riufc/26840 |
| Date | 31 August 2015 |
| Creators | Fernandes, Virginia Oliveira |
| Contributors | Montenegro Junior, Renan Magalhães |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Source | reponame:Repositório Institucional da UFC, instname:Universidade Federal do Ceará, instacron:UFC |
| Rights | info:eu-repo/semantics/openAccess |
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