Síndrome de Quilomicronemia Familiar: Algoritmo Diagnóstico
DOI:
https://doi.org/10.24950/rspmi.r.92.4.2021Palavras-chave:
Algoritmo; Hiperlipoproteinemia Tipo I/ diagnóstico; Técnicas de Apoio para a Decisão.Resumo
A hipertrigliceridemia, a par do aumento do risco cardiovascular pode, em níveis muito elevados, ter consequências como a pancreatite recorrente e dor abdominal. A síndrome da quilomicronemia familiar (SQF) é uma doença autossómica recessiva rara do metabolismo dos quilomicra, causada mais frequentemente por mutação do gene da lipoproteína lipase. A concentração plasmática de triglicéridos (TG) pode ser dez vezes superior ao normal. Distinguir esta condição da quilomicronemia multifactorial (QMM) pode tornar-se difícil pela semelhança fenotípica, sendo necessário realizar o teste genético. O tratamento da hipertrigliceridemia foca-se na prevenção da pancreatite em doentes com hipertrigliceridemia grave e na redução do risco cardiovascular global. O volanesorseno é um fármaco indicado na SQF que actua sobretudo pela clearance dos TG por vias independentes da LPL, atingindo em estudos de fase 2 reduções da apoC-III e de TG de 79,6% e 70,9% respectivamente; em estudos de fase 3, a redução de TG foi de 77%, com efeitos adversos minor. Os dados acerca da redução de risco cardiovascular são mais limitados. Tendo em conta a realidade nacional, os autores propõem um algoritmo de abordagem da hipertrigliceridemia que se inicia nos Cuidados de Saúde Primários com a exclusão de causas secundárias de hipertrigliceridemia e determinação da necessidade de referenciação a uma consulta de especialidade para confirmação do diagnóstico, com base no score do SQF sugerido por Moulin et al em 2018.
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Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, et al; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655-66. doi: 10.1016/S2213-8587(13)70191-8.
Konstantinides SV, Torbicki A, Agnelli G, for the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033- 69, 3069a-3069k. doi: 10.1093/eurheartj/ehu283. Erratum in: Eur Heart J. 2015;36:2666. Erratum in: Eur Heart J. 2015;36:2642.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082- -e1143. doi: 10.1161/CIR.0000000000000625. Erratum in: Circulation. 2019;139):e1182-e1186.
Mach F, Baigent C, Catapano AL, for the ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-88. doi: 10.1093/eurheartj/ehz455.
Cortez-Dias N, Robalo Martins S, Belo A, Fiúza M; em nome dos Investigadores do Estudo VALSIM. Caracterização do perfil lipídico nos utentes dos cuidados de saúde primários em Portugal. Rev Port Cardiol. 2013;32:987- 96. doi: 10.1016/j.repc.2013.06.008.
Chait A, Eckel RH. The Chylomicronemia Syndrome Is Most Often Multifactorial: A Narrative Review of Causes and Treatment. Ann Intern Med. 2019;170:626-34. doi:10.7326/M19-0203
Paquette M, Bernard S, Hegele RA, Baass A. Chylomicronemia: Differences between familial chylomicronemia syndrome and multifactorial chylomicronemia. Atherosclerosis. 2019;283:137-42. doi: 10.1016/j.atherosclerosis.2018.12.019.
Moulin P, Dufour R, Averna M, Arca M, Cefalù AB, Noto D, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an "FCS score". Atherosclerosis. 2018 ;275:265-272. doi: 10.1016/j.atherosclerosis.2018.06.814.
Reeskamp LF, Tromp TR, Stroes ESG. The next generation of triglyceride- -lowering drugs: will reducing apolipoprotein C-III or angiopoietin like protein 3 reduce cardiovascular disease? Curr Opin Lipidol. 2020;31:140-6. doi: 10.1097/MOL.0000000000000679.
Florentin M, Kostapanos MS, Anagnostis P, Liamis G. Recent developments in pharmacotherapy for hypertriglyceridemia: what’s the current state of the art? Expert Opin Pharmacother. 2020;21:107-20. doi: 10.1080/14656566.2019.1691523.
Reiner Ž. Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy. Korean Circ J. 2018;48:1097-119. doi: 10.4070/ kcj.2018.0343.
Minicocci I, Tikka A, Poggiogalle E, Metso J, Montali A, Ceci F, et al. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J Lipid Res. 2016;57:1097-107. doi: 10.1194/jlr.P066183.
Hegele RA, Berberich AJ, Ban MR, Wang J, Digenio A, Alexander VJ, et al. Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. J Clin Lipidol. 2018;12:920-7.e4. doi: 10.1016/j. jacl.2018.03.093.
Blom DJ, O'Dea L, Digenio A, Alexander VJ, Karwatowska-Prokopczuk E, Williams KR, et al. Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study. J Clin Lipidol. 2018;12:1234-43.e5. doi: 10.1016/j.jacl.2018.05.013.
Brahm AJ, Hegele RA. Chylomicronaemia--current diagnosis and futu re therapies. Nat Rev Endocrinol. 2015;11:352-62. doi: 10.1038/nrendo.2015.26.
Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200-6. doi: 10.1056/NEJMoa1400284.
Carr RA, Rejowski BJ, Cote GA, Pitt HA, Zyromski NJ. Systematic review of hypertriglyceridemia-induced acute pancreatitis: A more virulent etiology? Pancreatology. 2016;16:469-76. doi: 10.1016/j.pan.2016.02.011.
Davidson M, Stevenson M, Hsieh A, Ahmad Z, Crowson C, Witztum JL. The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. Expert Rev Cardiovasc Ther. 2017;15:415-23. doi: 10.1080/14779072.2017.1311786.
Davidson M, Stevenson M, Hsieh A et al. Examining the High Disease Burden and Impact on Quality of Life in Familial Chylomicronemia Syndrome Atherosclerosis 2018. Supplements 32:66 doi:10.1016/j.atherosclerosissup.2018.04.199
Ahmad Z, Halter R, Stevenson M. Building a better understanding of the burden of disease in familial chylomicronemia syndrome. Expert Rev Clin Pharmacol. 2017;10:1-3. doi: 10.1080/17512433.2017.1251839.
D. Gaudet, J. de Wal, K. Tremblay, S. Déry, S. van Deventer, A. Freidig, et al., Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency, Atheroscler Suppl 2010;11:55-60. doi: 10.1016/j.atherosclerosissup.2010.03.004.
Dron JS, Wang J, Cao H, McIntyre AD, Iacocca MA, Menard JR, et al. Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol. 2019;13:80-8. doi: 10.1016/j.jacl.2018.10.006.
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia. J Clin Lipidol. 2011;5:37-44. doi: 10.1016/j.jacl.2010.11.004.
Arca M, Hsieh A, Soran H, Rosenblit P, O'Dea L, Stevenson M. The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study. Expert Rev Cardiovasc Ther. 2018;16:537-46. doi: 10.1080/14779072.2018.1487290.
Ramírez-Bueno A, Salazar-Ramírez C, Cota-Delgado F, de la Torre-Prados MV, Valdivielso P. Plasmapheresis as treatment for hyperlipidemic pancreatitis. Eur J Intern Med. 2014;25:160-3. doi: 10.1016/j.ejim.2013.08.701.
Stock JK. Commentary on rare dyslipidaemia paper. Atherosclerosis. 2020;295:54-8. doi:10.1016/j.atherosclerosis.2019.12.012
Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res. 2019;124:386– 404.
Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res. 2015;56:1296–307. doi: 10.1194/jlr.M054882
Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377:222–32. doi: 10.1056/NEJMoa1701329
Paik J, Duggan S. Volanesorsen: First Global Approval. Drugs. 2019;79:1349-54. doi: 10.1007/s40265-019-01168-z.
Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112:1479-90. doi: 10.1161/CIRCRESAHA.111.300367.
Lee RG, Graham MJ, Fu W, et al. Antisense suppression of serum apoC- -III improves hypertriglyceridemia and insulin sensitivity in multiple species. Diabetes, volume 62:Suppl 1A:LB14
Alexander V, Gaudet D, Cheng W, et al. An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, very- -low-density lipoprotein cholesterol and particle number, and increases high-density lipoprotein cholesterol and particle number in hypertriglyceri demic patients on a fibrate. J Am Coll Cardiol. 2014; 63: A1453.
Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373:438-47. doi: 10.1056/NEJMoa1400283.
Gouni-Berthold I, Alexander V, Digenio A, et al. Apolipoprotein C-III inhibition with volanesorsen in patients with hypertriglyceridemia (COMPASS): a randomized, double-blind, placebo-controlled trial. Atherosclerosis Suppl. 2017;28:e1–e2 doi: https://doi.org/10.1016/j.jacl.2017.04.038
Gaudet D, Digenio A, Alexander V et al. The APPROACH study: a randomized, double blind, placebo-controlled, phase 3 study of volanesorsen administered subcutaneously to patients with familial chylomicronemia syndrome (FCS). J Clin Lipidol. 2017;11:814-5. doi: 10.1016/j.jacl.2017.04.071
Digenio A, Dunbar RL, Alexander VJ, Hompesch M, Morrow L, Lee RG, et al. Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes. Diabetes Care. 2016;39:1408-15. doi: 10.2337/dc16-0126.
Gordts PL, Nock R, Son NH, Ramms B, Lew I, Gonzales JC, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016;126:2855-66. doi: 10.1172/JCI86610.
Johansen CT, Hegele RA. Genetic bases of hypertriglyceridemic phenotypes. Curr Opin Lipidol. 2011;22:247-53. doi: 10.1097/ MOL.0b013e3283471972.
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