The panorama of familial hypercholesterolemia in Latin America: a systematic review

The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified. The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified. Familial hypercholesterolemia (FH) is a syndrome that causes defective clearance of LDL cholesterol (LDL-C) and results in premature coronary heart disease (CHD) (1.Singh S. Bittner V. Familial hypercholesterolemia–epidemiology, diagnosis, and screening.Curr. Atheroscler. Rep. 2015; 17: 482-485Crossref PubMed Scopus (0) Google Scholar, 2.Najam O. Ray K. Familial hypercholesterolemia: a review of the natural history, diagnosis, and management.Cardiol. Ther. 2015; 4: 25-38Crossref PubMed Google Scholar, 3.Benn M. Watts G. Tybjærg-Hansen A. Nordestgaard B. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.Eur. Heart J. 2016; 37: 1384-1394Crossref PubMed Scopus (242) Google Scholar). Two forms have been reported: autosomal dominant and autosomal recessive. The vast majority of cases have the autosomal dominant pattern of inheritance with 90% penetrance. Autosomal dominant FH is attributed to mutations in three different genes: LDL receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) (1.Singh S. Bittner V. Familial hypercholesterolemia–epidemiology, diagnosis, and screening.Curr. Atheroscler. Rep. 2015; 17: 482-485Crossref PubMed Scopus (0) Google Scholar, 3.Benn M. Watts G. Tybjærg-Hansen A. Nordestgaard B. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.Eur. Heart J. 2016; 37: 1384-1394Crossref PubMed Scopus (242) Google Scholar, 4.Medeiros A. Alves A. Bourbon M. Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.Genet. Med. 2016; 18: 316-324Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 5.Nordestgaard B. Chapman M. Humphries S. Ginsberg H. Masana L. Descamps O. Wiklund O. Hegele R. Raal F. Defesche J. et al.Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society.Eur. Heart J. 2013; 34: 3478-3490aCrossref PubMed Scopus (1556) Google Scholar). Other FH genes have been searched for using exome sequencing without success (2.Najam O. Ray K. Familial hypercholesterolemia: a review of the natural history, diagnosis, and management.Cardiol. Ther. 2015; 4: 25-38Crossref PubMed Google Scholar). FH caused by mutations in LDLR adaptor protein (LDLRAP) is known as autosomal recessive FH (2.Najam O. Ray K. Familial hypercholesterolemia: a review of the natural history, diagnosis, and management.Cardiol. Ther. 2015; 4: 25-38Crossref PubMed Google Scholar). FH is the most common monogenic disorder leading to premature CHD; despite this fact, it is notoriously underdiagnosed and undertreated worldwide (6.Rynkiewicz A. Cybulska B. Banach M. Filipiak K. Guzik T. Idzior-Waluś B. Imiela J. Jankowski P. Kłosiewicz-Latoszek L. Limon J. et al.Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum.J. Clin. Lipidol. 2013; 7: 217-221Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Homozygous FH (HoFH) is characterized by extremely high levels of LDL-C (460–1,160 mg/dl) and early onset coronary artery disease (typically by the second decade of life) (7.Farnier M. Bruckert E. Severe familial hypercholesterolaemia: current and future management.Arch. Cardiovasc. Dis. 2012; 105: 656-665Crossref PubMed Scopus (0) Google Scholar). Mean LDL-C concentration in untreated patients is close to 615 mg/dl (7.Farnier M. Bruckert E. Severe familial hypercholesterolaemia: current and future management.Arch. Cardiovasc. Dis. 2012; 105: 656-665Crossref PubMed Scopus (0) Google Scholar, 8.Vogt A. The genetics of familial hypercholesterolemia and emerging therapies.Appl. Clin. Genet. 2015; 8: 27-36Crossref PubMed Google Scholar). Patients are classified into two groups based on the level of LDLR activity, either <2% (receptor negative) or 2–25% (receptor defective). Receptor defective patients have a better prognosis than receptor negative cases (9.Ito M. Watts G. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia.Drugs. 2015; 75: 1715-1724Crossref PubMed Scopus (31) Google Scholar, 10.Santos R. Homozygous familial hypercholesterolemia: phenotype rules!.Atherosclerosis. 2016; 248: 252-254Abstract Full Text Full Text PDF PubMed Google Scholar, 11.Bell D.A. Watts G.F. Progress in the care of familial hypercholesterolemia: 2016.Med. J. Aust. 2016; 205: 232-236Crossref PubMed Scopus (0) Google Scholar). Heterozygous FH (HeFH) is caused by a single inherited copy of a mutation. The frequency of a heterozygous mutation is >90, 5, and <1% in the LDLR, APOB, and PCSK9 genes, respectively (5.Nordestgaard B. Chapman M. Humphries S. Ginsberg H. Masana L. Descamps O. Wiklund O. Hegele R. Raal F. Defesche J. et al.Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society.Eur. Heart J. 2013; 34: 3478-3490aCrossref PubMed Scopus (1556) Google Scholar). A causal mutation in one of these genes is identified in 60–80% of cases. Affected individuals are characterized by LDL-C levels two to three times greater than normal (190–400 mg/dl). The mean untreated LDL-C concentration is 199.9 mg/dl (12.Besseling J. Kindt I. Hof M. Kastelein J. Hutten B. Hovingh G. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.Atherosclerosis. 2014; 233: 219-223Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). HeFH is suspected with an elevated LDL-C (LDL-C >190 mg/dl), the presence of xanthomas (tendinous/tuberous), corneal arcus (<45 years old), family history of FH, and either a personal or family history of premature coronary artery disease. Traditionally, the prevalence of HeFH is considered to be 1 in 500 individuals. This figure is based on the results of a European survey of familial lipoprotein disorders in myocardial infarction survivors (13.Goldstein J. Hazzard W. Schrott H. Bierman E. Motulsky A. Hyperlipidemia in coronary heart disease I. Lipid levels in 500 survivors of myocardial infarction.J. Clin. Invest. 1973; 52: 1533-1543Crossref PubMed Google Scholar, 14.Genest J. Hegele R. Bergeron J. Brophy J. Carpentier A. Couture P. Davignon J. Dufour R. Frohlich J. Gaudet D. et al.Canadian Cardiovascular Society position statement on familial hypercholesterolemia.Can. J. Cardiol. 2014; 30: 1471-1481Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). However, recent work in a Dutch population estimated a prevalence of 1 in 137 persons (1.Singh S. Bittner V. Familial hypercholesterolemia–epidemiology, diagnosis, and screening.Curr. Atheroscler. Rep. 2015; 17: 482-485Crossref PubMed Scopus (0) Google Scholar, 10.Santos R. Homozygous familial hypercholesterolemia: phenotype rules!.Atherosclerosis. 2016; 248: 252-254Abstract Full Text Full Text PDF PubMed Google Scholar, 11.Bell D.A. Watts G.F. Progress in the care

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