Update on Sitosterolemia and Atherosclerosis.

PURPOSE OF REVIEW: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. RECENT FINDINGS: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program.

BACKGROUND: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. METHODS: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. RESULTS: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean ß-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. CONCLUSIONS: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Critérios diagnósticos e estratificação de risco na hipercolesterolemia familiar / Criteria diagnosis and risk stratification of familial hypercholesterolemia

A hipercolesterolemia familiar (HF) é uma doença genética relativamente comum caracterizada por níveis elevados de LDL-colesterol (LDL-C) e, por conseguinte, associada a risco de desenvolvimento prematuro de doença cardiovascular aterosclerótica. O tratamento hipolipemiante reduz significativamente o risco cardiovascular desses pacientes, tornando fundamental a identificação precoce desses indivíduos, seguida de tratamento adequado assim que possível. Para tanto, existem escores diagnósticos de HF, como o escore holandês Dutch Lipid Clinic Network, que avalia níveis de LDL-C, antecedente familiar e/ou pessoal de evento cardiovascular isquêmico e a presença de sinais físicos, como xantomas. Uma vez feito o diagnóstico de HF, torna-se muito importante a estratificação de risco desses pacientes. A identificação de fatores de risco associados (como tabagismo,diabetes mellitus, hipertensão arterial, aumento de Lp(a), entre outros) aliada ao uso de métodos para detecção de doença aterosclerótica subclínica em indivíduos com HF pode auxiliar na identificação daqueles que têm maior risco cardiovascular e são candidatos a estratégias mais agressivas de redução de LDL-C. Nesse artigo, revisamos os principais critérios diagnósticos de HF e a estratificação de risco desses pacientes

Familial hypercholesterolemia (FH) is a relatively common genetic disease that is characterized by elevated LDL-cholesterol (LDL-C) levels. As a consequence, it is associated with the risk of premature development of atherosclerotic cardiovascular disease.Lipid-lowering therapies significantly reduces the cardiovascular risk in these patients, making early identification of these individuals essential, followed by adequate treatment as soon as possible. There are diagnostic scores of FH for this purpose, such as the Dutch Lipid Clinic Network score, which evaluates LDL-C levels, family history and/or personal history of ischemic cardiovascular event and the presence of physical signs, such as xanthomas. Once FH has been diagnosed, it is very important to stratify the risk in these patients. The identification of associated risk factors (such as smoking, diabetes mellitus, high blood pressure, elevated Lp(a), among others), together with the use of methods to detect subclinical atherosclerotic disease in individuals with FH, can assist in the identification of those with a higher cardiovascular risk, and who are therefore candidates for more aggressive strategies to reduce LDL-C. This article gives a review of the main diagnostic criteria of FH, and the risk stratification in these patients

Use of statins and the incidence of type 2 diabetes mellitus / Uso de estatinas e a incidência de diabetes mellitus tipo 2

SummaryIntroduction:the use of statins is associated with reduced cardiovascular risk in studies of primary and secondary prevention, and the reduction is directly proportional to the reduction of LDL-cholesterol. Recent evidence suggests that statins may be associated with a higher incidence of new cases of diabetes. The aim of this review is to explore this possibility, identifying factors associated with the increase in risk and the potential diabetogenic mechanisms of statins. In addition, we evaluated if the risk of diabetes interferes with the reduction in cardiovascular risk achieved with statins.Methods:we reviewed articles published in the Scielo and Pubmed databases, which assessed or described the association between use of statins and risk of diabetes up to June 2015.Results:use of statins is associated with a small increase in the incidence of new cases of diabetes. Age, potency of statin therapy, presence of metabolic syndrome, impaired fasting blood glucose, overweight and previously altered glycated hemoglobin levels are associated with increased risk of diabetes, but there is no consensus about the possible diabetogenic mechanisms of statins. In patients candidate to hypolipemiant drug therapy, the benefit of reducing cardiovascular risk outweighs any risk increase in the incidence of diabetes.Conclusion:statins are associated with a small increase in incidence of diabetes in patients predisposed to glycemic alteration. However, since the benefit of cardiovascular risk reduction prevails even in this group, there is no evidence to date that this finding should change the recommendation of starting statin therapy.

ResumoIntrodução:o uso de estatinas está associado à redução do risco cardiovascular em estudos de prevenção primária e secundária, e essa redução ocorre de modo diretamente proporcional à redução de LDL-colesterol. Evidências recentes sugerem que estatinas podem estar associadas à maior incidência de novos casos de diabetes. O objetivo desta revisão é identificar os fatores associados ao aumento de risco e os potenciais mecanismos diabetogênicos das estatinas. Além disso, avaliou-se se o risco de diabetes interfere na redução de risco cardiovascular obtida com as estatinas.Métodos:foram revisados artigos publicados nas bases de dados Scielo e Pubmed, que avaliaram ou descreveram a associação do uso de estatinas com o risco de diabetes até junho de 2015.Resultados:o uso de estatinas está associado a um pequeno aumento na incidência de novos casos de diabetes. Idade, potência do tratamento com estatina, presença de síndrome metabólica, glicemia de jejum alterada, excesso de peso e hemoglobina glicada previamente alterada estão associados a um maior risco de diabetes, mas não há consenso sobre os possíveis mecanismos diabetogênicos das estatinas. Nos pacientes candidatos à terapêutica hipolipemiante, o benefício de redução do risco cardiovascular supera qualquer aumento de risco na incidência de diabetes.Conclusão:estatinas estão associadas a um pequeno aumento na incidência de diabetes em pacientes predispostos a alterações glicêmicas. Entretanto, como persiste, mesmo nesse grupo, o benefício da redução de risco cardiovascular, não há qualquer evidência até o momento de que esse achado deva mudar a decisão de iniciar o tratamento com estatinas.

Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity.

Adipose tissue (AT) can accumulate macrophages and secrete several inflammatory mediators. Despite its pivotal role in the progression of chronic inflammatory processes such as atherosclerosis, the adaptive role of immunity in obesity remains poorly explored. Visceral AT of diet-induced obese C57BL/6 mice had higher numbers of both CD4(+) and CD8(+) T cells than lean controls, monitored by flow cytometry. When stimulated in vitro, T cells from obese AT produced more interferon (IFN)gamma than those from controls. AT from obese animals also had more cells expressing I-A(b), a mouse class II histocompatibility marker implicated in antigen presentation, as determined by immunostaining. Differentiated 3T3-L1 cells stimulated with recombinant IFNgamma or T-helper 1-derived supernatant produced several chemokines and their mRNAs. Obese IFNgamma-deficient animals had significantly reduced AT expression of mRNA-encoding inflammatory genes such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1, decreased AT inflammatory cell accumulation, and better glucose tolerance than control animals consuming the same diet. Obese mice doubly deficient for IFNgamma receptor and apolipoprotein (Apo)E on a mixed 129SvEv/C57BL/6 (129/B6) genetic background, despite exhibiting similar AT mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 as 129/B6-ApoE(-/-) controls, had decreased expression of important T cell-related genes, such as IFNgamma-inducible protein-10 and I-A(b), and lower plasma triglycerides and glucose. These results indicate a role for T cells and IFNgamma, a prototypical T-helper 1 cytokine, in regulation of the inflammatory response that accompanies obesity.