Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Clinical Practice Recommendations for Pediatric Dyslipidemia.

The leading cause of mortality in the United States is atherosclerotic cardiovascular disease (ASCVD). Atherosclerotic lesions begin during childhood and can place individuals at greater risk for ASCVD. Providers play an active role in preventing the progression of risk factors and future ASCVD events through appropriate clinical management of genetic and acquired dyslipidemias in the pediatric population. Health care providers need to be aware of current recommendations related to screening for dyslipidemia, lifestyle modification strategies, pharmacologic treatment, and guidelines for ongoing monitoring. Most patients with mild to moderate dyslipidemia can be managed by a primary care provider. It is imperative that providers understand the pathophysiology, screening methods, and available treatment options to effectively manage the condition. Frequent reassessment of family history and adherence to lifestyle modifications and pharmacologic interventions is essential for effective treatment.

FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES.

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).

Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.

[Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]. / Hypertriglycéridémie familiale : étude biochimique, clinique et moléculaire dans une famille marocaine.

Familial hypertriglyceridemia is a rare autosomal recessive inborn error of metabolism. Mutation within the LPL gene constitutes the first cause of monogenic etiology. Lipoprotein lipase (LPL) is the key enzyme in triglyceride-rich lipoproteins catabolism. Familial LPL deficiency is expressed by eruptive xanthomatosis and acute pancreatitis. We report a Moroccan case with a monstrous hypertriglyceridemia caused by LPL gene mutation. We discuss pathophysiology aspects according to available investigations data and the relevance of familial screening. The proband is a 19-year-old woman originating from the village of Taourirt (South of Morocco). She was admitted in emergency for diabetic ketoacidosis. Clinical investigations and routine laboratory tests were performed upon admission. Then lipoprotein electrophoresis and sequencing of the LPL gene were practiced. A monstrous hypertriglyceridemia up to 199 mmol/L was found. Lipoprotein electrophoresis has objectified profound disturbances on chylomicrons, VLDL and IDL. The sequencing detected a missense mutation p.S286R at homozygous state in a consanguinity context. Discovery of this LPL gene mutation is the first indigenous and documented case, never related in any other ethnic group. It constitutes a novel proof of a founder effect in the south Moroccan population. Prevalence studies with familial screening should be done for preventative action which is the only acceptable way to limit the cardiovascular and pancreatitis risks in this population where inbreeding is a general rule.

[Dyslipidemia - when are lipid lowering medications useful in clinical practice?]. / Dyslipidämie - Wann ist der Einsatz von Lipidsenkern in der Praxis sinnvoll?

Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations.

La dyslipidémie est un facteur de risque cardiovasculaire majeur et influençable. L'efficacité des statines est bien établie dans la prévention secondaire des maladies cardiovasculaires et dans la prévention primaire chez les patients à haut risque. En prévention primaire, l'indication pour les hypolipémiants se base sur l'estimation de risque cardiovasculaire et le taux de LDL-cholestérol, bien que les preuves du bénéfice d'un traitement médicamenteux soient plus faibles pour les patients à faible risque. Le traitement repose essentiellement sur les statines, ainsi que les modifications du style de vie, comme la stabilisation ou une réduction du poids et une augmentation de l'activité physique. Les mesures de style de vie constituent l'intervention principale chez les patients à faible risque. Il est important d'identifier les dyslipidémies secondaires à une maladie chronique et les dyslipidémies familiales, comme l'hypercholestérolémie familiale et l'hyperlipidémie familiale combinée, vu que les scores de risque ne sont pas appropriés dans ces situations et leur prise en charge spécifique.

Laboratory-based assessment of plasma lipids and lipoproteins for the classification of familial hypercholesterolemic and hypertriglyceridemic states.

Laboratory-based coronary heart disease risk assessment classically involves measurement of lipids and lipoproteins. In this review, information is provided on the methods commonly used in laboratories for the diagnosis of hyperlipidemia, including aspects of precision and accuracy. The latter, when fulfilled, allows the use of uniform reference values. Special attention is paid to the risk estimation using apolipoprotein B and lipoprotein(a) measurement. The overall aim of this review is to simplify the laboratory-based risk estimation for coronary heart disease and to provide help in interpreting the results for effective prevention and treatment of this complex disease.

A newborn with lipemia rednalis.

Lipemia retinalis is a rare ocular manifestation of certain types of hyperlipidemia. A case of a newborn with lipemia retinalis evaluated by laboratory and dinical findings is described. A creamy white appearance of all retinal blood vessels was demonstrated by color fundus photographs. The patient had elevated levels of triglycerides (29,000 mg/dL) and cholesterol (1,470 mg/dL). Lipid electrophoresis indicated hyperprebetalipoproteinemia. Type IV primary hyperlipoproteinemia was diagnosed.

[Excessive hyperchylomicronemia--a rare cause of acute retrosternal and epigastric pain in pregnancy]. / Exzessive Hyperchylomikronämie--eine seltene Ursache für akuten Thorax- und Oberbauchschmerz in der Schwangerschaft.

CASE REPORT: A 24-year-old woman in her 13th gestational was admitted to our department with acute retrosternal and epigastric pain. She had been transferred from the gynecologic department where she was treated for vaginal bleeding because of abortus imminens. A cardiac cause was excluded by ECG and echo. Clinical chemistry and abdominal ultrasound confirmed the diagnosis of acute pancreatitis. The woman was known in our outpatient department for hyperchylomicronemia and had already had an earlier episode of acute pancreatitis under oral contraception years ago. At current admission, triglycerides were 11,500 mg/dl. To reduce plasma triglycerides, selective lipid apheresis was performed. Apheresis was well tolerated, and the patient became free of pain within the first 30 min of treatment. Triglycerides decreased to 6,600 mg/dl at this session. Keeping to a low-fat diet (< 30 g fat per day), the patient remained healthy and completed pregnancy with the delivery of a healthy girl in her 39th week of pregnancy. CONCLUSION: Selective lipid apheresis is a safe and effective option in the treatment of hyperlipidemic pancreatitis, even in pregnant patients.

Asymptomatic massive hypertriglyceridemia in an octogenarian.

OBJECTIVE: To report the case of an 85-year-old man with asymptomatic massive hypertriglyceridemia (MHTG). CLINICAL PRESENTATION AND INTERVENTION: Our case was a non-smoker, healthy 85-year-old Caucasian male, with no excessive alcohol intake and no evidence of an excessive sedentary lifestyle, body mass index = 23.2 kg/m(2), BP = 125/85 mm Hg and plasma triglyceride (TG) >1,000 mg/dl. The MHTG was an incidental finding at the age of 70. He had no cardiovascular disease, xanthomas, xanthelasmas or keratic precipitate. During the last 15 years, his average TG plasma levels showed a significant variability independent of specific diet treatment and fibrate therapy. Liver ultrasound examination excluded hepatomegaly and fatty degeneration. Carotid artery ultrasound showed only intimal thickening in both carotid bifurcations. CONCLUSION: In this patient, MHTG had been silent for many years, with no evidence of coronary heart disease and liver fatty degeneration, both typical complications present in MHTG subjects with low high-density lipoprotein. Hence, this case must be considered as a rarity.