Primary (Genetic) Dyslipidemias
Dyslipidemia is a common problem that doctors face in daily clinical practice. The causes can be broadly divided into primary (genetic) or secondary. The focus of this article is on the primary or genetic dyslipidemias, in particular familial hypercholesterolemia (FH), and why it is important to identify these patients.
Secondary causes must always be considered when managing newly diagnosed dyslipidemia. The most important secondary cause in developed countries is a sedentary lifestyle with excessive dietary intake of saturated fat, cholesterol, and trans-fats. Other common secondary causes include diabetes mellitus, alcohol overuse, chronic kidney disease, hypothyroidism, cholestatic liver diseases and drugs.
Common genetic dyslipidemias
Genetics variants in key genes that are involved in lipid synthesis, transportation or processing have a strong influence on blood lipid levels. However we must not forget that very often the secondary factors mentioned earlier combine with these genetic variations to result in an abnormal lipid phenotype.
The most common form of genetic dyslipidemia is polygenic, involving more than one genetic variation. This is usually less severe than monogenic or familial dyslipidemias. Mutations in genes that cause monogenic dyslipidemias tend to have more severe effects on the protein’s function. These individuals often have severely abnormal blood lipid levels, which results in early-onset cardiovascular disease. Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism that is typified by considerable elevations in levels of low-density lipoprotein cholesterol (LDL-C). The etiology of FH comprises of known mutations in the gene of the LDL receptor (LDLR), the proprotein convertase subtilisin-kexin type 9 (PCSK9) gene, the gene of apolipoprotein B (ApoB) or rare mutations in LDL receptor adapter protein 1 (LDLRAP1) gene.
Genetic disorders inherited in an autosomal dominant fashion are as follows: Familial hypercholesterolemia is due to mutation in the LDL receptor gene and has an estimated prevalence of 1 in 200 to 500 for the heterozygous form. Apolipoprotein B mutations which results in a defect in the LDL receptor binding region occur roughly 1 in 1000. Both lead to decreased LDL clearance, and can present with similar clinical signs of tendon xanthomas, corneal arcus, premature coronary artery disease (ages 30-50), and have a total cholesterol of between 250-500mg/dl (7-13mmol/L). PCSK9 gain of function mutations are probably rare, although true prevalence is unknown. Familial combined hyperlipidemia has a prevalence of 1 in 50 to 100. In addition to the above clinical findings, they also have raised triglycerides in the range of 250-750mg/dl (2.8-8.5mmol/L). The genetic mechanism is unknown, but possibly involves multiple gene defects.
The homozygous form of FH is thankfully very rare, about 1 in 1 million, but presents with the severest form of the disease. In addition to the above manifestations, they may have planar and tuberous xanthomas, and may get CAD even before the age of 20. Total cholesterol often exceeds 500mg/dl (>13mmol/L).
Autosomal recessive genetic dyslipidemias including LPL deficiency, Apo C-II deficiency, familial dysbetalipoproteinemia, Tangier disease and Sitosterolemia are generally rare and will not be discussed.
The diagnosis of both types of FH is based primarily on the finding of severe LDL-C elevations in the absence of secondary causes of hypercholesterolemia. There are several diagnostic tools for FH, a widely used one is the Simon Broome criteria, which takes into consideration cholesterol concentrations, clinical characteristics, molecular diagnosis, and family history. In general one should suspect FH if there is a family history of diagnosed FH, or an adult with plasma cholesterol of >8mmol/L (>310mg/dL), a child with plasma cholesterol of >6mmol/L (>230mg/dL), premature coronary artery disease, tendon xanthomas, or family history of premature coronary artery disease or sudden cardiac death. A substantial increase in serum triglyceride levels should also raise the possibility of another lipid disorder such as familial combined hyperlipidemia.
Clinical importance and therapeutic strategies
It is essential to consider the possibility of a genetic dyslipidemia because many of the common ones, such as FH have an autosomal dominant genetic transmission and therefore will be present in approximately 50% of other family members. The recognition of the possibility of a genetic disorder will lead to screening family members and early treatment initiation if abnormalities are found, which may prevent the adverse consequences of hyperlipidemia.
When considering treatment, contributing secondary factors including lifestyle factors need to be identified and concurrently addressed. Although we cannot change our genetic makeup, there is good evidence that healthy lifestyle habits such as good nutritional choices, physical activity are effective interventions for lowering triglycerides, increasing HDL, as well as reducing LDL cholesterol levels. Obesity, in particular central or visceral adiposity strongly promotes insulin resistance. Persistent insulin resistance, also known as metabolic syndrome prevents glucose and lipid uptake by the cells, leading to dyslipidemia.
However lifestyle modifications are less likely to reduce cholesterol levels adequately and drug therapy will often be required. This invariably will involve a potent statin, often in combination therapy with ezetimibe, bile acid sequestrants or niacin. In fact ACC/AHA recommend treating adults with LDL-C>4.9mmol/L (>190mmg/dL). PCSK9 monoclonal antibodies delivered as subcutaneous injections once or twice a month may be available soon in Singapore and is an excellent option, but cost may be an issue. They prevent PCSK9 from attaching to LDL receptors, leading to improved function of these receptors and LDL lowering by an impressive 40-70%. Long term clinical trials on cardiovascular outcomes are underway, but initial results are encouraging. In individuals suspected of genetic dyslipidemias, it might also be prudent to consider screening for asymptomatic cardiovascular disease.
A Specialist’s Point of View – Written by Dr. Peter Ting
Dr Peter Ting
Senior Cardiologist & Medical Director
StarMed Specialist Centre
MBBS, MRCP (UK), MPH (Harvard), FACC, FAsCC, FAMS
Dr. Ting is a senior consultant cardiologist with special interests in non-invasive imaging and management of heart valve disorders and coronary artery disease. He also plans structured lifestyle therapy programmes for patients to reverse or slow the progression of coronary artery disease, and treat other lifestyle related conditions such has hypertension, high cholesterol, diabetes and obesity. Recently, he is the first Singaporean doctor to be awarded a diplomate in the new medical field of Lifestyle Medicine, by the International Board of Lifestyle Medicine, and recognised by the American Board of Lifestyle Medicine. To fulfill his goal of making Lifestyle Medicine available to the public, he has set up a specialised clinic; the Preventive and Lifestyle Medicine Centre focuses on lifestyle prescriptions as the foundation of health management; to treat or reverse chronic diseases; and, optimise health in a sustainable manner. Dr. Ting has successfully treated many patients, improved their conditions and reduced their reliance on medications through the practice of Lifestyle Medicine.
About StarMed Specialist Centre
Founded with the vision to make private healthcare affordable and accessible for local and international patients, StarMed Specialist Centre (StarMed) is Singapore’s first private one-stop ambulatory care centre. StarMed will initially focus on cardio-vascular, digestive, minimally invasive surgeries and diagnostic services.
Located in a vibrant part of Central Singapore, StarMed spans approximately 16,000 square feet across four floors, and houses a multi-disciplinary medical centre, fully equipped day surgery centre, comprehensive diagnostic and interventional radiology centre, and endoscopy centre. The Centre also has day care beds and private rooms for patients’ convenience and comfort. StarMed is conveniently co-located with the 300-room Park Hotel Farrer Park and is situated just above Farrer Park MRT station, providing unparalleled convenience to patients.