Lipoprotein disorders are clinically important due to the of the role of lipoproteins in atherogenesis and the associated risk of atherosclerotic cardiovascular disease (ASCVD). For patients with known ASCVD (secondary prevention), cholesterol-lowering leads to a consistent reduction in cardiovascular mortality and cardiovascular events in men and women and middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data on reduction in atherosclerotic cardiovascular disease events with statin drugs is also well documented. Patients with triglyceride levels of more than 1000 mg/dl are at increased risk of acute pancreatitis.
Lipoproteins comprise lipids and protein and can be transported in plasma as such, for delivery of cholesterol, triglycerides, and fat-soluble vitamins to the respective organs as needed. In the past, lipoprotein disorders were the domain of specialized lipid physicians. However, the benefit of statin drugs, especially in reducing cardiovascular (CV) events has facilitated the treatment of hypercholesterolemia by family and internal medicine physicians. Despite this paradigm shift, the number of patients who could benefit from lipid-reducing drugs and who are not treated appropriately continues to be a major concern. Hence, the timely evaluation, diagnosis, and treatment of lipoprotein disorders are of primary importance in the practice of medicine. This article reviews a practical approach to hypercholesterolemia and its management. 
High cholesterol can be defined as a LDL-cholesterol greater than 190 mg/dL, greater than 160 mg/dL with one major risk factor, or greater than 130 mg/dL with two cardiovascular risk factors. The important risk factors include:
There are genetic and acquired causes of hypercholesterolemia. The classical genetic disorder is familial hypercholesterolemia due to mutations in the LDL-receptor gene resulting in LDL-C greater than 190 mg/dl in heterozygotes and greater than 450 mg/dl in homozygotes. This defect in the LDL receptor accounts for at least 85% of familial hypercholesterolemia. Familial hypercholesterolemia is caused by loss-of-function mutations in the gene encoding the LDL receptor. The reduction in LDL receptor activity in the liver results in a reduced rate of clearance of LDL from the circulation. The plasma level of LDL increases to a level such that the rate of LDL production equals the rate of LDL clearance by residual LDL receptors as well as non-LDL receptor mechanisms. More than 1600 mutations have been reported in association with familial hypercholesterolemia. The elevated levels of LDL-C in familial hypercholesterolemia are primarily due to a delayed removal of LDL from the blood. Because the removal of IDL is also delayed, the production of LDL from IDL is also increased. Individuals with two mutated LDL receptor alleles (familial hypercholesterolemia homozygotes or compound heterozygotes) have much higher LDL-C levels than those with one mutant allele (familial hypercholesterolemia heterozygotes).
Other genetic causes of familial hypercholesterolemia include:
All of the above genetic causes are transmitted in an autosomal dominant mode. Another rare genetic cause is autosomal recessive hypercholesterolemia, due to a mutation in the LDL receptor adaptor protein resulting in defective endocytosis of the LDL receptors. However, the commonest cause is polygenic hypercholesterolemia which results from an interaction of unidentified genetic factors compounded by a sedentary lifestyle and an increased intake of saturated and trans-fatty acids. Secondary causes include hypothyroidism, nephrotic syndrome, cholestasis, pregnancy, and certain drugs like cyclosporine, thiazide, and diuretics. These can easily be excluded by history, physical examination, and laboratory tests. It is believed that the elevated LDL particles permeate the vascular intima and get trapped by proteoglycans in the intima. In the intima, LDL is oxidatively modified and promote inflammation and fatty streak formation. Atherogenesis evolves through a fibrous plaque to the mature lesion with plaque rupture culminating in a CV event.
According to the Center for Disease Control and Prevention (CDC), 73.5 million or 31.7% of adults in the United States have high levels of LDL-C and are at twice the risk for heart disease than people with normal levels. Only 48.1% are receiving treatment to lower LDL-C levels. Recent data suggests that the classic disorder, familial hypercholesterolemia has a prevalence of estimate of 1/300,000 as homozygous and 1/250 as heterozygote. In certain populations such as the French Canadians, Lebanese, and Afrikaners it could be as high as 1/100.
In familial hypercholesterolemia, there is either a problem with the LDL receptor or it is missing. Without the receptor, uptake of cholesterol into the liver is not possible. The liver usually processes two-thirds of the circulating LDL. Hundreds of mutations of the LDL receptor have been identified, which express themselves as hypercholesterolemia.
Both history and physical examination can yield useful information. If there is a positive family history of premature atherosclerotic cardiovascular disease, constructing a family tree is useful. Also asking about secondary causes such as smoking, diabetes, dietary intake of total calories, saturated, and trans fats, physical activity, drug therapies, and symptoms of CV disease (angina pectoris, intermittent claudication, transient ischemic attacks) is also important. On physical examination look for features of hypothyroidism (bradycardia, dry skin, delayed reflexes) Nephrotic syndrome (edema, ascites), cholestasis (jaundice, hepatomegaly). In patients with hypercholesterolemia, palpitate all pulses and elicit carotids and femoral bruits. Also, carefully examine the tendon xanthoma (Achilles tendon and extensor tendons on the dorsum of the hand), xanthelasma, and arcus senilis if the patient is younger than 50 years old. In suspected familial hypercholesterolemia patients, a careful examination of the heart for supra-valvar aortic stenosis due to atheroma deposition is warranted.
A plasma lipid profile should be measured in all adults older than 40 years, preferably after a 10 to 12-hour overnight fast. The lipid profile reports the total cholesterol, triglycerides, and HDL-cholesterol, and calculates the LDL-cholesterol by the Friedewald Equation:
This formula (the Friedewald formula) is accurate if test results are obtained on fasting plasma and if the triglyceride level does not exceed 200 mg/dL. By convention, it cannot be used if the triglyceride level is greater than 400 mg/dL since high triglycerides alter the TG/5 or VLDL-C. Many methods can directly measure LDL-C. Secondary causes can be excluded by doing the following tests: TSH (hypothyroidism), glucose (diabetes), urinalysis and serum albumin (nephrotic syndrome), and bilirubin and alkaline phosphatase (cholestasis). Ideally, if there is an abnormal lipid profile (high cholesterol), the test should be repeated within 2 weeks to confirm the diagnosis before embarking on lifelong therapy.
The cornerstone of treatment of hypercholesterolemia is a healthy lifestyle, an optimum weight, no smoking, exercising for 150 minutes per week, and a diet low in saturated and trans-fatty acids and enriched in fiber, fruit, and vegetables and fatty fish. Plant stanols at a dose of 2 g/d can help reduce LDL-C levels. The drug class of choice is the statin which can lower LDL-C from 22% to 50%. Also, they have been shown to reduce cardiovascular events in both primary and secondary prevention trials. The major side effects are elevated transaminases, myalgia, and myopathy and new-onset diabetes. If transaminases exceed three times the upper limit of normal, the statin dose should be reduced, or a lower dose of another statin should be used. Myopathy is a serious problem since it can result in rhabdomyolysis and acute renal failure. Certain drugs in combination with statins increase this risk. These include gemfibrozil, macrolide antibiotics azole antifungals, protease inhibitors, cyclosporine, nefazodone, and other CYP3A4 inhibitors, and multisystem diseases. However, some patients cannot achieve adequate control of their LDL-C levels even with high-dose statin therapy and require additional drugs. Cholesterol absorption inhibitors (ezetimibe) and/or bile acid sequestrants are the next-line of drugs given their safety in combination with statins. Niacin in combination with the above can be used to further lower LDL-C in primary prevention but not in patients with atherosclerotic cardiovascular disease. Currently, heterozygous FH patients whose LDL-C levels remain markedly elevated (more than 200 mg/dL with cardiovascular disease or more than 300 mg/dL without CVD) on maximally tolerated drug therapy are candidates for LDL apheresis. This is a physical method of purging the blood of LDL in which the LDL particles are removed selectively from the circulation. Usually, LDL apheresis is performed every 2 weeks. A new class of drugs, PCSK9 inhibitors (monoclonal antibodies), can lower LDL-C up to 60% on statin therapy and are approved for use in FH and patients on statin therapy not at their goal.
Treatment of heterozygotes with HMG-CoA reductase inhibitors may normalize LDL levels. However, achieving optimal levels may require one of the combinations involving reductase inhibitors, niacin, bile acid sequestrants, and ezetimibe. Levels of LDL cholesterol less than 100 mg/dL can be obtained with combinations of these drugs in some patients. Treatment of individuals with homozygosity or combined heterozygosity is challenging. Partial control may be achieved with medications including antisense oligonucleotide directed at Apo B-100 synthesis, inhibition of microsomal triglyceride transfer protein, and ezetimibe. Statins and monoclonal antibodies directed at proprotein convertase subtilisin/kexin type 9 (PCSK9) protein are useful if some residual receptor activity is present and there is no null mutation. LDL apheresis in conjunction with medications can be very effective. Striking reduction of LDL levels is observed after liver transplantation, illustrating the important role of hepatic receptors in LDL metabolism.
In conclusion, hypercholesterolemia is a mammoth problem facing us, and it behooves us as health care professionals to get more patients on efficacious therapies like statins which are cost-effective since they are now largely generic. The optimum LDL-C for the population is less than 100mg/dL. In patients with atherosclerotic cardiovascular disease, the goal should be less than 70 mg/dl or a 50% reduction in LDL-C. For others, the goal should be an LDL-C less than 100 mg/dl or a 30% to 50% reduction in LDL-C.
Besides physicians, the role of the pharmacist, nurse and physical therapist are critical in the management of hypercholesterolemia. The nurse is an ideal position to educate the patient about changes in lifestyle, eating a healthy diet and resuming an active lifestyle. The pharmacist should ensure compliance with the statin medications and offer antismoking aids. Further, the pharmacist should also be aware of the side effects of statins like muscle pain and liver damage; and ensure that regular blood work is performed.
The patient should enroll in an exercise program and achieve a healthy body weight. Patients who fail to lower cholesterol with the above measures should be referred to a bariatric surgeon.  (level V)
With the availability of the statins, adverse effects of hypercholesterolemia have been decreased. More important, if the lifestyle is altered, then there is a significant improvement in body weight, hypertension, and diabetes. Cessation of smoking is also very important in improving outcomes. Countless studies have shown that when hypercholesterolemia is appropriately managed, the outcomes are good. (Level II)
|||Radaelli G,Sausen G,Cesa CC,Portal VL,Pellanda LC, Secondary Dyslipidemia In Obese Children - Is There Evidence For Pharmacological Treatment? Arquivos brasileiros de cardiologia. 2018 Aug 23 [PubMed PMID: 30156604]|
|||Zawacki AW,Dodge A,Woo KM,Ralphe JC,Peterson AL, In pediatric familial hypercholesterolemia, lipoprotein(a) is more predictive than LDL-C for early onset of cardiovascular disease in family members. Journal of clinical lipidology. 2018 Jul 31 [PubMed PMID: 30150142]|
|||Wiegman A, Lipid Screening, Action, and Follow-up in Children and Adolescents. Current cardiology reports. 2018 Aug 9 [PubMed PMID: 30090990]|
|||Dainis AM,Ashley EA, Cardiovascular Precision Medicine in the Genomics Era. JACC. Basic to translational science. 2018 Apr [PubMed PMID: 30062216]|
|||Sturm AC,Knowles JW,Gidding SS,Ahmad ZS,Ahmed CD,Ballantyne CM,Baum SJ,Bourbon M,Carrié A,Cuchel M,de Ferranti SD,Defesche JC,Freiberger T,Hershberger RE,Hovingh GK,Karayan L,Kastelein JJP,Kindt I,Lane SR,Leigh SE,Linton MF,Mata P,Neal WA,Nordestgaard BG,Santos RD,Harada-Shiba M,Sijbrands EJ,Stitziel NO,Yamashita S,Wilemon KA,Ledbetter DH,Rader DJ, Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. Journal of the American College of Cardiology. 2018 Aug 7 [PubMed PMID: 30071997]|
|||Mytilinaiou M,Kyrou I,Khan M,Grammatopoulos DK,Randeva HS, Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management. Frontiers in pharmacology. 2018 [PubMed PMID: 30050433]|
|||Rawshani A,Rawshani A,Franzén S,Sattar N,Eliasson B,Svensson AM,Zethelius B,Miftaraj M,McGuire DK,Rosengren A,Gudbjörnsdottir S, Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England journal of medicine. 2018 Aug 16 [PubMed PMID: 30110583]|
|||Ferrières J, Familial hypercholesterolaemia: a look toward the East. Kardiologia polska. 2018 [PubMed PMID: 29905363]|
|||Danese MD,Sidelnikov E,Kutikova L, The prevalence, low-density lipoprotein cholesterol levels, and treatment of patients at very high risk of cardiovascular events in the United Kingdom: a cross-sectional study. Current medical research and opinion. 2018 Aug [PubMed PMID: 29627994]|
|||Winter MP,Wiesbauer F,Blessberger H,Pavo N,Sulzgruber P,Huber K,Wojta J,Distelmaier K,Lang IM,Goliasch G, Lipid profile and long-term outcome in premature myocardial infarction. European journal of clinical investigation. 2018 Jul 30 [PubMed PMID: 30062727]|
|||Zuo HJ,Deng LQ,Wang JW, [Current status and the consistency analysis of using two criteria for decision making of aspirin use for the primary prevention of ischemic cardiovascular disease in outpatients]. Zhonghua xin xue guan bing za zhi. 2018 Apr 24 [PubMed PMID: 29747326]|
|||Migliara G,Baccolini V,Rosso A,D'Andrea E,Massimi A,Villari P,De Vito C, Familial Hypercholesterolemia: A Systematic Review of Guidelines on Genetic Testing and Patient Management. Frontiers in public health. 2017 [PubMed PMID: 28993804]|
|||Tomlinson B,Chan JC,Chan WB,Chen WW,Chow FC,Li SK,Kong AP,Ma RC,Siu DC,Tan KC,Wong LK,Yeung VT,But BW,Cheung PT,Fu CC,Tung JY,Wong WC,Yau HC, Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin. Hong Kong medical journal = Xianggang yi xue za zhi. 2018 Aug [PubMed PMID: 30100583]|
|||McPherson R, The Cardiovascular Burden of Undiagnosed Familial Hypercholesterolemia: Need to Modify Guidelines to Encourage Earlier Diagnosis and Therapy. The Canadian journal of cardiology. 2018 Jul 11 [PubMed PMID: 30093301]|
|||Harada-Shiba M,Arai H,Ishigaki Y,Ishibashi S,Okamura T,Ogura M,Dobashi K,Nohara A,Bujo H,Miyauchi K,Yamashita S,Yokote K, Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017. Journal of atherosclerosis and thrombosis. 2018 Aug 1 [PubMed PMID: 29877295]|
|||Castelnuovo G,Pietrabissa G,Manzoni GM,Corti S,Ceccarini M,Borrello M,Giusti EM,Novelli M,Cattivelli R,Middleton NA,Simpson SG,Molinari E, Chronic care management of globesity: promoting healthier lifestyles in traditional and mHealth based settings. Frontiers in psychology. 2015 [PubMed PMID: 26528215]|
|||Fidelix YL,Farias Júnior JC,Lofrano-Prado MC,Guerra RL,Cardel M,Prado WL, Multidisciplinary intervention in obese adolescents: predictors of dropout. Einstein (Sao Paulo, Brazil). 2015 Jul-Sep [PubMed PMID: 26466062]|
|||Vickery AW,Bell D,Garton-Smith J,Kirke AB,Pang J,Watts GF, Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services. Heart, lung [PubMed PMID: 25130889]|
|||Gorina M,Limonero JT,Álvarez M, Effectiveness of primary healthcare educational interventions undertaken by nurses to improve chronic disease management in patients with diabetes mellitus, hypertension and hypercholesterolemia: A systematic review. International journal of nursing studies. 2018 Jun 30 [PubMed PMID: 30007585]|