THE IMPACT OF FAMILIAL HYPERCHOLESTEROLEMIA ON CARDIOVASCULAR DISEASE

Transcription

1 Med. Surg. J. Rev. Med. Chir. Soc. Med. Nat., Iaşi 2018 vol. 122, no. 4 INTERNAL MEDICINE - PEDIATRICS REVIEWS THE IMPACT OF FAMILIAL HYPERCHOLESTEROLEMIA ON CARDIOVASCULAR DISEASE Alexandra Maștaleru, Maria-Magdalena Leon-Constantin *, Andra Oancea, R. C. Anghel, Alexandra Jitaru, F. Mitu Grigore T. Popa University of Medicine and Pharmacy Iasi Faculty of Medicine Department of Medical Specialties (I) * Corresponding author. leon_mariamagdalena@yahoo.com THE IMPACT OF FAMILIAL HYPERCHOLESTEROLEMIA ON CARDIOVASCULAR DISEASE (Abstract): Familial hypercholesterolemia is one of the most common inherited diseases, that leads to an important cardiovascular morbidity and mortality, especially in d e- veloped countries. It is characterized by early coronary artery disease associated with chol esterol deposits that lead in time to atherosclerotic plaques, because of high levels of circula t- ing cholesterol for a long period of time. Romania is in the group of countries at high risk for cardiovascular disease, being recommended that all internal medicine doctors and cardiologists use the SCORE Risk Chart, to calculate the cardiovascular risk for the next 10 years. The causes of hypercholesterolemia are multiple. On the one hand, the exogenous intake of dietary principles with high cholesterol content is incriminated, and on the other hand is the involvement of the genetic factor. Regarding the treatment in familial hypercholesterolemia, the most recent guidelines state that statins are the mainstay of treatment, but in addition we can also use new drugs like PCSK9 inhibitors, in combination with lifestyle changes. Through this article, we want to draw attention once again to the need for hypercholesterolemia treatment, in line with the latest recommendations of the guidelines. Keywords: FAMILIAL HYPERCHOLESTEROLEMIA, SCORE RISK CHART, CARDIO- VASCULAR DISEASE. Familial hypercholesterolemia is one of the most common inherited diseases, that leads to an important cardiovascular morbidity and mortality, especially in developed countries. It is characterized by early coronary artery disease associated with cholesterol deposits that lead in time to atherosclerotic plaques, because of high levels of circulating cholesterol for a long period of time. Aging and modern lifestyles have been increasingly associated with high levels of cholesterol in people all around the world, this being one of the most important cardiovascular risk factors (1). Regarding the mentioned risk, researchers described in the last dyslipidemia guideline that was published in 2016the importance of screening in all men over 40 years and in all women over 50 years or post menopause. By screening, they refer to the evaluation of all lipid fractions (total cholesterol, HDL-cholesterol, LDLcholesterol, triglycerides) (2). Moreover, given the fact that Romania is in the group of countries at high risk for 670

2 The impact of familial hypercholesterolemia on cardiovascular disease cardiovascular disease, it is recommended that all internal medicine doctors and cardiologists use the SCORE Risk Chart, to calculate the cardiovascular risk for the next 10 years. Within the SCORE Risk Chart, it is taken into consideration the value of cholesterol, blood pressure, the smoker / non-smoking status, age and the patient gender. The main factor in calculating total cardiovascular risk through the SCORE Risk Chart is total cholesterol (3). The causes of hypercholesterolemia are multiple. The exogenous intake of dietary principles with high cholesterol content and/or the involvement of the genetic factor are incriminated. Thus, we can say that hypercholesterolemia can have monogenic or multifactorial determinism. The most common monogenic form (1/200 individuals) is familial hypercholesterolemia (4, 5). The disease is transmitted predominantly autosomal dominant (new mutations are extremely rare) and is caused by mutations in LDLR genes (60-80% of cases), APOB (1-5% of cases) and PCSK9 (0-3% of cases), in 20-40% of cases the defect remaining unknown. Differential diagnosis includes hypercholesterolemia secondary to obesity, diabetes, hypothyroidism, drugs or kidney disease, where the distribution of cases in the family is non-mandala. Also included in the differential diagnosis are autosomal recessive hypercholesterolemia (LDLRAP1 gene mutations), combined familial hyperlipidemia (associated with increased value of LDL-C and triglycerides, produced by mutations in the LPL gene) and polygenic hypercholesterolemia (determined by various genetic polymorphisms and environment side effects).genetic testing is indicated in people with a family history of hypercholesterolemia and consists of complete sequencing (including 5', 3' regions and introns) of the LDLR, APOB and PCSK9 genes (in this order). Next Generation Sequencing can check the sequence of the three genes at the same time. In negative cases, it is recommended to study polymorphisms that are associated with hypercholesterolemia (6). In heterozygous patients that are not receiving treatment, cholesterol levels typically range between 250 and 300 mg/dl and cardiovascular events develop in men by years and in women by years. On the other hand, in homozygous patients, the cholesterol levels are much higher ( mg/dl), and important atherosclerotic events start from early childhood. If left untreated, homozygous patients generally die before the age of 30 years due to accelerated severe atherosclerotic cardiovascular events (1). The latest studies show that in Europe are approximately 4.5 million people that are affected by familial hypercholesterolemia, of whom 20-25% are children and adolescents. Of those, less than 10% are diagnosed. For a better quantification of dyslipidemia, it is necessary to dose each lipid fraction: HDL-cholesterol, which has the role of cardiovascular protection, respectively LDL-cholesterol, the main factor determining the atherosclerosis process, regardless of age (7). According to the Safe heart cohort data, only 68.2% of patients with familial hypercholesterolemia younger than 18 years old are on statins, and only 41.5% of patients had LDL-C < 3.4 mmol/l(8). Patients with familial hypercholesterolemia may show clinical manifestations, like corneal arcus, xanthelasmas and xanthomas, but they should be looked after with attention, this leading to an earlier diagnosis and 671

3 Alexandra Maștaleru et al. treatment. Worldwide, familial hypercholesterolemia is underdiagnosed and undertreated, generally being detected late in adults, in part because existing diagnostic criteria are complex and not widely used outside of specialty lipid clinics (9, 10). There are described 3 different criteria for familial hypercholesterolemia diagnosis. First, there is Simon Broome criteria that includes familial history, clinical signs, cholesterol values and genetic testing (tab. I). The advantage of this criteria is that it is very easy to remember and its applicability in a day-to-day clinic is easy and effective. The disadvantage would be that Simon- Broome criteria fails to differentiate between classical familial hypercholesterolemia due to LDLR mutations and the other genetic origins of familial hypercholesterolemia such as ApoB-100 and PCSK9 (11). TABLE I Simon Broome familial hypercholesterolemia register diagnostic criteria for familial hypercholesterolemia (adapted after Singh, 2015) Criteria Description 1 Total cholesterol concentration above 7.5 mmol/l (290 mg/dl) in adults or a total cholesterol concentration above 6.7 mmol/l (260 mg/dl) in children aged less than 16 years, or low-density lipoprotein (LDL) cholesterol concentration above 4.9 mmol/l (190 mg/dl) in adults or above 4.0 mmol/l (155 mg/dl) in children 2 Tendinous xanthoma in the patient or a first-degree relative 3 DNA-based evidence of mutation in the LDLR, Apo B-100, or PCSK9 mutation 4 Family history of myocardial infarction before age 50 years in a second -degree relative or before age 60 years in a first-degree relative 5 Family history of raised total cholesterol concentration above 7.5 mmol/l (290 mg/dl) in a firstor second-degree relative or greater than 6.7 mmol/l (260 mg/dl) in child or sibling aged younger than 16 years Definite FH diagnosis requires either criteria 1 and 2 or criteria 3. Probable FH diagnosis requires either criteria 1 and 4 or criteria 1 and 5. The second criteria is Dutch Lipid Clinic Network diagnostic criteria. They are similar to the Simon Broome register criteria but require that at least one clinical criterion be met besides molecular DNA diagnosis for FH to be diagnosed (tab. II). The most important advantage of this criteria is that it addresses the molecular defect that leads to FH and this in turn will help to provide the diagnosed FH patient with a better therapeutic strategy/treatment. The disadvantages would be the lack of versatility and the fact that is very expensive (12). The third is US MedPed program diagnostic criteria, that have total cholesterol cutoffs derived from mathematical models constructed using published cholesterol levels for familial hypercholesterolemia individuals in the USA and Japan. The cutoffs consider degree of relatedness (individuals with a relative with familial hypercholesterolemia have a higher probability of having the disease) and age (as cholesterol levels increase with age) (11, 12) (tab. III). Reducing cholesterol levels is essential and can be achieved by lifestyle changes and by using pharmacological agents such as statins or newer therapy such as inhibitors of proprotein convertase subtilisinkexin type 9 (13). In addition, many studies 672

4 The impact of familial hypercholesterolemia on cardiovascular disease suggest that for a better lowering of the LDL-cholesterol, a decrease in triglyceride and lipoprotein (a) would reduce the risk of ischemic cardiopathy (14). TABLE II Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia (adapted after Singh, 2015) Criteria Points Family history First-degree relative with known premature (men <55 years; women <60 years) 1 coronary and vascular disease, or first-degree relative with known LDL-C above the 95th percentile First-degree relative with tendinous xanthomata and/or arcus corneal is, 2 or children aged less than 18 years with LDL-C above the 95th percentile Clinical history Patient with premature (men <55 years; women <60 years) cerebral or peripheral vascular disease 1 Patient with premature (men <55 years; women <60 years) coronary a rtery disease 2 Physical exam Arcus corneal is prior to age 45 years 4 Tendinous xanthoma 6 Cholesterol levels mmol/l(mg/dl) LDL-C ( ) 1 LDL-C ( ) 3 LDL-C ( ) 5 LDL-C 8.5 (329) 8 DNA tests Functional mutation in the LDLR gene 8 Definite FH diagnosis requires more than 8 points. Probable FH diagnosis requires 6 8 points. Possible FH diagnosis requires 3 5 points. TABLE III US MedPed program diagnostic criteria for probable heterozygous familial hypercholesterolemia (adapted after Al-Rasadi, 2014) Total cholesterol cut points mmol/l(mg/dl) Age (years) First-degree relative with FH Second-degree relative with FH Third-degree relative with FH General population < (220) 5.9 (230) 6.2 (240) 7 (270) (240) 6.5 (250) 6.7 (260) 7.5 (290) (270) 7.2 (280) 7.5 (290) 8.8 (340) (290) 7.8 (300) 8 (310) 9.3 (360) Regarding the treatment in familial hypercholesterolemia, the most recent guidelines state that statins are the mainstay of treatment, in combination with lifestyle changes. In a cohort study realized on 2,146 patients diagnosed with familial hypercholesterolemia but without coronary heart disease, after a follow-up of 8.5 years, the treatment with statins reduced the risk for coronary heart disease by 76%. 673

5 Alexandra Maștaleru et al. According to the guidelines, if the patient does not reach the LDL-cholesterol targets with the highest recommended or tolerable dose of statin, it should be considered the combination with ezetimibe. If the patients still do not reach the LDL-cholesterol targets after ezetimibe and statins, bile acid sequestrants can be considered (15). Monoclonal antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9) are proteases that are synthesized in the liver and small intestine. PCSK9 is secreted from liver cells, binds to the LDL receptor and is subsequently internalized together with the LDL receptor and targets the receptor for lysosomal degradation. Therefore, the inhibition of PCSK9 determines an increased expression of LDL receptors on hepatocytes and decreased LDL-C levels in the circulation. This leads to the fact that patients with the loss of function mutations in the PCSK9 gene have very reduce LDL-C level, whereas the gain of function mutations cause familial hypercholesterolemia. Commercially available are two monoclonal antibodies that inhibit PCSK9, alirocumab and evolocumab (15). CONCLUSIONS In our study we considered the importance of the implication of nonmodifiable risk factors (age, gender, genetic factors) in the development of cardiovascular disease, being required a more stringent control of the modifiable factors (blood pressure, blood glucose, cholesterol, stress). Through this article, we want to draw attention once again to the need for hypercholesterolemia treatment, in line with the latest recommendations of the guidelines. 674 REFERENCES 1. Kayikcioglu M, Tokgozoglu L, Dogan V, Ceyhan C, Tuncez A, Kutlu M et al. What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)? Atheroscl 2018; 277: Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H et al ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atheroscl 2016; 253: Gierach M, Gierach J, Junik R. Evaluation of lipid profiles in patients with metabolic syndrome according to cardiovascular risk calculated on the basis of the SCORE chart. Endokrynol Pol 2016; 67(3): Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG.Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.j Clin Endocrinol Metab. 2012; 97(11): Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS 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(45): Knowles JW, Rader DJ, Khoury MJ. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing.JAMA. 2017; 318(4): Ibarretxe D, Rodríguez-Borjabad C, Feliu A, Bilbao JÁ, Masana L, Plana N. Detecting familial hypercholesterolemia earlier in life by actively searching for affected children: The DECOPIN project. Atheroscl 2018; 278:

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