scholarly journals Familial Hypercholesterolemia: Three “under” (Understood, Underdiagnosed, and Undertreated) Disease

Author(s):  
Vladimir O. Konstantinov

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among “healthy” population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ingunn Narverud ◽  
Jeaninen R van Lennep ◽  
Jacob J Christensen ◽  
Jorie Versmissen ◽  
Jon M Gran ◽  
...  

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused primarily by mutations in the low density lipoprotein (LDL) receptor gene. FH patients have increased total- and LDL cholesterol leading to accelerated atherosclerosis and premature cardiovascular disease (CVD). In an FH pregnancy the absolute rise in lipid levels are often much higher than in healthy pregnancies, and this maternal hypercholesterolemia may thus contribute to an unfavorable in utero environment potentially increasing susceptibility of adult CVD. Few studies have investigated whether maternal FH is associated with an unfavorable phenotype in offspring compared with paternal FH inheritance. Hypothesis: The aim of the present study was to investigate the impact of maternal vs. paternal FH on pre-treated plasma lipids. In addition, the effect of LDL receptor mutation types and Family history of early CVD in FH children was evaluated Methods: We included 1063 children with FH (0-19 years) in the study. Five-hundred had inherited FH maternally and 563 paternally. Furthermore, 624 children with FH had an LDL receptor negative mutation and 332 of the FH children had an FH grandparent suffering from early CVD whereas the remaining children had an FH grandparent with late or no CVD. Differences were tested for using a random intercept mixed model taking account for between-family variation. Results: Children with maternal FH did not have different levels of total-, LDL- or HDL-cholesterol, triglycerides, apoA1, apoB, lipoprotein (a) compared with children With paternal FH. Moreover, children with LDL receptor negative mutations had higher levels of total- and LDL cholesterol in addition to apoB, and concomitantly lower levels of HDL-cholesterol and apoA-1 than children with other LDL receptor mutations. Finally, children with an FH grandparent with early CVD had significant higher LDL-cholesterol levels than children without. Conclusions: Maternal FH does not lead to a more unfavorable phenotype in untreated FH children. However, both FH children with LDL receptor negative mutation and FH children with early CVD in family had a more unfavorably phenotype. Hence statin treatment should potentially be initialized earlier in this group.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
V Konstantinov ◽  
T Kuznetsova ◽  
V Korneva ◽  
M Serebrenitskaya

Abstract Familial hypercholesterolemia (FH) is one of the most common inherited diseases that lead to premature atherosclerosis and coronary heart disease (CHD). Aim of the study to ascertain genetic and environmental factors influencing the time course of FH during a 15-year follow-up in a large FH cohort from the North-West region of Russia. We screened more than 1ehz746.0302 high risk patients in order to reveal FH in Saint-Petersburg and Petrozavodsk using DLCN criteria. In most patients DNA analysis was also performed. Definite FH (≥8 according to DLCN) was found in 315 patients (221 - in Saint-Petersburg, 94 - in Petrozavodsk). These patients were followed-up for 15 years and more. CHD was more frequent in male patients, patients older than 60 years of age and was associated with higher levels of total cholesterol, LDL cholesterol, lower levels of HDL cholesterol, arterial hypertension, smoking and higher DLCN scoring. Patients without CHD had lowest LDL/HDL ratio (5.2±0.45) whereas patients with stable and progressive CHD had LDL/HDL ratio - 7.7±0.89 and 10.4±0.78, respectively (p≤0.05). Genetic study revealed only 1 homozygous patient and 1 patient with apoB-100 (FDP) gene mutation. Only 1 case of FH-North Karelia mutation that is typical for Finland was found in Petrozavodsk. Most of revealed mutations in LDL-receptor gene were unique i.e. found only in 1 family. This suggest the absence of a strong founder effect associated with FH in the North-West Region of Russia. Due to high heterogeneity of FH-causing mutations we failed to establish interrelations between type of LDL-receptor gene mutations and severity of atherosclerosis and CHD time course. 14% of FH patients didn't take any hypolipidemic medications at the onset of the follow-up, whereas 61% took statins and 25% statin + ezetimibe. Homozygous patient was treated both with statin, ezetimibe, evolocumab and LDL-apheresis. Nevertheless, 26% of the treated group didn't achieve the target LDL-C levels. It is interesting that 40% of patients who didn't reach LDL-goals were current smokers (compared with 5% of patients who reached LDL-goals). 33 patients (10.5%) died during the follow-up mostly due to cardiovascular complications. Death rates in FH patients were strongly associated with age, male sex, LDL/HDL ratio, smoking and effectiveness of hypolipidemic treatment. FH is strongly associated with high CHD risk; the time course of FH is much more favourable in females, in patients with low LDL/HDL ratio and free of other modifiable risk factors. Type of LDL-receptor gene mutation doesn't influence lipid levels or clinical manifestations of FH.


2008 ◽  
Vol 54 (6) ◽  
pp. 1038-1045 ◽  
Author(s):  
Gilles Lambert ◽  
Nicolas Ancellin ◽  
Francesca Charlton ◽  
Daniel Comas ◽  
Julia Pilot ◽  
...  

Abstract Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. Methods: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. Results: We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). Conclusions: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol–lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.


1999 ◽  
Vol 45 (9) ◽  
pp. 1424-1430 ◽  
Author(s):  
Sung Han Kim ◽  
Ji Hyun Bae ◽  
Jae Jin Chae ◽  
Un Kyung Kim ◽  
Seong-Joon Choe ◽  
...  

Abstract Background: The LDL receptor is a cell-surface protein that regulates plasma cholesterol by specific uptake of LDL particles from the blood circulation. Familial hypercholesterolemia (FH) results from defective catabolism of LDL, which is caused by mutations in the LDL-receptor gene. Methods: For the rapid and reliable detection of large rearrangements in the LDL-receptor gene, we established a screening method based on long-distance PCR as an alternative to Southern-blot hybridization. Using long-distance PCR, 45 unrelated Korean subjects heterozygous for FH were screened to assess the frequency and nature of major structural rearrangements in the LDL-receptor gene. Results: Two different deletion mutations, FH6 (same type as FH3 and FH311) and FH 32, were detected in four families by long-distance PCR. Detailed restriction mapping and sequence analysis showed that FH6 was a 5.71-kb deletion extending from intron 8 to intron 12 and that FH32 was a 2-kb deletion extending from intron 6 to intron 7. Sequence analysis for the breakpoints of all deletions detected in Korean FH patients showed that only the left arms of the Alu repetitive sequences were involved in the deletion event. Conclusions: The screening method based on long-distance PCR provides a powerful strategy for the detection of large rearrangements in the LDL-receptor gene and is a rapid and reliable screening alternative to Southern-blot hybridization.


2016 ◽  
Vol 62 (7) ◽  
pp. 930-946 ◽  
Author(s):  
Børge G Nordestgaard ◽  
Anne Langsted ◽  
Samia Mora ◽  
Genovefa Kolovou ◽  
Hannsjörg Baum ◽  
...  

Abstract AIMS To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1–6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; −0.2 mmol/L (8 mg/dL) for total cholesterol; −0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; −0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). CONCLUSIONS We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.


2018 ◽  
Vol 59 (6) ◽  
pp. 982-993 ◽  
Author(s):  
Romeo Papazyan ◽  
Xueqing Liu ◽  
Jingwen Liu ◽  
Bin Dong ◽  
Emily M. Plummer ◽  
...  

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.


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