Homozygous Form Of Familial Hypercholesterolemia Research Articles

Management of Familial Hypercholesterolemia with Special Emphasis on Evinacumab.

Familial hypercholesterolemia (FH) is an underdiagnosed disease that contributes to a significant number of cardiovascular incidents through high serum Low-Density Lipoprotein Cholesterol (LDL-C) values. Its treatment primarily requires healthy lifestyle and therapy based on statins, ezetimibe and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); however, there are also new treatment options that can be used in patients who do not respond to therapy, among which we highlight evinacumab. Elevated LDL-C values, together with clinical manifestations associated with cholesterol deposition (e.g., tendon xanthomas, xanthelasma and arcus cornealis) and family history are the main elements in the diagnosis of FH. Pathognomonic signs of FH include extensor tendon xanthomas; however, their absence does not exclude the diagnosis. Elevated LDL-C levels lead to premature Atherosclerotic Cardiovascular Disease (ASCVD), which is why early diagnosis and treatment of FH is essential. Evinacumab, a novelty in pharmacological practice, having a complex mechanism of action, causes desirable changes in lipid parameters in patients with homozygous form of familial hypercholesterolemia (HoFH). This review collects and summarizes the most important aspects of the new drug, especially being a discovery in the treatment of HoFH, giving these patients hope for a longer and more comfortable life.

Pregnancy in homozygous familial hypercholesterolemia – A case series

Background and Aims : Familial hypercholesterolemia (FH) is an autosomal codominant lipid metabolism disorder mostly caused by defects of a low-density lipoprotein (LDL) receptor gene. This condition results in lifelong elevation of plasmatic LDL-cholesterol (LDL-C) levels, followed by premature atherosclerosis and an increase in cardiovascular risk. Management of women suffering from the homozygous form of FH (HoFH) poses difficult demands on physicians, regarding specific phases of their patients' lives.

Clinical Evaluation Of Evolocumab For The Treatment Of Homozygous Familial Hypercholesterolemia In Chinese Patients.

Evolocumab, which can lower low-density lipoprotein (LDL) cholesterol levels by approximately 60% and prevent cardiovascular events in patients with cardiovascular disease, is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Some studies have investigated its efficacy and safety in the treatment of the homozygous form of familial hypercholesterolemia (HoFH), and others have focused on its efficacy and safety in Asians with high cardiovascular risk. Although no direct evolocumab clinical trials have been conducted in Chinese HoFH patients, its efficacy and safety in the Chinese population should be similar to those in other ethnic groups.

General characteristics of pacients with homozygous form of familial hypercholesterolaemia in the Czech Republic

Aim: Aim of project was to define general characteristics of patients with homozygous form of familial hypercholesterolaemia in the Czech Republic.

General Characteristics of Patients with Homozygous Form of Familial Hypercholesterolaemia in the Czech Republic

Aim: Aim of project was to define general characteristics of patients with homozygous form of familial hypercholesterolaemia in the Czech Republic. Methods: Set of hoFH patients has 19 patients, including 5 ceased. Patients were selected by the genetic testing or phenotypic criteria for hoFH. Data were extracted from the Czech national FH registry (MedPed). Results: Median of age at diagnosis was 30,0; R(7-63) years. Baseline total cholesterol (T-C) level had median 12.85; R(6.4-22.8)mmol/l and LDL-cholesterol (LDL-C) 10.27; R(4.29-21.26)mmol/l. 18 homozygotes were confirmed by genotyping – 77.8% of patients had LDLR/LDLR mutation and 22.2% had apoB/apoB mutation. All of the patients with apoB mutation are true homozygotes, while only 4 patients with LDLR mutation were true homozygotes and 10 patients were compound heterozygotes. There were no double heterozygotes. Premature atherosclerotic vascular disease was diagnosed in 74%, xanthomas in 37%, arcus lipoides corneae in 11% and xanthelasma in 16% cases. 5 patients died, median age of death was 45; R(32-68) years. All patients were treated with statins, 93% had a statin-ezetimibe combination, 50% were on triple therapy with PCSK9-i, 5 patients had regular LDL-apheresis. Median of on-treatment LDL-C was 3.64; R(1.04-6.03)mmol/l. Patients with LDLR/LDLR mutation compared to apoB/apoB homozygotes have better on-treatment levels of LDL-C and T-C, even though the baseline LDL-C and T-C levels were higher. 33% patients reached LDL-C targets. Conclusions: Our study demonstrated important clinical and laboratory differences between LDLR and apoB FH homozygous individuals including target values attainment variability.

Nonclinical Pharmacology/Toxicology Study of AAV8.TBG.mLDLR and AAV8.TBG.hLDLR in a Mouse Model of Homozygous Familial Hypercholesterolemia.

The homozygous form of familial hypercholesterolemia (HoFH) is an excellent model for developing in vivo gene therapy in humans. The success of orthotropic liver transplantation in correcting the metabolic abnormalities in HoFH suggests that the correction of low-density lipoprotein receptor (LDLR) expression in hepatocytes via gene therapy should be sufficient for therapeutic efficacy. Vectors based on adeno-associated virus serotype 8 (AAV8) have been previously developed for liver-targeted gene therapy of a number of genetic diseases, including HoFH. In preparation for initiating a Phase 1 clinical trial of AAV8-mediated LDLR gene therapy for HoFH, a combined pharmacology/toxicology study was conducted in a mouse model of HoFH. No dose-limiting toxicities were found at or below 6.0 × 1013 GC/kg. Therefore, the maximally tolerated dose is greater than the highest dose that was tested. Mild and transient liver pathology was noted at the highest dose. Therefore, the no effect dose was greater than or equal to the middle dose of 7.5 × 1012 GC/kg. The minimally effective dose was determined to be ≤7.5 × 1011 GC/kg, based on stable reductions in cholesterol that were considered to be clinically significant. This translates to a therapeutic window of ≥80-fold for the treatment of HoFH.

Familial Hypercholesterolemia: Defective Binding of Lipoproteins to Cultured Fibroblasts Associated with Impaired Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity

Abstract Monolayers of cultured fibroblasts from normal human subjects bind 125I-labeled low-density lipoproteins with high affinity and specificity. High affinity binding of similar magnitude was not observed in cells from five unrelated subjects with the homozygous form of familial hypercholesterolemia. In normal cells incubated at 37°, the binding sites were saturated at a low-density lipoprotein concentration of 20 μg/ml. A maximum of approximately 250,000 molecules could be bound to each cell. Whole serum and very-low-density lipoproteins displaced 125I-labeled low-density lipoproteins from the binding sites, but high-density lipoproteins, the lipoprotein-deficient fraction of serum, and abetalipoproteinemic serum did not. This binding appears to be a required step in the process by which low-density lipoproteins normally suppress the synthesis of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. The demonstration of a defect in binding of low-density lipoproteins to cells from subjects with the homozygous form of familial hypercholesterolemia appears to explain the previously reported failure of lipoproteins to suppress the synthesis of this enzyme and hence may account for the overproduction of cholesterol that occurs in these cultured cells.

LDL-apheresis as treatment of severe familial hypercholesterolemia

Autosomal dominant hypercholesterolemia is caused by mutations in genes that encode for either the receptor or ligand of Low Density Lipoproteins (LDL). The rare homozygous form of familial hypercholesterolemia (FH) is characterized by severely elevated plasma cholesterol levels (4–5x normal), disfiguring xanthomas in skin and tendons, but more importantly, severe and premature coronary artery disease. Without treatment most of these patients die before adulthood from coronary heart disease. Liver transplantation has been performed to provide LDLreceptors and thereby restore the clearance of LDL from plasma, but this procedure has the obvious disadvantage of immunosuppressive therapy. The preferred way to treat these patients is selective LDL apheresis to remove these cholesterol containing particles from plasma. Several systems have been developed for this purpose: immuno-absorption columns, chemo absorption onto dextran sulphate cellulose beads (Kaneka), heparin precipitation (HELP system) and the Direct Absorption of Lipoproteins (DALI) system. These systems are able to decrease the plasma level of LDL in 2–3 h by more than 60%, and because of the rebound of the plasma

Preimplantation genetic diagnosis for familial hypercholesterolaemia: a commentary on the recent HFEA decision

The Human Fertilisation and Embryology Authority have recently granted a licence to perform preimplanation genetic diagnosis (PGD) for the homozygous form of familial hypercholesterolaemia (FH), explicitly excluding its use for the heterozygous form. The grounds for such decisions centre on how serious a condition is thought to be as well as on the availability of effective treatment, and decisions are made on a case-by-case basis. The case for licensing homozygous FH is discussed and compared with other cases, and the case for making a distinction between PGD for homozygous and heterozygous FH is also examined. Testing for homozygous FH raises difficult issues of non-disclosure of results for heterozygous FH. Fears that this decision may represent a ‘slippery slope’ to more widespread testing are argued to be overstated.

Clinical applications of long-term LDL-apheresis on and beyond refractory hypercholesterolemia

Premature coronary heart disease (CHD) can result from high LDL cholesterol levels even in the absence of any other risk factors. A striking example is found in children who have the homozygous form of familial hypercholesterolemia (FH) with extremely high levels of LDL-cholesterol, and severe atherosclerosis and CHD often develop during the first decades of life. LDL-apheresis was developed for the treatment of severe type of FH patients who are resistant to lipid-lowering drug therapy. Clinical efficacy and safety of the therapeutic tool which directly removes LDL from circulation have already been established in the treatment for refractory hypercholesterolemia in FH patients. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate column. In addition to benefits derived from the stabilization or regression of arterial lesions, we highlight other possible clinical applications of LDL-apheresis. However, most of these clinical benefits came from case reports or retrospective studies. Mechanisms related these clinical improvement remain unclear, and prospective randomized controlled trials should be performed for the new clinical indications of LDL-apheresis.

Apheresis Technology for Prevention and Regression of Atherosclerosis

Familial hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism, which is due to a deficiency in low-density lipoprotein (LDL) receptors. The homozygous form of FH is especially liable to coronary artery disease (CAD) in youth because of the very high LDL-cholesterol levels. It is resistant to drug therapy, and LDL-apheresis is the only practical way of treatment for these patients. Some patients with heterozygous FH also have high LDL-cholesterol levels that cannot be brought down into the optimum range by any combination drug therapy. We have treated or are treating 10 homozygous and 28 heterozygous FH patients in our hospital or in affiliated hospitals expert in blood purification. Among the 10 homozygous patients, 2 died of myocardial infarction. Only one young female patient is still free of symptoms, and the other patients have been suffering from regurgitation through the aortic valve although they have not experienced myocardial infarction. Rapid rebound of LDL-cholesterol after each apheresis treatment limits the period during which LDL-cholesterol is in the optimum range. The use of atorvastatin at a high dose (40 mg/day) was attempted to suppress this rebound. In contrast with good results in receptor-defective-type patients, receptor-negative-type patients did not show a response in LDL-cholesterol levels to the statin therapy although there was a slight increase in high-density lipoprotein (HDL)-cholesterol with a decrease in very-low-density lipoprotein-triglyceride and -cholesterol. Follow-up study of the patients with heterozygous FH revealed that LDL-apheresis was effective in lengthening the life expectancy of the patients with pre-existing CAD, especially those who had received intervention coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It was also shown that the use of probucol in combination with LDL-apheresis was effective in reducing coronary events as shown by the necessity of CABG or PTCA. Clinical data on the effect of LDL-apheresis, recently reported from some other institutions in Japan, will also be reviewed.

LDL-apheresis: Clinical experience and indications in the treatment of severe hypercholesterolemia

LDL-cholesterol is the leading risk factor which influences the clinical outcome of patients with preexisting coronary heart disease. Clinical trials show that plasma LDL-cholesterol below 100 mg/dL decrease the rate of recurrent myocardial infarction and can induce regression in patients with coronary heart disease. However, in most cases of severe hypercholesterolemia with plasma LDL-cholesterol concentrations above 220 mg/dL LDL cannot be sufficiently decreased by maximal dietary and pharmacological therapy alone. Today this group of high risk CHD patients can be treated in addition with an extracorporeal procedure to eliminate LDL from the plasma circulation, the H.E.L.P.-LDL-apheresis. This method for selective removal of LDL, lipoprotein(a) and fibrinogen from plasma has been shown to be a clinically safe and very efficient method for the treatment of patients with homozygous familial hypercholesterolemia or CHD patients with severe hypercholesterolemia. Treatments with 1 week H.E.L.P. intervals revealed a mean reduction of minus 51% for LDL, of minus 45% for Lp(a) and of minus 46% for apo B, while HDL was increased by + 12%. Fibrinogen was decreased by minus 46%. Besides the marked reduction of LDL and fibrinogen plasma concentrations the H.E.L.P. treatment significantly improves hemorheological parameters and increases the oxygen tension in the tissue. We have also investigated the efficiency of a combined therapy, using HMG-CoA reductase inhibitors together with the H.E.L.P.-apheresis. Under this combined treatment, a reduction of the interval LDL-cholesterol levels of 70–80% has been achieved, while Lp(a) and fibrinogen were not further affected. We now report about our long-term clinical experience with the H.E.L.P. system in treating patients with different lipoprotein disorders: 1. (1) Homozygous form of familial hypercholesterolemia; 2. (2) CHD patients with familial and non-familial hypercholesterolemia; 3. (3) CHD patients with very high concentrations of lipoprotein(a); and 4. (4) Hypercholesterolemic patients after heart transplantation. Based on present experience guidelines for secondary prevention of coronary heart disease indications for the H.E.L.P.-LDL-apheresis treatment are discussed.

Low-density lipoprotein plasmaphaeresis with and without lovastatin in the treatment of the homozygous form of familial hypercholesterolaemia

A 7-year-old girl with homozygous familial hypercholesterolaemia and plasma low-density lipoprotein(LDL)-cholesterol levels of 820 mg/dl (21.2 mmol/l) and progressive xanthomata was treated with heparin extracorporeal low-density lipoprotein precipitation (HELP) to lower her plasma LDL. On weekly HELP treatment she maintained her pre-HELP treatment LDL-cholesterol levels at 409 mg/dl (10.6 mmol/l). The long-term HELP treatment was well tolerated and led to regression of her xanthomata. Subsequently, lovastatin [Mevacor; Merck Sharp & Dohme, Westpoint, Pa., USA (20 mg/day)] was added to the regimen, causing a further 20% decrease in her pre-HELP treatment plasma LDL-cholesterol levels. Lovastatin alone did not sufficiently lower her plasma LDL and could not replace the weekly HELP therapy. Our data show that lovastatin is an effective adjunctive therapy for lowering plasma LDL-cholesterol in a homozygous patient, once plasma LDL levels have already been lowered by regular HELP treatment.

Antipeptide antibody against the human low-density-lipoprotein receptor. Characterization and cross-reactivity with bovine lymphocytes.

A dodecapeptide corresponding to the external N-terminal sequence of the human low-density-lipoprotein (LDL) receptor was synthesized. Antibodies raised in rabbits against the peptide were purified and were shown to react specifically with the peptide and with human LDL receptor of fibroblasts, HeLa cells and lymphocytes using binding studies and immunoblotting. By indirect immunogold analysis, antibodies bound to the LDL receptor of human lymphocytes could be revealed as clusters. Anti-receptor peptide immunoglobulins specifically bound to the human HeLa cell's LDL receptor with a lower affinity than LDL (Kd x 3). The anti-receptor peptide immunoglobulins and 125I-labelled-LDL competed with each other for the LDL-receptor sites. Antibodies failed to react with lymphocytes of subjects with the homozygous form of familial hypercholesterolaemia. Cross-reactivity with the dodecapeptide of the bovine LDL receptor was limited, but this cross-reactivity was confirmed by the binding of anti-receptor peptide immunoglobulins to the LDL receptor from bovine lymphocytes.

5 years follow-up of a male patient homozygous for familial hypercholesterolemia treated with repeated plasma exchanges

A boy suffering from multiple tendinous xanthomas has been diagnosed as being affected by the homozygous form of familial hypercholesterolemia (FH) at the age of 16 years. Both parents had hypercholesterolemia, the patient had total cholesterol 650, LDL-chol. 570 and LDL-Apo B of 253 mg/dl prior to treatment. Coronary angiography showed complete stenosis of LAD, the patients fibroblasts were LDL-receptor negative. Dietary and drug regimen did not show any significant cholesterol lowering; repeated plasma exchanges have been performed in order to remove the atherogenic LDL particles. In total, within 5 years 55 exchanges have been performed without any problems. During these procedures approx. 110 1 plasma has been removed, containing about 300 g pure cholesterol. Repeated coronary angiography after 4 years did not reveal any signs of a progression of the atherosclerotic process. It is concluded from the long-term observation that continuous plasma exchange is to be considered as an effective treatment of the homozygous form of FH and definitively inhibits the progression of atherogenesis.

Meaning of a modified LDL in humans.

Abundant epidemiological experimental and clinical data support a primary atherogenic role for plasma low density lipoproteins (LDL) (1). The mechanism by which LDL are mostly cleared from the blood circulation is the LDL receptor pathway which is normally regulated by a feedbak mechanism thus preventing the accumulation of cholesterol esters in the cells (2). This pathway is altered in familial hypercholesterolemia (FH). The homozygous form of FH, in which LDL receptors are severely deficient (10%), occurs in only one subject out of every million. Heterozygotes, with a consistent reduction of receptors (50%), represent one out of every 500 persons (3). Among patients with myocardial infarctions under age 60 5% have a genetic defect of the LDL specific receptors (3). It happens therefore that coronary atherosclerosis, as well the others pictures of the clinical atherosclerosis, is mostly present in people having a normal receptorial system. The accumulation of cholesteryl esters in the foam cells, the peculiar trait of the atherosclerotic plaque, has to happen therefore through other pathways. Foam cells derive from two cellular sources: the arterial smooth muscle cells (SMC) and the monocytes-derived macrophages (MM) (4). The latter cells type, unlike many other cells, take up only a little amount of LDL by the receptor-mediated endocytosis mechanism, but have a distinct receptorial system that binds and degrades the more negatively charged LDL (5, 6).KeywordsCholesteryl EsterCholesterol EsterFamilial HypercholesterolemiaFamilial HypercholesterolemiaArterial Smooth Muscle CellThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Articular manifestations of familial hypercholesterolaemia.

Familial hypercholesterolaemia is characterised by a decreased removal of low density lipoproteins and premature coronary artery disease. Tendinous xanthomata are a hallmark of the disease. The affected joints may also be the sites of inflammation and pain. Arthropathy has been associated mainly with the homozygous form of familial hypercholesterolaemia, but it is also known to occur in the heterozygous form. We report on the articular manifestations in 73 patients with heterozygous familial hypercholesterolaemia. About 40% of these patients had at least one episode of articular symptoms. The observed articular manifestations may be classified into four types: Achilles pain (18%), Achilles tendinitis (11%), oligoarticular arthritis (7%), polyarticular or rheumatic fever-like arthritis (4%). It is concluded that in heterozygous familial hypercholesterolaemia articular manifestations are frequent, diverse, and may be the first symptom of this metabolic disorder.

Vitamin E is delivered to cells via the high affinity receptor for low-density lipoprotein

The high affinity receptor for low-density lipoprotein (LDL) is demonstrated to function as a mechanism for delivery of vitamin E to cells. After incubation for 24 h with lipoprotein-depleted serum (which induces LDL receptor synthesis), and then incubation for 24 h with an increasing amount of LDL (from 10 to 250 µg of protein per ml), the tocopherol contents of normal fibroblasts increased in a saturable fashion from 19 to 103 ng of tocopherol per mg cell protein. In contrast, similarly incubated LDL receptor-negative fibroblasts (from a patient with the homozygous form of familial hypercholesterolemia) only increased from 18 to 39 ng of tocopherol per mg. Estimation of the amount of LDL degraded from the cellular tocopherol uptake by normal cells yielded values virtually identical to the actual values of protein degradation as measured using 125I-LDL.

Low density lipoprotein metabolism in cultured fibroblasts from a new group of patients presenting clinically with homozygous familial hypercholesterolemia.

The metabolism of low density lipoproteins (LDL) was studied in cultured fibroblasts obtained from five local patients diagnosed, on the basis of clinical features and serum cholesterol concentrations, as having the homozygous form of familial hypercholesterolemia. LDL receptor function was assessed by measuring the binding, internalization, and degradation of 125I-labeled LDL, and by measuring the stimulation of cellular acyl-CoA cholesterol acyltransferase (ACAT) activity which followed exposure to LDL. Fibroblasts from two cases (CF and GM) showed receptor activities which were approximately 10% of the values obtained with normal cells, while ACAT stimulation by LDL was very low. These two patients were classified as homozygous for a receptor-defective abnormality. However, fibroblasts from the other three patients (JG, ES, and TT) showed greater than 25% of normal receptor activity, as assessed by 125I-LDL binding and catabolism. ACAT stimulation by LDL in cells from JG and ES was within the range of values shown by cells previously characterized as heterozygous for a receptor-negative mutation. Cells from ES behaved atypically: a low, but nonsaturable, activation by LDL was evident. ACAT stimulation by LDL was normal in cells from TT. Receptor activities of the cells from the available parents, assessed on the basis of LDL binding and degradation or of ACAT stimulation, were not clearly distinguishable from those of normal cells. These results add to the growing evidence of genetic heterogeneity underlying the clinical picture associated with familial hypercholesterolemia in different geographical distributions.

Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein.

During studies on binding of low density lipoprotein (LDL) to fibroblasts from patients with the homozygous form of familial hypercholesterolemia (FH), a unique line was derived from subject M.N. This line could bind as much LDL as normal cells, or even more. However, like fibroblasts from other patients with the homozygous form of FH, it failed to show regulation of cholesterol synthesis. Analyses of the LDL receptors showed that this line could not mediate internalization of receptor-bound LDL. Studies on the fibroblasts of the parents of this subject showed that the inability to internalize LDL was hereditary and that the subject was a pure homozygote for this defect. The plausibility of this finding was supported by the fact that her parents were first cousins. The possible existence of a homozygous state of this defect was predicted by Goldstein et al. [Goldstein, J. L., Brown, M. S. & Stone, N. J. (1977) Cell 12, 629-41], but an actual case of the internalization defect in a pure homozygous form had not been found. There were no differences from normal cells in the nature of the LDL binding activity of this line, such as in its specificity, affinity, or Ca2+ requirement.