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Pathology Feb 2019Dyslipidaemias encompass about two dozen relatively rare monogenic disorders and syndromes for which the genetic basis has largely been defined. In addition, the complex... (Review)
Review
Dyslipidaemias encompass about two dozen relatively rare monogenic disorders and syndromes for which the genetic basis has largely been defined. In addition, the complex polygenic basis of disturbed lipids and lipoproteins has been characterised in many patients, and has been shown to result from accumulation of many common polymorphisms with small effects on lipids. Genetic technologies, including dedicated genotyping and sequencing methods can detect both rare and common DNA variants underlying dyslipidaemias. Some dyslipidaemias may be clinically silent for years, but early diagnosis, including genetic diagnosis, may permit early intervention to prevent or delay deleterious downstream clinical consequences, such as premature vascular disease or acute pancreatitis. The potential clinical utility of genetic testing for familial hypercholesterolaemia, familial chylomicronaemia syndrome, lysosomal acid lipase deficiency and some others will increase demand for reliable genetic diagnostic methods. We review some current technologies, such as targeted next-generation sequencing that seem to be helpful with DNA diagnosis of dyslipidaemias. We also address technical, biological and clinical limitations of genetic testing in dyslipidaemias. Finally, genetic counselling issues, the potential impact of results on patients and health care providers, current gaps and future directions will be discussed.
Topics: DNA Copy Number Variations; Dyslipidemias; Genetic Counseling; Genetic Testing; Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Hyperlipoproteinemia Type I; Hyperlipoproteinemia Type II; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Sequence Analysis, DNA
PubMed: 30558903
DOI: 10.1016/j.pathol.2018.10.014 -
Current Opinion in Lipidology Dec 2022We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable... (Review)
Review
PURPOSE OF REVIEW
We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm.
RECENT FINDINGS
Lowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH.
SUMMARY
Hypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.
Topics: Humans; Hyperlipoproteinemia Type II; Anticholesteremic Agents; Cholesterol, LDL; Homozygous Familial Hypercholesterolemia; Receptors, LDL; Algorithms; Homozygote
PubMed: 36206078
DOI: 10.1097/MOL.0000000000000853 -
Journal of Atherosclerosis and... 2012Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by...
Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by a decisive abnormality of the lipoprotein lipase (LPL)- apolipoprotein C-II system, whereas the cause of type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. Since the relationship of hypertriglyceridemia with atherosclerosis is not as clear as that of hypercholesterolemia, and since type I and V hyperlipoproteinemia are relatively rare, few guidelines for their diagnosis and treatment have been established; however, type I and V hyperlipoproteinemia are clinically important as underlying disorders of acute pancreatitis, and appropriate management is necessary to prevent or treat such complications. Against such a background, here we propose guidelines primarily concerning the diagnosis and management of type I and V hyperlipoproteinemia in Japanese.
Topics: Disease Management; Humans; Hyperlipoproteinemia Type I; Hyperlipoproteinemia Type V; Lipoprotein Lipase; Practice Guidelines as Topic
PubMed: 22129523
DOI: 10.5551/jat.10702 -
Progress in Cardiovascular Diseases 2016Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk... (Review)
Review
Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH.
Topics: Cardiovascular Diseases; Early Diagnosis; Humans; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Lipoproteins, LDL; Medication Therapy Management
PubMed: 27477957
DOI: 10.1016/j.pcad.2016.07.006 -
Journal of the American College of... Jul 2019
Topics: Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Multifactorial Inheritance
PubMed: 31345426
DOI: 10.1016/j.jacc.2019.06.006 -
Clinical Research in Cardiology... Mar 2017In contrast to existing EAS/ESC guidelines on the management of lipid disorders, current recommendations from nephrological societies are very conservative and... (Review)
Review
In contrast to existing EAS/ESC guidelines on the management of lipid disorders, current recommendations from nephrological societies are very conservative and restrictive with respect to any escalation of lipid lowering/statin therapy. Furthermore, lipoprotein(a) (Lp(a)) - an established cardiovascular risk factor - has not even been mentioned. While a number of retrospective and prospective studies suggested that Lp(a) has relevant predictive value and might have - at least in stage-3 chronic kidney disease (CKD) - the same negative effects if draged along in non-CKD patients, there is no guidance on diagnostic or therapeutic procedures. The persistent lack of recognition automatically leads to therapeutic nihilism, which might pose a number of relatively young patients to a significantly increased risk for adverse cardiovascular events. Further evaluation of Lp(a) in CKD is very important to provide appropriate treatment to patients with high Lp(a) levels, even in the presence of CKD.
Topics: Biomarkers; Cardiovascular Diseases; Humans; Hyperlipoproteinemias; Kidney Diseases; Lipoprotein(a); Prognosis; Risk Assessment; Risk Factors; Up-Regulation
PubMed: 28181057
DOI: 10.1007/s11789-017-0086-z -
Clinical Research in Cardiology... Mar 2017A high level of lipoprotein(a) (Lp(a)) is recognized as an independent and additional cardiovascular risk factor contributing to the risk of early onset and progressive... (Review)
Review
A high level of lipoprotein(a) (Lp(a)) is recognized as an independent and additional cardiovascular risk factor contributing to the risk of early onset and progressive course of cardiovascular disease (CVD). All lipid lowering medications in use mainly lower low density lipoprotein-cholesterol (LDL-c) with no or limited effect on levels of Lp(a). Niacin, the only component lowering Lp(a), is firstly often poorly tolerated and secondly not available anymore in many countries. A level of <50 mg/dl was recommended recently as the cut off level for clinical use and decision making. Since lipoprotein apheresis (LA) lowers not only LDL-c but also Lp(a) significantly, its use is recommended in some countries in very high-risk patients with early or progressive CVD. Retrospective analyses show that regular LA improves the course of CVD. This is supported by a recent prospective observational trial and data of the German Lipoprotein Apheresis Registry. Despite many treatment options, all too often it is not possible to reduce LDL-c levels to target and to reduce Lp(a) levels sustainably at all. Therefore, new drug therapies are awaited. Some of the lipid modifying drugs in development lower Lp(a) to some extent in addition to LDL-c; the only specific approach is the apoprotein(a) antisense oligonucleotide. Currently LA is the standard of care as a last resort treatment in high-risk patients with elevated Lp(a) and severe CVD despite optimal control of all other cardiovascular risk factors.
Topics: Animals; Biomarkers; Blood Component Removal; Cardiovascular Diseases; Cholesterol, LDL; Genetic Therapy; Humans; Hyperlipoproteinemias; Hypolipidemic Agents; Lipoprotein(a); Molecular Targeted Therapy; Oligonucleotides, Antisense; PCSK9 Inhibitors; Proprotein Convertase 9; Risk Factors; Serine Proteinase Inhibitors; Treatment Outcome
PubMed: 28185213
DOI: 10.1007/s11789-017-0083-2 -
Circulation Jun 2020
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hyperlipoproteinemia Type II; Prevalence
PubMed: 32479201
DOI: 10.1161/CIRCULATIONAHA.120.046961 -
International Journal of Molecular... Sep 2023Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease,... (Review)
Review
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apoprotein(a); Lipoprotein(a); Apolipoproteins A; Hyperlipoproteinemias; Aortic Valve Stenosis
PubMed: 37686428
DOI: 10.3390/ijms241713622 -
Journal of Atherosclerosis and... Sep 2021Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs)... (Review)
Review
Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.
Topics: Abdominal Pain; Animals; Disease Management; Humans; Hyperlipoproteinemia Type I; Pancreatitis; Prognosis; Triglycerides
PubMed: 33980761
DOI: 10.5551/jat.RV17054