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Familial Hypercholesterolemia

Autosomal Dominant Type B Hypercholesterolemia

Familial hypercholesterolemia (FCH) is a rather common genetic disorder characterized by prominent hypercholesterolemia due to the selective elevation of low-density lipoproteins (LDL), triglyceride levels within reference ranges, and a tendency to develop xanthomas and coronary heart disease. It is also referred to as hyperlipoproteinemia type 2 and is inherited in an autosomal dominant manner. The underlying mutations interfere with the LDL receptor-mediated uptake of cholesterol. Patients may be heterozygous or homozygous for pathogenic mutations, with homozygosity implicating an increased severity of the disease.


Presentation

While those suffering from homozygous FCH generally present in childhood or adolescence, heterozygotes don't usually experience any symptoms until early adulthood [1]. Hypercholesterolemia is the hallmark of both variants and is associated with the deposition of cholesterol-rich material in distinct tissues:

  • In the cornea, it leads to the formation of an arcus senilis, a light gray or yellowish ring around the rim of the iris.
  • Excess lipids may also be deposited underneath the skin, giving rise to the formation of xanthelasmas. They are yellowish-orange papules or plaques that preferentially develop on the eyelids or elsewhere in the face.
  • Tuberous xanthomas are nodular cutaneous xanthomas that develop on the extensor surfaces of joints and pressure areas, such as the elbows, knees, and heels.
  • Firm subcutaneous nodules under unaltered skin may correspond to tendon xanthomas. Predilection sites are the extensor tendons of the hand and the Achilles tendon [2].

Furthermore, cholesterol-rich lipids are deposited in the arteries. While this is not readily visible, it may induce life-threatening cardiovascular disease. Atherosclerosis and coronary heart disease are frequent findings in FCH patients, and they may be diagnosed at the age of just 3 years [3]. Furthermore, thickening of the aortic valve and aortic root may lead to aortic regurgitation or stenosis [1]. The descending aorta, carotid, renal, and ileo-femoral arteries may also be affected [4].

Coronary Atherosclerosis
  • Pediatric patients with familial hypercholesterolemia may present with premature coronary atherosclerosis requiring coronary artery bypass grafting. In situ internal mammary artery grafts should be the graft of choice.[ncbi.nlm.nih.gov]
  • Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. To date, 71 mutations in the LDL receptor gene have been characterized at a molecular level.[ncbi.nlm.nih.gov]
  • This can lead to premature coronary atherosclerosis and cardiac-related death. The symptoms are more severe in the homozygous type of the disease.[ncbi.nlm.nih.gov]
  • Although both carotid intima-media thickness (cIMT) and carotid plaque score (cPS) determined by carotid ultrasonography reflect the severity of coronary atherosclerosis, there are few reports on direct comparisons of their clinical utilities in patients[ncbi.nlm.nih.gov]
  • We aimed to compare the risk factors of carotid plaques, which are reliable surrogates of coronary atherosclerosis, in men and women with FH. METHODS: 154 patients with FH (40.9% men) were included, diagnosed according to Simon Broome criteria.[ncbi.nlm.nih.gov]
Coarctation of the Aorta
  • Coarctation of the aorta is rarely involved in this disease. The ideal surgical approach for management of coexisting coronary artery disease and coarctation of the aorta in a child with familial hypercholesterolemia is unclear.[ncbi.nlm.nih.gov]
  • Coarctation of the Aorta The pathophysiology for acquired cardiovascular disease associated with coarctation of the aorta is primarily related to systemic hypertension. 326 Arterial abnormalities may persist after correction of the coarctation and result[doi.org]
Turkish
  • To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis.[ncbi.nlm.nih.gov]
  • Humphries, The molecular basis of familial hypercholesterolaemia in Turkish patients, Atherosclerosis, 180, 1, (63), (2005). Fengcheng Sun, Rita Kohen Avramoglu, Gerard Vassiliou, Robert J. Brown, Kerry W.S.[doi.org]
Difficulty Walking
  • The patient was a 49-year-old male who presented to our clinic with complaints of difficulty walking and swelling in both heels. The swellings had started insidiously without a trauma history.[ncbi.nlm.nih.gov]
Regurgitation
  • Furthermore, thickening of the aortic valve and aortic root may lead to aortic regurgitation or stenosis. The descending aorta, carotid, renal, and ileo-femoral arteries may also be affected.[symptoma.com]
Right Flank Pain
  • BACKGROUND This is a case report of a male patient who presented with a history of right flank pain based on renal infarction. Initially the symptoms were misdiagnosed as acute pyelonephritis.[ncbi.nlm.nih.gov]
Family History of Heart Disease
  • Other signs and symptoms of hyperlipoproteinemia include: pancreatitis (type 1) abdominal pain (types 1 and 5) enlarged liver or spleen (type 1) lipid deposits or xanthomas (type 1) family history of heart disease (types 2 and 4) family history of diabetes[healthline.com]
  • Patients with an extensive family history of heart disease should also be screened by measuring Lp(a) levels.[merckmanuals.com]
Arthralgia
  • […] symptoms Homozygous FH Signs and symptoms of homozygous FH in children include the following: Symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis Articular symptoms such as tendonitis or arthralgias[emedicine.com]
Migratory Polyarthritis
  • Here is presented a case of a young girl with migratory polyarthritis, who was diagnosed as probable homozygote familial hypercholesterolemia with hypercholesterolemic arthritis.[ncbi.nlm.nih.gov]
Costovertebral Angle Tenderness
  • Physical examination revealed hypertension, subfebrile temperature, and costovertebral angle tenderness.[ncbi.nlm.nih.gov]
Arcus Senilis
  • Hypercholesterolemia is the hallmark of both variants and is associated with the deposition of cholesterol-rich material in distinct tissues: In the cornea, it leads to the formation of an arcus senilis, a light gray or yellowish ring around the rim of[symptoma.com]
  • Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as xanthelasma palpebrarum), the outer margin of the iris (known as arcus senilis corneae), and in the tendons of the hands, elbows, knees[en.wikipedia.org]
  • senilis (gray or white discoloring of the eye’s cornea.[availclinical.com]
  • Although the diagnosis is primarily biochemical, two physical signs may be evident in patients with familial hypercholesterolaemia: Premature arcus senilis - a white or gray opaque ring in the corneal margin [ 7 ] .[patient.info]
  • senilis, tendon xanthomas Bile acid sequestrants, statins, niacin Clear One in 500 for heterozygotes b 144250 Familial combined hyperlipidemia Decreased LDL receptor and increased ApoB LDL and VLDL Statins, niacin, fibrate Turbid One in 100 Type III[en.wikipedia.org]
Xanthoma
  • Xanthoma should be considered in cases with swellings in the Achilles tendon. Total resection is necessary to avoid recurrence of the xanthomas.[ncbi.nlm.nih.gov]
  • When patients present with tendon xanthomas and FH is ruled out, clinicians should consider CTX as a possible diagnosis.[ncbi.nlm.nih.gov]
  • Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia. Figure. Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia.[doi.org]
  • Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients.[ncbi.nlm.nih.gov]
Xanthelasma
  • Her mother and maternal grandmother both had a history of hypercholesterolemia and had developed extensive xanthelasma palpebrarum from early adult life.[ncbi.nlm.nih.gov]
  • RESULTS: Comparing patients with genetically confirmed FH to those without it, the former had a higher clinical score for FH, more often had xanthelasma and had higher LDL-C and apo B levels.[ncbi.nlm.nih.gov]
  • He had tendinous xanthomas, xanthelasmas and elevated levels of total and LDL cholesterol, at 11.2 and 9.69 mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13 mmol/L, respectively.[ncbi.nlm.nih.gov]
  • Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients.[ncbi.nlm.nih.gov]
  • A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, but are non-specific findings.[en.wikipedia.org]
Skin Lesion
  • After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions.[ncbi.nlm.nih.gov]
  • A xanthoma is a skin lesion caused by the accumulation of fat in macrophage immune cells in the skin and more rarely in the layer of fat under the skin.[dermnetnz.org]
  • lesions, such as cutaneous xanthomas at birth or by early childhood (eg, planar xanthomas, tuberous xanthomas; later, tendon xanthomas) Corneal arcus may be present and is sometimes circumferential Murmur of aortic stenosis may be present Most patients[emedicine.com]
Cutaneous Manifestation
  • A proper knowledge of cutaneous manifestations helps to identify patients at risk, establish the underlying diagnosis, and start early and effective therapy.[ncbi.nlm.nih.gov]
  • Recognition of the cutaneous manifestations of FH permits early diagnosis and treatment to prevent the otherwise severe and inevitable cardiovascular complications. [23, 24] Heterozygous FH Premature CAD is the most serious and preventable manifestation[emedicine.com]
Psychiatric Manifestation
  • The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities.[en.wikipedia.org]
Cesarean Section
  • At 36 weeks of gestation, we carried out cesarean section in view of poor biophysical profile. Familial hypercholesterolemia is a very rare disorder with only a few cases reported in the published work during pregnancy.[ncbi.nlm.nih.gov]
Flank Pain
  • BACKGROUND This is a case report of a male patient who presented with a history of right flank pain based on renal infarction. Initially the symptoms were misdiagnosed as acute pyelonephritis.[ncbi.nlm.nih.gov]
Stroke
  • These drugs help lower your risk of heart attack and stroke.[nlm.nih.gov]
  • Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004 ;35: 2902 - 2909 26. Crouse JR III, Grobbee DE, O'Leary DH, et al.[dx.doi.org]
  • The primary end point was all-cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives.[ncbi.nlm.nih.gov]
  • This can lead to heart attacks, strokes, and other problems. What are the causes and risks of the condition? This disease is inherited and occurs in about 1 in 1000 people.[medicineonline.com]
Neurologic Manifestation
  • Markedly, the typical neurological manifestations of CTX were absent, suggestive of a protective role of LDL-receptor deficiency against the severe neurological consequences of CTX. 2011 John Wiley & Sons A/S.[ncbi.nlm.nih.gov]
Cognitive Deficit
  • Studies exploring the possible influence of cognitive deficits on adherence should be conducted also. The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.[ncbi.nlm.nih.gov]

Workup

Clinical findings should raise suspicion of hypercholesterolemia. This suspicion may be supported by information as to the medical condition of the patient's parents and grandparents: Since FCH is inherited in an autosomal dominant pattern, there may be reports about elevated blood fat levels, xanthomas, and cardiovascular disorders.

In any case, standard analyses of blood samples reveal elevated levels of total cholesterol and LDL. As a rule of thumb, LDL concentrations are about four and two times increased in individuals with homozygous and heterozygous FCH, respectively, when compared to healthy relatives [4]. The specific threshold concentrations of lipids depend on the age of the patient and their family history [5], and it may not always be possible to confirm or refute the tentative diagnosis on the basis of laboratory results.

A more reliable diagnosis of FCH is based on the identification of the underlying mutation of the LDLR gene [6]. In this context, straight-forward analyses may be carried out if the parents' genotype is known. Otherwise, LDLR gene sequencing is required. Genes APOB and PCSK9 may be assessed if LDLR mutations are not detected, but despite all efforts, the molecular biological confirmation of FCH is not universally achieved. For homozygous FCH, the following criteria may then be applied to make a clinical diagnosis [4]:

  • Untreated LDL levels of >13 mmol/l or 500 mg/dl, or treated LDL levels of >8 mmol/l or 300 mg/dl, and
  • Untreated LDL levels consistent with heterozygous FCH in both parents, or cutaneous or tendon xanthomas before the age 10 years

Patients who have been diagnosed with FCH should undergo regular screenings for aortic and coronary heart disease [4].

Calcified Aortic Valve
  • Even for experiences surgeons, this surgery could prove challenging for this group of patients due to aggressive degenerative tissue calcification of the aortic root, which often presents an extremely calcified aortic valve with a small annulus associated[ncbi.nlm.nih.gov]
Hypercholesterolemia
  • . 1 If a child with familial hypercholesterolemia is identified, the parent with familial hypercholesterolemia may then be identified.[doi.org]
  • CONCLUSIONS: Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C.[ncbi.nlm.nih.gov]
  • (0.4% of the 10,095 children, including 32 children who had a familial hypercholesterolemia mutation and 8 who did not have the mutation) and 40 parents who had positive screening results for familial hypercholesterolemia.[ncbi.nlm.nih.gov]
  • Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia. Figure. Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia.[doi.org]
Hypertriglyceridemia
  • Familial chylomicronemia or hyperlipoproteinemia type 1 Type 2A: FCH or hyperlipoproteinemia type 2, as described here Type 2B: Familial combined hyperlipidemia Type 3: Familial dysbetalipoproteinemia or hyperlipoproteinemia type 3 Type 4: Familial hypertriglyceridemia[symptoma.com]
  • Hubacek JA et al. (2005) Hypertriglyceridemia: interaction between APOE and APOAV variants. Clin Chem 51 : 1311–1313 39.[nature.com]
  • […] and/or fenofibrate type 5 mixed hypertriglyceridemia Increased production or decreased clearance of VLDL and chylomicrons.[quizlet.com]
  • , familial combined hyperlipidemia, sporadic hypertriglyceridemia, diabetes N V Creamy top, turbid bottom Chylomicrons, VLDL Diabetes Note that the WHO classification is simply a biochemical phenotypic classification based on which lipoprotein is raised[gpnotebook.co.uk]
  • To assess the possibly confounding effect of hypertriglyceridemia, 14 samples of serum with a mean triglyceride value of 2.6 mmol per liter (range, 0.98 to 5.24) were assayed for lipoprotein(a) before and after ultracentrifugation at 1.006Xg.[doi.org]
LDL Increased
  • Examples of secondary hyperlipidaemias and the associated lipoprotein abnormalities Condition Serum lipid pattern Diabetes mellitus Increased triglycerides, decreased HDL Obesity Increased triglycerides, decreased HDL Hypothyroidism Increased LDL, increased[diapedia.org]
  • When the [ 125 I]LDL preparation was preincubated with varying amounts of an antibody to LDL, increasing amounts of the radioactivity were precipitated ( Fig. 5 ).[doi.org]
Hepatocellular Carcinoma
  • Author information 1 Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania. irinel.popescu@icfundeni.ro Abstract A 46-yr-old female with hepatocellular carcinoma and severe hepatitis B-related liver cirrhosis[ncbi.nlm.nih.gov]

Treatment

Cholesterol-lowering drug therapy is the mainstay of treatment and should be initiated as early as possible. In this context, statins, ezetimibe, and bile acid sequestrants are most commonly prescribed. The patients' response to therapy varies largely and cannot be predicted based on the results of genetic studies [6] [7]. If LDL target levels cannot be achieved, weekly or biweekly adjunctive lipoprotein apheresis is recommended. The following target levels have been defined by the European Atherosclerosis Society [6]:

  • LDL <3.5 mmol/l or <135 mg/dl in children
  • LDL <2.5 mmol/l or <100 mg/dl in adults
  • LDL <1.8 mmol/l or <70 mg/dl in adults with atheroscleroslerotic cardiovascular disease and/or diabetes mellitus

These values apply to both homozygous and heterozygous FCH.

In any case, medical therapy should be complemented by lifestyle adjustments. Patients are to receive dietary counseling and should be advised on how to reduce the intake of exogenous cholesterol and saturated fats [1]. Regular, moderate exercise is recommended if cardiovascular findings don't suggest an imminent risk of angina pectoris upon exertion [4]. FCH patients should be discouraged from smoking [6].

Prognosis

Since FCH is associated with an elevated risk to develop coronary heart disease and other life-threatening cardiovascular disorders, the early diagnosis and appropriate management of the disease is essential for obtaining a favorable outcome [3] [8]. If left untreated, homozygous FCH is generally fatal before the age of 30 years [4]. Those suffering from heterozygous FCH have a 5%, 20% and 50% risk of coronary artery disease at ages 30, 40 and 50 years, respectively [1]. The adequate treatment of FCH is assumed to increase the patients' life expectancy by several decades [9].

Etiology

FCH is caused by mutations of the LDLR gene. This gene is located on the short arm of chromosome 19 and encodes for the LDL receptor, which mediates the uptake of LDL. The life cycle of the LDL receptor comprises LDL binding, the formation and internalization of endocytic vesicles, the dissociation from these vesicles, and the return to the cell surface. Either of these processes may be impaired in FCH patients, and pathogenic mutations of LDLR are thus classified into distinct groups [7] [9]:

  • Defective intracellular transport
  • Defective ligand binding
  • Defective internalization
  • Defective recycling
  • Null mutations resulting in no detectable protein

More than 1,200 mutations of LDLR have been described to date [6]. Certain genotype-phenotype correlations could be established: In patients suffering from homozygous FCH, the residual activity of the LDL receptor correlates with the severity of the disease. Somewhat surprisingly though, LDL receptor activity is unsuited to predict the course of the disease in heterozygous individuals. In general, genetic modulators and environmental factors seem to considerably affect the outcome. Those who are exposed to cigarette smoke are at increased risks of cardiovascular disorders, as are those suffering from diabetes mellitus, males and elder patients [7] [9].

Epidemiology

The prevalence of heterozygous FCH has been estimated at 1 in 500 persons. Accordingly, the frequency of homozygous FCH may approximate 1 in 1,000,000 inhabitants [4] [7]. Particularly high prevalence rates due to founder effects have been described for Christian Lebanese, French Canadians, and South African Afrikaners, among others [9]. Males and females are affected equally.

Literature contains contradictory data regarding the penetrance of LDLR mutations. Some experts state the penetrance to be almost 100%, while others describe considerable shares of normocholesterolemic carriers in affected families [9] [10]. It has been speculated that the existence of protective factors and cholesterol-lowering gene variants may account for this phenomenon, but evidence has yet to be provided [10].

Sex distribution
Age distribution

Pathophysiology

LDL consist of apolipoprotein B-100 and other proteins, of triglycerides, phospholipids, cholesteryl esters, and free cholesterol. They are remnants of very-low-density lipoproteins (VLDL) that have delivered triglycerides to peripheral tissues, where they are used as energy substrates. Accordingly, the relative contents of cholesterol and cholesteryl esters increase when VLDL convert to LDL. Cells in need of either lipid enhance the expression of LDL receptors, which are able to bind and internalize circulating LDL. In this context, hepatocytes remove the major portion of LDL from the circulation. After their uptake into cells, LDL are disassembled: Proteins are lysosomally degraded, cholesterol esters are hydrolyzed, and cholesterol is made available for the inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting enzyme in cholesterol synthesis.

In patients carrying loss-of-function mutations of the LDLR gene, clearing LDL from blood is largely impaired. The regulatory mechanism described above is overridden, and HMG-CoA reductase continues to provide mevalonate for the synthesis of cholesterol. Both conditions contribute to the elevation of blood levels of LDL [7]. Excess lipids are eventually deposited in the cornea, skin, tendons, and arteries. The accumulation of foam cells in the intima of arteries may rapidly progress to occlusive atherosclerosis, plaque formation, coronary ostial stenosis, and myocardial infarction [1].

Prevention

Due to the high prevalence of FCH and the clear benefits of an early diagnosis and initiation of therapy, population screenings have repeatedly been considered. The genetic heterogeneity of FCH, patients, however, imposes severe practical limitations on this proposition. The screening of families known to harbor pathogenic mutations of the LDLR gene is the better approach: It is more cost-effective and may involve straight-forward analyses for those mutations detected in the index case [7].

The prenatal diagnosis of FCH is feasible if the parents' genotype has been determined.

Summary

Owing to its specific features, FCH is considered both a type of autosomal dominant hypercholesterolemia and primary hyperlipidemia. The corresponding classification systems shall be briefly summarized in this paragraph to dispel doubts as to the nomenclature, which may be confusing.

Hyperlipidemias are divided into categories according to the Fredrickson classification [11]. There are six types of primary hyperlipidemias:

  • Type 1: Familial chylomicronemia or hyperlipoproteinemia type 1
  • Type 2A: FCH or hyperlipoproteinemia type 2, as described here
  • Type 2B: Familial combined hyperlipidemia
  • Type 3: Familial dysbetalipoproteinemia or hyperlipoproteinemia type 3
  • Type 4: Familial hypertriglyceridemia
  • Type 5: Primary mixed hyperlipidemia

Contrary to the other types of primary hyperlipidemia, FCH is not associated with increased levels of triglycerides, but with pure hypercholesterolemia. More than 80 genes have been shown to affect cholesterol levels, and pathogenic mutations of those genes may result in increased levels of cholesterol [8]. Distinct types of hypercholesterolemia may be classified according to the underlying gene defects, the pattern of inheritance, the clinical presentation, or biochemical findings such as the elevated lipoprotein fraction. Because the vast majority of cases may be attributed to mutations of genes LDLR, APOB, and PCSK9, they provide the basis of current classification systems [8]:

  • FCH or hyperlipoproteinemia type 2, as discussed in this article, is primarily caused by LDLR mutations.
  • Mutations of the APOB gene may result in hypercholesterolemia type B. This disease is also referred to as familial defective apolipoprotein B-100.
  • Finally, PCSK9 mutations may lead to autosomal dominant hypercholesterolemia type 3.

As implied above, a minor share of patients diagnosed with autosomal dominant hypercholesterolemia tests negative for any of the aforementioned mutations. Even though mutations may be detected that predispose for hypercholesterolemia, such as anomalies of genes GSBS and ITIH4, these are not usually considered sufficient to induce the disease. The true causes of these cases remain unknown, and they are not covered by the current classification scheme. The need for revision will eventually arise, as the molecular biological background and the pathogenesis of hypercholesterolemia are increasingly better understood.

Patient Information

Hyperlipoproteinemia type 2 is also referred to as familial hypercholesterolemia. It is a hereditary disorder of cholesterol metabolism, and affected individuals present increased levels of total cholesterol and low-density lipoproteins (LDL), whereby LDL are commonly described as "bad cholesterol". Eventually, excess blood fats are deposited in the cornea, skin, tendons, and arteries. The formation of plaques in the arterial walls is least visible but most detrimental; it leads to atherosclerosis and may trigger coronary heart disease and myocardial infarction.

Familial hypercholesterolemia is caused by mutations in the gene encoding for the LDL receptor. About 1 in 500 people has inherited such a mutation from one of their parents and is heterozygous for the pathogenic allele. Homozygosity, i.e., the inheritance of two defective alleles from both parents, occurs about once in a million births. Symptom onset in childhood and severe atherosclerosis by the end of the second decade of life are characteristic of homozygous familial hypercholesterolemia, but in heterozygous individuals, the risk of cardiovascular complications is far from negligible either: By the age of 50 years, 50% of patients have been diagnosed with coronary artery disease.

Although the deposition of blood fats in the arteries does not imply obvious complaints, it should be taken seriously. The life expectancy of people carrying defective LDL receptors largely depends on the early diagnosis and appropriate management of the disease.

References

Article

  1. Rahalkar AR, Hegele RA. Monogenic pediatric dyslipidemias: classification, genetics and clinical spectrum. Mol Genet Metab. 2008; 93(3):282-294.
  2. Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: clinical and pathophysiological relations. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014; 158(2):181-188.
  3. Nelson RH. Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care. 2013; 40(1):195-211.
  4. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014; 35(32):2146-2157.
  5. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004; 160(5):407-420.
  6. Nordestgaard BG, Chapman MJ, Humphries SE, 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):3478-3490a.
  7. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007; 4(4):214-225.
  8. Volta A, Hovingh GK, Grefhorst A. Genetics of familial hypercholesterolemia: a tool for development of novel lipid lowering pharmaceuticals? Curr Opin Lipidol. 2018; 29(2):80-86.
  9. De Castro-Orós I, Pocoví M, Civeira F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet. 2010; 3:53-64.
  10. Garcia-Garcia AB, Ivorra C, Martinez-Hervas S, et al. Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family. Atherosclerosis. 2011; 218(2):423-430.
  11. Hegele RA, Pollex RL. Hypertriglyceridemia: phenomics and genomics. Mol Cell Biochem. 2009; 326(1-2):35-43.

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Last updated: 2019-07-11 20:16