Materiały źródłowe

• #1 Reviewing Evidence on the Screening, Diagnosis, and Care of Familial Hypercholesterolemia – The Cardiology Advisor

  https://www.thecardiologyadvisor.com/home/topics/metabolic/dyslipidemia/familial-hypercholesterolemia-is-one-of-the-most-clinically-relevant-monogenic-disorders-contributing-to-ascvd/

  Familial hypercholesterolemia (FH) is one of the most clinically relevant monogenic disorders contributing to the development of atherosclerotic cardiovascular disease (ASCVD). The prevalence of FH was estimated to be 1 in 200 to 1 in 250 individuals in studies in which genetic testing was conducted on large community population samples. However, the disease often remains undetected and thus untreated, with only 10% of individuals with FH receiving adequate diagnosis and treatment. […] A combination of selective, opportunistic (eg, genetic screening of blood donors), systematic, and universal screening approaches is recommended to improve the detection of FH. Universal screening of children and child-parent (reverse) cascade testing is potentially a highly effective method for detecting patients with FH at a young age, before they develop ASCVD and might be particularly relevant to communities with gene founder effects, noted the review authors. All children with FH should ideally be detected from the age of 5 years or earlier if homozygous FH (hoFH) is suspected.

• #2 Familial Hypercholesterolemia | Test Summary | Quest Diagnostics Familial HypercholesterolemiaFamilial Hypercholesterolemia

  https://testdirectory.questdiagnostics.com/test/test-guides/TS_FH/familial-hypercholesterolemia

  These tests are used to genetically diagnose familial hypercholesterolemia (FH) in individuals suitable for testing. […] Clinical use: Diagnose familial hypercholesterolemia (FH). […] Early diagnosis of FH is crucial for disease management and reducing risk of premature ASCVD (ie, in men ≤55 years, women <65 years). [...] Despite the potential benefits of early diagnosis and treatment, FH remains undiagnosed in over 90% of affected individuals in the United States. [...] According to International Atherosclerosis Society guidelines, clinical diagnostic criteria for FH include personal or family history of premature ASCVD, physical findings of tendon xanthomas (yellowish patches or lumps of cholesterol buildup in the tendons of the hands, feet, and heel) or corneal arcus (opaque ring in the corneal margin), and elevated LDL-C.

• #3 Familial Hypercholesterolaemia Diagnosis and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6159470/

  Familial hypercholesterolaemia is the most common monogenic disorder associated with premature coronary artery disease. Clinical criteria can be used to make the diagnosis; however, genetic testing will confirm the disorder and is very useful for cascade screening. […] Patients with familial hypercholesterolaemia are considered at high cardiovascular risk and the treatment target is LDL cholesterol 2.6 mmol/l or at least a 50 % reduction in LDL cholesterol. […] A clinical diagnosis of FH is made based on high plasma levels of LDL-C, family history of hypercholesterolaemia, a history of premature ASCVD and the presence of tendon xanthomas. […] In the past 30 years, three different clinical criteria have been developed for the diagnosis of FH. […] The most accepted and commonly used FH diagnosis criteria are the Dutch Lipid Clinic Network criteria.

• #4

  https://link.springer.com/article/10.1007/s11883-014-0482-5

  Familial hypercholesterolemia is among the commonest inherited metabolic disorders and is characterized by severely elevated LDL cholesterol levels. […] Three formal diagnostic criteria have been proposed to diagnose FH in practice-MedPed, Simon Broome, and Dutch Lipid Clinic Network. […] The role of genetic testing and cascade screening among families is discussed in this review. […] Reviews screening, diagnosis, and management of FH. […] Reviews screening and diagnosis of FH in children and young adults. […] Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. […] Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. […] Cascade screening for familial hypercholesterolemia and its effectiveness in the prevention of vascular disease. […] Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

• #5 FH Diagnosis, Management and Family Screening | the Family Heart Foundation

  https://familyheart.org/diagnostic-criteria-for-familia-hypercholesterolemia2

  FH is commonly diagnosed based on clinical criteria; however, there is genetic testing available. The genetic test should identify mutations in the low-density lipoprotein reception (LDLR) gene, the apolipoprotein B (apoB), or the proprotein convertase subtilisin/kexin (PCSK9) genes. […] The presence of xanthomas, corneal arcus and xanthelasmas before the age of 60 are highly suggestive of FH, more specifically homozygous FH (HoFH), although sitosterolemia should be ruled out as a cause. […] Assessment of family history of high LDL-C and premature coronary heart disease is crucial for HoFH diagnosis. […] There are currently three accepted resources for FH diagnosis: the Simon Broom criteria, the Med Ped Criteria, and the FH Dutch Lipid Clinic Criteria. […] Each first-degree relative of an individual with FH has a 50% chance of also having FH. […] Therapy should be initiated between the ages of 8-10 for children with heterozygous FH. […] Family cascade screening may help identify patients at an earlier age, increasing the proportion of individuals with FH receiving timely and appropriate treatment.

• #6 Genetic Testing for Familial Hypercholesterolemia

  https://www.southcarolinablues.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-familial-hypercholesterolemia/

  Genetic testing to establish a molecular diagnosis of familial hypercholesterolemia (FH) is considered MEDICALLY NECESSARY when both of the following criteria are met: […] When FH is clinically suspected (based on clinical features, family history, physical exam, lipid levels, etc.) and a definitive diagnosis is required; […] When the result of the test will directly impact the treatment being delivered to the individual. […] For asymptomatic close blood relatives of an individual affected with FH, genetic testing for a known familial mutation associated with FH is considered MEDICALLY NECESSARY. […] For all other situations not described above, genetic testing to confirm a diagnosis of FH is considered NOT MEDICALLY NECESSARY. […] At least three current diagnostic criteria have been developed (Simon Broome, Dutch Lipid Clinic Network (DLCN), and the US Make Early Diagnosis to Prevent Early Death [MEDPED]).

• #7 Familial Hypercholesterolemia: Early Diagnosis and Treatment is Key for Cardiovascular Prevention

  https://www.acc.org/Latest-in-Cardiology/Articles/2020/04/16/09/58/Familial-Hypercholesterolemia

  One of the most widely used clinical scoring systems to diagnose FH is the Dutch Lipid Network Criteria (DLNC). The DLNC yields a score based on clinical criteria including lipid levels, physical exam, and family history, as well as genetic data if available. A score of higher then 8 makes a diagnosis of „definite” FH. […] It is important to note that genetic criteria are not needed to make a diagnosis. […] The question that arises then is, what is the utility of genetic testing? Genetic testing is considered the gold standard for diagnosing FH. […] Once an individual is identified with FH it is important to also determine who else in the family is at risk. A commonly used screening strategy is known as cascade screening where LDL-C measurement, genetic testing, or both are done in consenting relatives of patients with FH.

• #8 Familial hypercholesterolaemia: A guide for general practice

  https://www1.racgp.org.au/ajgp/2019/september/familial-hypercholesterolaemia

  This guide provides a practical approach to making a clinical, phenotypic diagnosis of familial hypercholesterolaemia (FH) in general practice. […] FH should always be considered in adults with a total cholesterol level of 7.5 mmol/L or a low-density lipoprotein cholesterol (LDL-C) level of 5.0 mmol/L, especially if there is a personal or family history of premature coronary heart disease (CHD). […] In Australia, the Dutch Lipid Clinic Network Score (DLCNS; Table 1) is used to make a probable or definite clinical diagnosis of FH on the basis of phenotypic criteria. […] A DLCNS of 68 indicates probable FH, while a total score 8 indicates definite FH. […] Patients with a DLCNS 6 should be advised they have a phenotypic diagnosis of FH. […] It is recommended to advise patients that if FH is left untreated, up to half will have a fatal or non-fatal CVD event by the age of 50 years (men) or 60 years (women).

• #9 Familial Hypercholesterolaemia Diagnosis and Management | ECR Journal

  https://www.ecrjournal.com/articles/familial-hypercholesterolaemia-diagnosis-and-management?language_content_entity=en

  The most accepted and commonly used FH diagnosis criteria are the Dutch Lipid Clinic Network criteria. […] FH should be suspected in children and adolescents where LDL-C 4.9 mmol/l after the exclusion of secondary causes of hypercholesterolaemia, or where LDL-C 3.9 mmol/l and one parent has confirmed FH. […] The diagnosis of HoFH is typically based on very high levels of LDL-C (untreated LDL-C 13 mmol/l or treated LDL-C 7.8 mmol/l on maximum lipid-lowering treatment) and the presence of cutaneous and tendon xanthomas in the first decade of life. […] Genetic testing is the gold standard for the diagnosis of the disorder and facilitates cascade screening. […] Early identification of FH is important for the prevention of coronary artery disease. […] International guidelines consider LDL-C 2.6 mmol/l as the optimal target in adults with FH; 1.8 mmol/l in adults with FH and cardiovascular disease or type 2 diabetes; and at least a 50 % reduction in LDL-C levels if these goals cannot be achieved with maximally tolerated lipid-lowering therapy. […] Patients require high-intensity statin therapy and ezetimibe.

• #10 Hypercholesterolemia – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/170

  Hypercholesterolemia is diagnosed by a lipid profile, consisting of measurements of total cholesterol, LDL-C (estimated or direct), HDL-C, and triglycerides. Non-HDL-C is calculated by the subtraction of HDL-C from total cholesterol. […] Diagnostic tests include lipid profile, serum thyroid-stimulating hormone (TSH), and lipoprotein(a). […] Genetic testing should also be considered.

• #11 Familial hypercholesterolemia – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/familial-hypercholesterolemia/diagnosis-treatment/drc-20353757

  Adults who have familial hypercholesterolemia usually have low-density lipoprotein (LDL) cholesterol levels over 190 mg/dL (4.9 mmol/L). Children who have the disorder often have LDL cholesterol levels over 160 mg/dL (4.1 mmol/L). In severe cases, LDL cholesterol levels can be over 500 mg/dL (13 mmol/L). […] A genetic test can confirm familial hypercholesterolemia, but it’s not always necessary. However, a genetic test can help determine whether other family members also may be at risk. […] If you are diagnosed with familial hypercholesterolemia, doctors usually recommend that your first-degree relatives such as siblings, parents and children be checked for the disorder. This will allow treatment to begin early, if needed.

• #12 Heterozygous Familial Hypercholesterolemia: Causes, Symptoms, Treatment

  https://www.webmd.com/cholesterol-management/heterozygous-familial-hypercholesterolemia

  You’ve probably heard that you need to watch your cholesterol to keep heart disease away. That’s also true of heterozygous familial hypercholesterolemia. The disease can cause your cholesterol numbers to go way up. If your doctor tells you that you have it, it’s important to get treatment to cut your chances of a heart attack or stroke. […] Some simple exams can help your doctor figure out if you or your child has HeFH. It’s important to get the right diagnosis, as early as you can, to start treatment to bring your cholesterol levels down. […] Your doctor will also do one or more tests to check you or your child for HeFH. […] If your doctor thinks you have HeFH, theyll do a blood test to check your cholesterol level. With HeFH, your: Total cholesterol level will be over 300 mg/dL; LDL cholesterol level will be over 200 mg/dL. […] The most common genetic sign of HeFH is a mutation, or change, in your LDLR gene. That’s the gene that affects your cholesterol levels. […] If high cholesterol or heart attacks run in your family, everyone can be tested for these gene problems.

• #13 Familial Hypercholesterolaemia Diagnosis and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6159470/

  The diagnosis of HoFH is typically based on very high levels of LDL-C (untreated LDL-C 13 mmol/l or treated LDL-C 7.8 mmol/l on maximum lipid-lowering treatment) and the presence of cutaneous and tendon xanthomas in the first decade of life. […] Genetic testing is the gold standard for the diagnosis of the disorder and facilitates cascade screening. […] Early identification of FH is important for the prevention of coronary artery disease. […] International guidelines consider LDL-C 2.6 mmol/l as the optimal target in adults with FH; 1.8 mmol/l in adults with FH and cardiovascular disease or type 2 diabetes; and at least a 50 % reduction in LDL-C levels if these goals cannot be achieved with maximally tolerated lipid-lowering therapy.

• #14 Homozygous Familial Hypercholesterolemia: Diagnosis and Emerging Therapies

  https://www.acc.org/Latest-in-Cardiology/Articles/2022/02/18/18/04/Homozygous-Familial-Hypercholesterolemia

  Homozygous familial hypercholesterolemia (HoFH), due to mutations in two alleles, is much more lethal. […] The diagnosis of HoFH can be made based on clinical and/or genetic criteria that endorsed by the European Atherosclerosis Society (EAS). […] The diagnosis includes meeting one of the following: 1) genetic confirmation of two mutant alleles of the LDLR, Apo(b), PCSK9, or LDLR adaptor protein 1 gene locus; or 2) an untreated LDL-C 500 mg/dL or treated LDL-C 300 mg/dL together with either cutaneous or tendon xanthoma before 10 years of age or untreated elevated LDL-C levels consistent with HeFH in both parents. […] To address the difficulties with diagnosis, a scientific statement from the American Heart Association (AHA) proposed a simpler classification for HoFH. […] Once a diagnosis is established, systematic cascade screening is essential to identify family members with FH given the autosomal-dominant inheritance pattern of the disease.

• #15 Detecting familial hypercholesterolaemia in general practice

  https://www.racgp.org.au/afp/2012/december/familial-hypercholesterolaemia

  Familial hypercholesterolaemia can be diagnosed with phenotypic criteria or a DNA test. […] Familial hypercholesterolaemia meets all of the World Health Organization screening criteria as defined by Wilson and Jungner. […] The most cost effective method of screening for FH is cascade screening family members of known 'index cases’ of FH but at a population level this requires that an efficient method be adopted to detect index cases. […] The probability of a person having FH can be determined using the Dutch Lipid Clinic Network Criteria which scores people for their clinical history, physical features, and the plasma level of LDL-cholesterol. […] It is important to note that before making a phenotypic diagnosis of FH in adults and children, secondary causes of hypercholesterolaemia such as hypothyroidism, nephrosis, cholestasis and use of steroids must be excluded.

• #16 Familial hypercholesterolemia – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/familial-hypercholesterolemia/diagnosis-treatment/drc-20353757

  A detailed family history is an important key to diagnosing familial hypercholesterolemia. Doctors will be interested to know if your siblings, parents, aunts, uncles or grandparents ever had high cholesterol levels or heart disease especially during childhood. […] During the physical exam, doctors usually check for cholesterol deposits that may occur in the skin around the hands, knees, elbows and eyes. Tendons in the heel and hand may be thickened, and a gray or white ring may develop around the iris of the eye. […] The National Heart, Lung, and Blood Institute recommends that a person’s first cholesterol screening should occur between the ages of 9 and 11, and then be repeated every five years after that. Earlier or more-frequent screenings may be suggested for families with a history of childhood heart disease.

• #17 Recommendations | Familial hypercholesterolaemia: identification and management | Guidance | NICE

  https://www.nice.org.uk/guidance/cg71/chapter/recommendations

  Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with: a total cholesterol level greater than 7.5 mmol/l or a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative). Healthcare professionals should exclude secondary causes of hypercholesterolaemia before a diagnosis of FH is considered. Use the Simon Broome criteria or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings. This should be done by a healthcare professional competent in using the criteria. Refer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5. Healthcare professionals should be aware that the absence of clinical signs (for example, tendon xanthomata) in adults and children and young people does not exclude a diagnosis of FH. To confirm a diagnosis of FH, healthcare professionals should undertake 2 measurements of LDLC concentration because biological and analytical variability occurs. When considering a diagnosis of FH, healthcare professionals with expertise in FH should use standardised pedigree terminology to document, when possible, at least a three-generation pedigree. Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDLC concentration does not meet the diagnostic criteria. In a family where a DNA mutation is identified, not all family members may have inherited the mutation. When DNA testing has excluded FH in a member of a family, healthcare professionals should manage the person’s coronary heart disease risk as in the general population. In children aged 0 to 10 years at risk of FH because of 1 affected parent, offer a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test. In children at risk of homozygous FH because of 2 affected parents or because of the presence of clinical signs, for example, cutaneous lipid deposits (xanthomata), LDLC concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDLC concentration is greater than 11 mmol/l then a clinical diagnosis of homozygous FH should be considered. Healthcare professionals should offer all children and young people diagnosed with, or being investigated for, a diagnosis of FH a referral to a specialist with expertise in FH in children and young people. This should be in an appropriate child and young person-focused setting that meets the standards within the National service framework for children, young people and maternity services.

• #18 Exams and Tests

  https://www.cardiosmart.org/topics/familial-hypercholesterolemia/exams-and-tests

  A diagnosis of familial hypercholesterolemia (FH) is usually based on: […] A simple blood test to measure the amount of cholesterol in your blood. LDL-cholesterol is much higher among people with FH. […] A thorough family history. FH runs in families. Your care team will want to know if a close relative has FH, very high LDL cholesterol, or has died from heart or blood vessel disease at an early age. […] A physical exam, to look for any physical signs, including cholesterol deposits or bumps under the skin or around the eyes. […] Genetic testing may be used to confirm that someone has FH. Testing looks for gene changes, or variants, that have been linked to FH. […] If you have FH, family tracing or cascade screening with lipid and/or genetic testing can help identify other first-degree family members who might be affected. […] If there is suspected or confirmed FH in a parent, consider screening children starting at age 2. If both parents have FH, consider screening their children at birth.

• #19 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  If a patient is found to have familial hypercholesterolemia, family members should be screened for it in a cascading process. […] Genetic testing is the gold standard for diagnosing familial hypercholesterolemia. Most of the known mutations are in LDLR, but APOB, PCSK9, and potentially other genes involved in LDL-C catabolism can also have mutations. Several mutations remain unknown, and not finding a genetic mutation does not exclude the diagnosis, especially if there is strong phenotypic evidence. […] Finding a mutation also has prognostic value. At any LDL-C level, a gene-positive individual carries a higher risk of atherosclerotic cardiovascular disease than does a gene-negative one. […] Thus, early diagnosis of familial hypercholesterolemia is essential for risk stratification. […] The Dutch Lipid Network Criteria, the most widely used of the 3 sets of criteria, yields a score based on LDL-C level, physical findings, premature cardiovascular disease in relatives, and positive genetic testing if available. A score higher than 8 makes the diagnosis definite, as 80% of people in that category were found to have a genetic mutation.

• #20 Familial Hypercholesterolemia | Test Summary | Quest Diagnostics Familial HypercholesterolemiaFamilial Hypercholesterolemia

  https://testdirectory.questdiagnostics.com/test/test-guides/TS_FH/familial-hypercholesterolemia

  Alternatively, genetic testing alone can provide a definitive diagnosis. […] An international expert panel convened by the FH Foundation recommends testing for variants in the 3 genes most commonly associated with FH: LDLR, APOB, and PCSK9. […] For genetic diagnosis of FH, Quest Diagnostics offers DNA tests such as the Familial Hypercholesterolemia Panel (test code 94877), which tests for variants in LDLR, APOB, and PCSK9. […] A positive result indicates the presence of 1 or more pathogenic or likely pathogenic variants in LDLR, APOB, or PCSK9 genes and constitutes a genetic diagnosis of FH. […] A negative result indicates absence of a known pathogenic variant but does not exclude FH in a symptomatic patient; the disorder may be caused by variants in unexamined gene regions (ie, deep intronic) or other genes.

• #21 Familial hypercholesterolemia in adults: Overview – UpToDate

  https://www.uptodate.com/contents/familial-hypercholesterolemia-in-adults-overview

  Familial hypercholesterolemia (FH) is a common genetic disease caused by mutation of one or more of the genes critical for low-density lipoprotein cholesterol (LDL-C) catabolism. […] An individual may be labeled as having FH in one of two ways: DNA-based evidence of mutation in the LDLR, PCSK9, or APOB gene. Each of these genes influence LDL-C levels.

• #22 Familial hypercholesterolemia > Fact Sheets > Yale Medicine

  https://www.yalemedicine.org/conditions/familial-hypercholesterolemia

  Familial hypercholesterolemia (FH) is a genetic disorder that interferes with the body’s ability to process LDL cholesterol. […] FH can be diagnosed through clinical and/or genetic tests. Cholesterol screening is recommended to begin between ages 9 and 11 and once more between ages 17 and 21 and should be continued through adulthood. If the following criteria is met, then a diagnosis of FH could be considered: […] Multi-gene panel testing (a genetic test that searches for mutations in several genes at once) that searches for variants in the LDLR, LDLRAP1, APOB, and PCSK9 genes can also be used to diagnose FH. […] A genetic mutation within one of four well-studied genes LDLR, LDLRAP1, APOB, or PCSK9 causes the disorder. […] If left untreated, FH can be a life-threatening disorder. […] The Centers for Disease Control and Prevention (CDC) lists FH as a tier one genomic health condition, which means that studies have shown that medical interventions can decrease the likelihood a person with the genetic mutation will develop the disease. […] At Yale Medicine, our physicians work with patients diagnosed with FH closely to ensure they have the most personalized medication and treatment program possible. We have experts that can diagnose the condition and provide best therapies.

• #23 Genetic Testing for Familial Hypercholesterolemia

  https://www.southcarolinablues.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-familial-hypercholesterolemia/

  The Simon Broome and DLCN diagnostic criteria consider DNA-based evidence of mutations in any of APOB, LDLR, or PCSK9 to be suitable evidence for a definite diagnosis of FH. […] However, 10% of FH cases are identified, despite an estimated prevalence of 1:200 to 1:500. […] The authors concluded that Child-parent screening was feasible in primary care practices at routine child immunization visits. […] Genetic testing for patients with suspected FH should, at a minimum, include analysis of LDLR, APOB, and PCSK9. […] The EAS also recommends that cascade testing be performed when a causative mutation is known in an index case of heterozygous FH. […] The AHA noted that in healthcare systems that are less cohesive such as the US system, genetic testing is controversial for individuals in confirming diagnosis.

• #24 Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis

  https://www.mdpi.com/1648-9144/58/11/1665

  FH can be inspected using different diagnostic systems. The criteria of the Dutch Lipid Clinic are the most widely used in clinical practice. Based on these criteria, FH is diagnosed referring to blood lipid levels, family history of IHD (early death from myocardial infarction (MI) or other early IHD), patient’s history of early coronary artery disease (CAD), objective examination (tendon xanthoma, arcus cornealis), and naive lipidogram. […] Gene mutations are discovered in only 60–70% of individuals diagnosed with definite or probable FH according to clinical criteria. This means that some cases of FH are of polygenic origin or cause mutations in genes that have not been identified yet.

• #25 Familial Hypercholesterolemia (FH): Diagnosis, Genetics

  https://heartcare.sydney/familial-hypercholesterolemia/

  FH should be suspected in patients with a history of premature atherosclerotic cardiovascular disease or stroke, specifically in men under the age of 55 and women under 65. […] To formally diagnose FH, we often use a set of criteria like the Dutch Lipid Score, which considers the above factors, along with specific cholesterol levels and Genetic Testing results, if available. […] The Dutch Lipid Score assigns a numerical value to the individual based on several factors, including LDL-Cholesterol level, Family history of high cholesterol or early-onset cardiovascular disease, Personal history of early-onset cardiovascular disease, and Physical examination findings, such as xanthomas or corneal arcus. […] Genetic testing to establish the diagnosis of FH, should be considered in the following individuals: LDL-C 252 mg/dl (6.5 mmol/L), LDL-C level 193 mg/dl (5.0 mmol/L) plus clinical features suggestive of FH or established ASCVD, Dutch Lipid Score 6, and First- or second-degree relative with a confirmed genetic diagnosis of FH in one of the three genes known to cause FH.

• #26 What is Familial Hypercholesterolemia? | American Heart Association

  https://www.heart.org/en/health-topics/cholesterol/genetic-conditions/familial-hypercholesterolemia-fh

  Familial hypercholesterolemia (FH) is an inherited defect in how the body recycles LDL, or “bad” cholesterol. […] Both types of FH can be diagnosed with a physical exam and lab results, as well as personal and family history. They also can be discovered through molecular diagnosis, genetic diagnosis or genetic testing. It’s helpful when genetic testing reveals FH because it can alert relatives to their risk. […] If one person in a family has FH, then all immediate relatives — parents, siblings, children — should be checked for it. Similarly, if someone in a family has an early heart attack, it’s a good idea for other family members to get tested. […] Children with increased risk for FH should be screened beginning at age 2. All children should have their cholesterol checked between ages 9 and 11 and again between ages 17 and 21.

• #27

  https://link.springer.com/article/10.1007/s11883-021-00926-3

  The characteristic physical finding of tendon xanthomata and xanthelasmas is infrequently seen in HeFH children and is usually present in HoFH children. […] Three sets of phenotype-associated criteria for FH exist, in which clinical diagnostic tools are used for the identification of FH: the United States Make Early Diagnosis to Prevent Early Death (MedPed) Program, the Simon Broome Register Group in the UK, and the Dutch Lipid Clinic Network. […] While genetic confirmation of FH, by demonstrating of one of the causative mutations, is encouraged by several research groups and organizations, there is no universal agreement for the indication of mandatory genetic testing once the phenotype of FH is found. […] Cascade Screening occurs when screening of one patient results in a diagnosis that requires screening of additional family members for that same diagnosis. Following the diagnosis of FH at the proband, it is essential to examine additional family members for FH.

• #28 Familial Hypercholesterolemia: Screening, Diagnosis, and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2024/0900/editorial-hypercholesterolemia.html

  Familial hypercholesterolemia, an autosomal dominant genetic disorder, is characterized by markedly increased low-density lipoprotein (LDL) cholesterol that causes premature arteriosclerotic cardiovascular disease (ASCVD). Homozygous familial hypercholesterolemia typically presents with pathognomonic physical findings such as xanthomas or a corneal arcus. In contrast, heterozygous familial hypercholesterolemia is not indicated by clinical findings and is typically not diagnosed until after an early-onset ASCVD event (younger than 50 years). […] Screening for and diagnosing familial hypercholesterolemia in childhood can lead to treatment with lifestyle changes and medication, reducing the serious vascular effects of this dyslipidemia. […] The National Heart, Lung, and Blood Institute and American Academy of Pediatrics recommend universal screening for children 9 to 11 years of age as one approach.

• #29 Diagnosis of Familial Hypercholesterolemia in Children and Young Adults

  https://www.mdpi.com/1422-0067/25/1/314

  Diagnosis of Familial Hypercholesterolemia in Children and Young Adults […] The early detection and treatment of familial hypercholesterolemia (FH) in childhood and adolescence are critical for increasing life expectancy. […] For the diagnosis of FH in childhood and adolescence, in accordance with Russian clinical guidelines, the Simon Broome criteria are recommended; for the diagnosis of FH in adults 18 years of age and older, the Dutch criteria are advisable (Dutch Lipid Clinic Network [DLCN] Criteria). […] Molecular genetic testing is recommended to confirm an FH diagnosis in individuals with a score of ≥6 on the DLCN clinical criteria or with a “definite” diagnosis according to the Simon Broome criteria. […] Therefore, cascade screening for FH in children is relevant as the most effective way to identify new patients with FH.

• #30 Familial Hypercholesterolemia : LearnYourLipids

  https://www.learnyourlipids.com/lipid-disorders/familial-hypercholesterolemia/

  FH can be diagnosed by a blood cholesterol test, called a lipid panel, along with detailed personal and family history of heart disease and stroke. […] Although genetic testing is not always necessary, it can confirm the presence of mutations associated with FH. […] The American Heart Association has proposed the following criteria for heterozygous FH that can be used to diagnose FH: An untreated LDL-C 190mg/dl and either a first degree relative with LDL-C 190 or with known premature coronary heart disease (55 years in men and 60 years in women). […] Genetic testing with a mutation associated with FH. […] Criteria for homozygous FH: Untreated LDL-C over 400mg/dl. […] Skin or tendon xanthomas before the age of 10 years and untreated elevated LDL-c levels consistent with heterozygous FH in both parents. […] Testing close family members enables early detection of the disease.

• #31 Familial hypercholesterolemia – Wikipedia

  https://en.wikipedia.org/wiki/Familial_hypercholesterolemia

  On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations, ApoB mutations, and PCSK9 can be performed. […] FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. […] The most common genetic defects in FH are LDLR loss of function mutations, ApoB loss of function mutations, PCSK9 gain of function mutations and LDLRAP1. […] Genetic counseling can help assist in genetic testing following a positive cholesterol screen for FH.

• #32 The genetics and screening of familial hypercholesterolaemia | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-016-0256-1

  Recent research has developed a FH prognostic model, Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT), composed of nine clinical factors, to enhance FH case identification in primary care. […] FH must also be differentiated from other dyslipidaemias such as Familial Combined Hyperlipidaemia (FCHL) and polygenic hypercholesterolaemia with increased Lp(a), both of which may be associated with increased vascular risk and may present with a clinical phenotype suggestive of FH. […] In order to diagnose FH, secondary causes of hyperlipidaemia must be ruled out by excluding cholestatic liver disease, hypothyroidism, significant proteinuria, diabetes mellitus and excess alcohol. […] The National Institute for Health and Care Excellence (NICE) in the UK recommends FH cases should target a reduction in LDL-C levels of over 50 % from baseline (i.e. LDL-C levels before therapy).

• #33 The genetics and screening of familial hypercholesterolaemia | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-016-0256-1

  Cascade screening (CS), whereby family members are traced from an established FH index case, is more cost effective than any other screening strategy currently available and is recommended in NICE guidelines. […] International guidelines advocate targeted screening for the identification of new FH index cases in which screening can be directed at specific patient groups likely to show a high prevalence of FH such as those post acute coronary syndrome. […] The value of screening for FH mutations is not without controversy. As FH is only an indicator for likely elevated LDL-C and a proportion of elevated LDL-C cases are negative for the canonical variants, it has been argued that screening should focus on phenotype rather than genotype, both for the identification of index cases and in cascade screening, and that a focus on genetic screening can offer false reassurances to variant-negative patients who might still be at risk.

• #34 FH Genetic Test – Hypercholesterolaemia | Sonic Genetics

  https://www.sonicgenetics.com.au/patient/test-information/fh/

  FH can be clinically diagnosed using a combination of medical history, family history, the doctors clinical examination and measurement of cholesterol level in blood. […] However, genetic testing provides a definitive diagnosis of FH, and helps to define a persons risk of serious complications such as heart disease or stroke. […] The Australian Department of Health recommends that a person who fulfils one or more of the following conditions be tested for FH: […] Your doctor may also recommend testing of a person who does not fulfil any of these criteria. […] If the result of your FH genetic test is that a pathogenic mutation has been found, this confirms that you have a genetic diagnosis of FH. […] We strongly recommend that your first- and second-degree relatives have a genetic test for FH, preferably by the age of 10 years. […] Early treatment has been shown to manage cholesterol levels and reduce the chance of cardiovascular disease in later life. Both national and international guidelines recommend that children in a family with FH be tested by 10 years of age.

• #35 Screening for Familial Hypercholesterolemia: a Model for Preventive Medicine – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-screening-for-familial-hypercholesterolemia-model-articulo-S1885585714001212

  The most common genetic cause of premature coronary artery disease (CAD) is familial hypercholesterolemia (FH), an autosomal dominant condition in which half the offspring of an affected individual will also be affected from birth. The causative mutations are mainly found in the LDL receptor gene (LDLR) and less frequently in the apolipoprotein B gene and the proprotein subtilisin/kexin type 9 gene (PCSK9). The prevalence of heterozygous FH ranges from 1 in 300 to 1 in 500 individuals in the general population, and this condition is estimated to affect at least 100,000 people in Spain. Furthermore, FH accelerates atherosclerotic coronary disease by 10 to 40 years. In Spain, 55% of men and 24% of women with FH between 50 and 59 years of age have had some clinical manifestation of CAD, such as myocardial infarction and chest angina. Patients with homozygous FH, which affects approximately 1 per million inhabitants, have total cholesterol levels 500mg/dL and very premature CAD. Untreated, these individuals die before they are 20 years old. Therefore, FH is a public health problem, and diagnosis and treatment are mandatory.

• #36 Finding missed cases of familial hypercholesterolemia in health systems using machine learning | npj Digital Medicine

  https://www.nature.com/articles/s41746-019-0101-5

  Familial hypercholesterolemia (FH) is an underdiagnosed dominant genetic condition affecting approximately 0.4% of the population and has up to a 20-fold increased risk of coronary artery disease if untreated. […] Simple screening strategies have false positive rates greater than 95%. […] We developed a classifier to identify potential FH patients using electronic health record (EHR) data at Stanford Health Care. […] Our classifier obtained a positive predictive value (PPV) of 0.88 and sensitivity of 0.75 on a held-out test-set. […] In external validation on 466 FH patients (236 with genetically proven FH) and 5000 matched non-cases from the Geisinger Healthcare System our FH classifier achieved a PPV of 0.85. […] Our EHR-derived FH classifier is effective in finding candidate patients for further FH screening.

• #37 Finding missed cases of familial hypercholesterolemia in health systems using machine learning | npj Digital Medicine

  https://www.nature.com/articles/s41746-019-0101-5

  The importance of differentiating FH from other causes of high LDL-C is reflected by guidelines from multiple national and international organizations, with FH-specific recommendations covering diagnosis, treatment and cascade screening. […] Despite the morbidity and mortality associated with FH and the clear benefits of timely management, it is estimated that less than 10% of persons with FH in the US have been diagnosed, with the identification of index FH cases (probands) as a major bottleneck. […] Currently, guidelines recommend the application of diagnostic criteria (e.g., Dutch Lipid Clinic Network (DLCN) or Simon-Broome) in adults for which there is high clinical suspicion, which is usually based on untreated LDL-C values 190mg/dl plus a positive family history of early onset ASCVD.

• #38 Finding missed cases of familial hypercholesterolemia in health systems using machine learning | npj Digital Medicine

  https://www.nature.com/articles/s41746-019-0101-5

  The utility of these criteria is unclear given the real-world challenges in obtaining detailed family histories, low prevalence of variables such as physical exam findings like tendon xanthomas or elevated lipid levels and ASCVD events in relatives. […] Our random forest classifier demonstrated good positive predictive value and sensitivity upon application to an unseen internal test dataset (ppv 0.88, sensitivity 0.75) and an external Geisinger EHR dataset (ppv 0.85, sensitivity 0.67) including those with genetically confirmed FH. […] The ultimate utility of any screening test must be considered in the context of its cost-effectiveness. […] We believe the use of supervised learning to build a classifier that finds undiagnosed cases of FH is a compelling example of machine learning that matters. […] In conclusion, we have demonstrated that a supervised machine learning approach to building a classifier for finding patients that might have FH using EHR data is feasible with a positive predictive value of 0.88, sensitivity of 0.75 and specificity of 0.99.

• #39 Familial hypercholesterolaemia: symptoms, causes and treatments – BHF

  https://www.bhf.org.uk/informationsupport/conditions/familial-hypercholesterolaemia

  FH is not easy to diagnose. Your doctor may suspect FH if: […] If your results come back high, or if your doctor notices some of the physical signs of FH listed above, they will refer you to a specialist for an assessment, which is likely to include genetic testing. […] Genetic testing is a DNA test thats done to see if you have a faulty gene which can cause an inherited condition. […] If youre diagnosed with FH, your first-degree relatives (parents, siblings, children) should also be tested as soon as possible. […] Early diagnosis of FH means you can get treatment and improve your lifestyle to lower your cholesterol and avoid risk to your health.

• #40

• #41 Screening for Familial Hypercholesterolemia: a Model for Preventive Medicine – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-screening-for-familial-hypercholesterolemia-model-articulo-S1885585714001212

  Diagnosis of FH is based on high concentrations of low-density lipoprotein cholesterol (LDL-C), family history of hypercholesterolemia, presence of premature CAD, and cholesterol deposition in the form of xanthomas and/or arcus senilis. Early diagnosis allows preventive measures to be taken. If patients with FH and no history of CAD are treated with statins, the risk of CAD is reduced by 79%, to a level similar to that of the general population. […] Although many recent guidelines for the management of FH have highlighted the high associated cardiovascular risk, most patients with FH remain undiagnosed and untreated. There are a series of barriers to diagnosis and treatment. First, patients with most severe FH are usually first identified in specialist care or lipid clinics, whereas most patients are attended in primary care. Many individuals and family members with FH who have CAD have other common risk factors and so genetic hypercholesterolemia is not diagnosed. In the case of treatment, statin doses are insufficient and combination treatment is used too sparingly. Moreover, therapy is often started in the late stages of disease, when atherosclerosis has already developed as a result of life-long high LDL-C concentrations. Finally, health care systems are not sufficiently aware of the problem and there is a lack of screening programs.

• #42 Familial hypercholesterolaemia: A guide for general practice

  https://www1.racgp.org.au/ajgp/2019/september/familial-hypercholesterolaemia

  Once a diagnosis of FH is confirmed, lipid-lowering treatment (usually a statin, eg 20 mg rosuvastatin or 40 mg atorvastatin) should be commenced. […] Diagnosis of FH in children ideally occurs before the age of 10 years. […] Most patients diagnosed with FH in primary care can be managed by their general practitioner, especially if asymptomatic LDL-C levels are well controlled, and the patients dietary and lifestyle compliance is good. […] Because FH is a hereditary, lifelong condition likely to result in premature CHD or death unless properly managed, affected patients should have care plans developed to maximise best practice approach to treatment. […] Primary care physicians are uniquely placed to play an active part in detection and management of FH, but greater public and health professional awareness of the condition is needed.

• #43 Detecting familial hypercholesterolaemia in general practice

  https://www.racgp.org.au/afp/2012/december/familial-hypercholesterolaemia

  There are several important reasons for referring patients with probable FH to a specialist lipid clinic: Confirmation of the diagnosis, Cascade screening of family members, Cardiovascular disease assessment and disease prevention. […] Familial hypercholesterolaemia is an important but underdiagnosed cause of premature coronary artery disease. General practice could play an important role in identifying families with this condition and, in collaboration with specialist lipid clinics, instituting effective disease prevention.

• #44 Screening for Familial Hypercholesterolemia: a Model for Preventive Medicine – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-screening-for-familial-hypercholesterolemia-model-articulo-S1885585714001212

  Despite the growing interest in the investigation of FH, care of patients and their family members remains inadequate and substantial improvement in health services at all levels of care is needed. For a cascade screening program to be successful, the primary care system must be involved, engaging the family physician in the identification of the IC and in subsequent diagnoses when screening family members. Most CAD-free patients with FH can be identified by the family physician. The availability of clinical and laboratory data in electronic format in the health system provides an efficient means of opportunistic searching for undiagnosed patients. Most patients with FH whose management is straightforward can be attended in the long term in primary care. These patients are thought to account for 80% of all patients with FH. To improve the care of these patients, primary care physicians should be trained in the diagnosis and treatment of FH.

• #45 Homozygous Familial Hypercholesterolemia: Diagnosis and Emerging Therapies

  https://www.acc.org/Latest-in-Cardiology/Articles/2022/02/18/18/04/Homozygous-Familial-Hypercholesterolemia

  After consent is obtained, family members should be offered a standard lipid panel and genetic testing if a specific mutation is known. […] Genetic counseling also may help patients and their families better understand their diagnosis and future implications. […] The advent of monoclonal antibodies (mAbs) targeted against PCSK9 has ushered in a new era in lipid lowering among patients with hypercholesterolemia. […] Notably, only evolocumab carries an FDA indication for LDL-C lowering in HoFH. […] The ongoing ORION-5 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) will examine the LDL-C lowering efficacy of inclisiran among 56 patients with HoFH on a background of maximally tolerated lipid-lowering therapy. […] Survival is contingent on early identification and treatment with combination lipid-lowering therapies. […] Although defects in the LDLR have previously limited therapeutic options for patients with HoFH, several new and emerging LDLR-independent medications have made low LDL-C possible, potentially circumventing the need for invasive treatments, including lipoprotein apheresis and liver transplant.

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