This document discusses familial hypercholesterolemia (FH), a genetic disorder characterized by severely elevated cholesterol levels. FH is caused by mutations in the LDL receptor gene and has two main types: homozygous FH and heterozygous FH. Homozygous FH causes much higher cholesterol levels and earlier onset of heart disease. The document reviews the pathophysiology and genetics of FH, signs and symptoms, diagnosis, and treatment options such as statins, resins, and PCSK9 inhibitors. Early detection and treatment are important to prevent premature heart attacks in those with FH.
7. Definition
• Familial hypercholesterolemia (FH)
is an autosomal dominant disorder
that causes severe elevations in
total cholesterol and low-density
lipoprotein cholesterol (LDLc).
16. 3 Forms of FH
Familial
Hyperchol
esterolemi
a
Autosomal
Dominant
Hypercholes
terolemia
Autosomal
dominant
hypercholest
erolemia,
type B
Autosomal
recessive
hypercholest
erolemia
18. FLDB = Familial ligand defective apoB-100 , CHD = Coronary Heart Disease
Homozygous FH Heterozygous FH
Symptomatic in Childhood Symptomatic mainly in Adulthood
Normal Triglycerides Normal Triglycerides
LDLc >600 mg/dL LDLc Usually >250 mg/dL
<20 yrs: LDLc>200 mg/dL is FH/ (FLDB)
Adults >20 yrs: >290-300 mg/dL
Total Cholesterol >600 mg/dL Total Cholesterol>250 mg/dL
Two major genetic defects in
LDL metabolism
One major genetic defect in LDL
metabolism
Tendon and cutaneous
xanthomas often before age 10
years
Arcus cornealis and Achilles tendon
xanthomas often present
CHD onset in childhood CHD onset 30-60 years
Poorly responsive to drugs;
apheresis often indicated
Most respond to drugs, but individual
response variable
26. The Urgency!
“For untreated FH homozygotes, the
prognosis is down-right tragic. Heart
attacks have been documented in 2-year-
old infants and more frequently at ages 8,
10, and 12 due to extremely aggressive
coronary atherosclerosis. Untreated, most
FH homozygotes will have heart attacks in
their late teens, and few will survive past
their 20s.”
- Bob Carlson, MHA, Biotechnol Healthc Senior Contributing
Editor
27. Routine Lipid Screening
Prenatal testing for pregnancies at high risk
Serial single-gene testing
Multi-gene panel testing
Laboratory
Genetic testing can identify genetic mutations associated with FH
34. References
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http://emedicine.medscape.com/article/121298-clinical
2. Jeffrey S. (2016). Very High LDL Seldom Caused By FH Gene Variants. Medscape
http://www.medscape.com/viewarticle/861390
3. Gidding SS, et al. (2015). The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart
Association. AHA Journals. 2015;132:2167-2192. http://circ.ahajournals.org/content/132/22/2167
4. Belgian Artherosclerosis Society. (2015). Prevention : Familial hypercholesterolaemia in children and adolescents: gaining
decades of life by optimizing detection and treatment. http://www.lipidclub.be/newsletter.php
5. SNPedia. (2016). Familial Hypercholesterolemia. https://www.snpedia.com/index.php/Familial_hypercholesterolemia
6. SNPedia. (2011). Hypercholesterolemia. https://www.snpedia.com/index.php/Hypercholesterolemia
7. Soutar AK, Naoumova RP. (2004). Autosomal recessive hypercholesterolemia. Semin Vasc Med. 4(3):214-8.
https://www.ncbi.nlm.nih.gov/pubmed/15630633
8. Youngblom E, Pariani M, & Knowles JW. (2016). Familial Hypercholesterolemia. GeneReviews [Internet].
https://www.ncbi.nlm.nih.gov/books/NBK174884/
9. Sharifi M, et al. (2016). Cardiovascular biomarkers in monogenic familial hypercholesterolaemia and polygenic
hypercholesterolaemia. Artherosclerosis Journal. 2016.09.055 http://www.atherosclerosis-journal.com/article/S0021-
9150(16)31369-7/abstract
10. Orsó E1, Ahrens N, Kilalić D, & Schmitz G. (2009). Familial hypercholesterolemia and lipoprotein(a) hyperlipidemia as
independent and combined cardiovascular risk factors. PubMed. 2009 Dec 29;10(5):74-8.
https://www.ncbi.nlm.nih.gov/pubmed/20129380
11. Novelli G, et al. (2008). Genetic tests and genomic biomarkers: regulation, qualification and validation. Clin Cases Miner
Bone Metab. 2008 May-Aug; 5(2): 149–154. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781197/
12. Brumit ML. (2014). Heterozygous vs Homozygous FH. Familial Hypercholesterolemia Foundation.
https://thefhfoundation.org/heterozygous-vs-homozygous-fh
13. Familial Hypercholesterolemia Foundation. (N/A). About HoFH. https://thefhfoundation.org/about-fh/homozygous-
familial-hypercholesterolemia
14. Staff FH Foundation. (2016). FH and Personalized Medicine. The Familial Hypercholesterolemia Foundation. March 10,
2016. https://thefhfoundation.org/fh-and-personalized-medicine
15. Huber J. (2016). Familial hypercholesterolemia: A genetic disease in need of early testing. Stanford Medicine.
http://scopeblog.stanford.edu/2016/04/26/familial-hypercholesterolemia-a-genetic-disease-in-need-of-early-testing/
16. National Human Genome Research Institute. (2013). Learning About Familial Hypercholesterolemia.
https://www.genome.gov/25520184/
Hinweis der Redaktion
4 typical mutations: 1. LDL Receptor gene, codes for LDL Receptor on hepatocytes, which binds to ApoB on LDL particle, inducing endocytosis of LDL. 2. ApoB gene, codes for ApoB which acts as a ligand, binding LDL particle on receptor. 3. PCSK9 gene codes for PCSK9 enzyme which degrads LDL receptors? 4. LDLRAP1 (ARH) gene, mediates internalization via clathrin coated pits