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.

1. Dr. Julius King Kwedhi,
ЦИОП, 4th Year

2. Objectives
Review Lipoproteins
Familial Hypercholesterolemia, a
Genetic Disorder
Pathophysiology of FH
Types of FH
FH Clinical Presentation
Diagnosis & Management
Treatment

3. Lipoproteins

5. LDL Endocytosis

6. LDL Endocytosis

7. Definition
• Familial hypercholesterolemia (FH)
is an autosomal dominant disorder
that causes severe elevations in
total cholesterol and low-density
lipoprotein cholesterol (LDLc).

8. A Genetic Disorder

9. HoFH HeFH

10. Epidemiology of FH

11. 4 Known Genes Involved

12. Single
Nucleotide
Polymorph
isms
rs7566605,(In
sulin-induced
gene 2
(INSIG2),
Chromosome
2)
rs854560,
(Paraoxonases
1(PON1
gene),
Chromosome
2)
rs505151
(PCSK9 gene,
Chromosome
1)
rs12720762,
APOB gene,
Chromosome
19

13. Chromosome 19
 FH is an autosomal dominant disorder
 Mutations in the LDL receptor gene on
Chromosome 19

14. Pathophysiology

16. 3 Forms of FH
Familial
Hyperchol
esterolemi
a
Autosomal
Dominant
Hypercholes
terolemia
Autosomal
dominant
hypercholest
erolemia,
type B
Autosomal
recessive
hypercholest
erolemia

17. 2 Types of FH

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

19. Lipoproteins Distribution

20. Signs & Symptoms

21. Achilles Tendons Xanthomas

22. Corneal Arcus

23. Metacarpal Phalangeal
Extensor Tendons Xanthoma

24. Tendon Xanthomas

25. Xanthelasmas

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

28. Treatment
HMG-CoA
Reductase
Inhibitors
(Statins)
Vitamins
Bile acid
Sequestrant
s (resins)
Lipid-
Lowering
Agents,
Other
PCSK9
Inhibitors
Liver
Transplantat
ion
Portacaval
anastomosis
Estrogen
replacement
Therapy in
postmenopa
usal women
LDL
Apheresis

30. Treatment

31. Interindividual Variations

32. Gene Therapy

33. FH Management

34. References
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familial-hypercholesterolemia
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