IPS #14 Familial Hypercholesterolemia

What is familial hypercholesterolemia?

genetic condition causing high ‘bad’ cholesterol low-density lipoproteins (LDL) levels from a young age

what mutations can cause familial hypercholesterolemia?

LDLR, ApoB, PCKS9, LDLRAP1

how does a mutation in LDLR lead to familial hypercholesterolemia?

defective LDL receptors lead to cholesterol build up

how does a mutation in ApoB lead to familial hypercholesterolemia?

impaired recognition of LDL particles

how does a mutation in PCSK9 lead to familial hypercholesterolemia?

Increases LDL receptor degradation, reducing their availability

What is the inheritance pattern of familial hypercholesterolemia?

Autosomal dominant

-heterozygous is more common and more manageable

-homozygous is rarer and much more severe

t/f it is not important to catch this early, the cardiovascular risk is the same from birth?

false- early diagnosis and treatment is critical to lower cholesterol and reduce cardiovascular risks

How common is heterozygous FH?

1 in 250 people

how common is homozygous FH?

rare ~1 in a million people

what are the symptoms of FH, besides high cholesterol?

family history of: early heart attacks and coronary artery disease

Arcus senilis (white/gray ring around cornea due to cholesterol build up)

xanthoma (build up of cholesterol in the skin and tendons, can be painful)

xanthelasma (yellowish cholesterol deposits found on or around eyelids)

what are the steps of LDL recycling?

In the liver

1) LDL binds to LDLR and ApoB

2) LDL-LDLR complex group inside clathrin coated pits which is endocytosed

3) Complex moves to the endosome, LDLR releases LDL

4) LDLR is sent back to cell surface to bind to more LDL paricles

5) LDL is sent to lysosome for breakdown

what are 5 major classes of defects associated with the LDL receptor that have been identified in FH

class I- no synthesis of LDLR

class II- no transport of LDLR

class III- no binding of LDLR

class IV- no internalization of LDLR

class V- no recycling of LDLR

healthy ApoB-100

found in LDL, role in transporting and metabolism of lipoproteins, acts as a ligand for LDLR which allows LDL to be recognized by LDLR and taken away from blood

defective ApoB-100

autosomal dominant disorder, most frequently a point mutation (arg→gln residue at 2500), prevents binding of LDL to LDLR which prevents LDL receptor mediated clearance which increases LDL cholesterol levels

healthy PCSK9

regulates LDLR levels on the cell surface (decreases amount of LDLR), binding to LDLR → targets it for lysosomal degradation which increases LDL levels

defective PCSK9

missense gain of function mutation, induces greater levels of degradation of LDLR which lowers levels of LDLR which increases LDL levels

healthy LDLRAP1

helps with LDLR internalization, cytosolic adaptor protein in clathrin-coated pits that interacts with cytoplasmic tail of LDLR → mediates endocytosis of LDL-LDLR complex

defective LDLRAP1

induces the recessive type of familial hypercholesterolemia which is rare, leads to impaired LDLR function → reduces ability of moving LDL from blood into cell → elevates LDL cholesterol levels

How do you verify a diagnosis of familial hypercholesterolemia?

clinical assessment and family history, lipid profile testing, genetic testing

what is considered a high LDL cholesterol level for adults?

over 190 mg/dL

what is considered a high LDL cholesterol level in children?

over 160 mg/dL

what is the first line of treatment for familial hypercholesterolemia?

statins (atorvastatin/simvastatin)- inhibit cholesterol production in the liver (can lower LDL by ~50%)

what are the oral medications that can be used to treat familial hypercholesterolemia?

statins, cholesterol absorption inhibitors, bile acid sequestrants

how do cholesterol absorption inhibitors work?

limits cholesterol absorption in the intestines, can be used with statins for additional LDL reduction

how do bile acid sequestrants work?

bind to bile acids to reduce cholesterol reabsorption, often a secondary option due to the digestive side effects

what type of injection can be given as an FH treatment?

PCSK9 inhibitors- helps liver remove LDL cholesterol from the bloodstream, used when statins and other oral medications are not enough

what are the treatment options for severe cases of FH?

LDL apheresis- similar to dialysis: removes blood, filters out LDL cholesterol and returns blood to the body

liver transplant- reserved for extreme cases that are unresponsive to other treatments, replaces liver to improve cholesterol metabolism

what lifestyle modifications can be made with FH?

Diet, exercise, stop smoking, weight management

how can FH affect the oral cavity?

increased systemic inflammation (periodontal disease), xanthomas on the gingiva or oral mucosa, atherosclerosis (impaired circulation weakens immune response)

t/f oral medications and statins do not cause xerostomia so there is nothing to worry about when your patient is prescribed these medications

false

what is an oral health concern with LDL apheresis?

usage of anticoagulants during the procedure may increase risk of bleeding or bruising

what are oral health concerns with a liver transplant?

immunosuppressant medications that are prescribed during transplantation increase risk of oral infections and can cause gingival hyperplasia

what medication is used as the first line of treatment for FH?

atorvastatin / simvastatin

t/f hairy tongue is a possible effect of FH on the oral cavity

false

what separates the LDL-LDLR complex?

endosome

class I defect

no synthesis

class II defect

no transport

class III defect

no binding

class IV defect

no internalization

class V defect

no recycling