Transcript Familial Hyperlipidemias - Welcome to the Department of

FAMILIAL HYPERLIPIDEMIAS
Julia Creider, PGY4 Endocrine
OBJECTIVES
 Review
lipid and lipoprotein classification and
nomenclature
 Understand the pathways of cholesterol
biosynthesis and metabolism
 Review primary disorders of hyper- and
hypolipidemia
Low-Density Lipoprotein (LDL)
 Triglycerides (TG)
 High-Density Lipoprotein (HDL)

LIPIDS
 Group
of naturally occurring molecules
 Biologically important lipids





Free cholesterol
Cholesterol esters (CE)
Triglycerides (TG)
Phospholipids
Fat soluble vitamins (A, D, E, and K)
 Main
biological functions include
Storing energy
 Signaling
 Structural components of cell membranes

LIPOPROTEINS
 Large
macromolecular complexes that transport
hydrophobic lipids surrounded by hydrophilic
phospholipids and proteins
LIPOPROTEINS
Type
Site of Origin
Major Lipids
Major
Apolipoprotiens
Chylomicrons
(CM)
Intestine
85% TG
B48, A1, AIV
CM Remnant
Intestine
60% TG, 20% C B48, E
VLDL
Liver
55% TG, 20% C B100, E, C1, CII,
CIII
IDL
From VLDL
35% C, 25% TG B100, E
LDL
From IDL
60% C, 5% TG
HDL
Liver, intestine, 25% PL, 20% C, A1, AII, C1, CII,
plasma
5% TG (50%
CIII, E
protein)
Lp(a)
Liver
60% C, 5% TG
B100
B100, (a)
LIPOPROTEINS
Lp(a)
APOLIPOPROTEINS
 Protein
component of lipoproteins
 Function
Activate enzymes important to lipid metabolism
 Act as ligands for cell surface receptors

Apolipoprotein
Site of Synthesis
Major Functions
Structural protein of HDL
Cofactor for LCAT
Ligand for ABCA-1 and SR-B1
ApoA-1
Liver, intestine
ApoA-II
Liver
ApoA-IV
Intestine
ApoA-V
Liver
Activator of LPL lipolysis
ApoB-100
Liver
Protein for VLDL, IDL, LDL
ApoB-48
Intestine
Inhibits apo-E binding to receptors
Activator of LCAT
Facilitates lipid secretion from intestine
Protein for CMs
ApoC-1
Liver
Modulates apo-E mediated binding of
remnants
Activate LCAT
ApoC-II
Liver
Cofactor for LPL
ApoC-III
Liver
Remnant binding to receptors
Inhibitor of LPL
ApoE
Liver, brain, skin,
spleen, testes
Apo(a)
Liver
Ligand for LDL & remnant receptor
Reverse cholesterol transport
Unknown
RECEPTORS
 Low-Density
Lipoprotein Receptor (LDLR)
Present on cells throughout the body
 Mediates uptake of cholesterol-rich lipoproteins
 Requires specific proteins on lipoprotein surface

ApoB-100 (LDL)
 ApoE (CM remnants, VLDL, IDL, and HDL)


Number of LDLR on cell surface is tightly regulated by
intracellular cholesterol content
 Low-Density



Lipoprotein Receptor-Related Protein (LRP)
Aka Remnant receptor
Binds with high affinity to ApoE (CM remnants, VLDL)
Does not bind LDL
IMPORTANT ENZYMES
 Lipoprotein







Lipase (LPL)
Bound to capillary endothelial cells
Mediates hydrolysis of TGs to release FFA from CMs
and VLDL
Requires ApoC-II as cofactor
Activated by ApoA-V
Inhibited by ApoC-III
Activated by insulin in adipocytes
Activated by glucagon and adrenaline in muscle and
myocardial tissues
IMPORTANT ENZYMES
 Hepatic
Lipase (HL)
Hydrolyzes TGs in final processing of CM remnants
 Completes processing of IDL to LDL
 Facilitates interaction of remnant lipoproteins with
LRP for internalization by hepatocytes
 Participates in conversion of HDL2 back to HDL3

WHAT HAPPENS WHEN YOU EAT? (1)
 Brush
boarder of epithelial cells of small intestine
(duodenum and proximal jejunum) synthesize
CMs from dietary fat and cholesterol
 CMs enter mesenteric lymph and are absorbed
into general circulation by the thoracic duct
 Newly synthesized CMs have:
ApoB-48
 ApoA-1
 ApoA-IV

 They
acquire ApoE and C-apolipoproteins
(primarily from HDL)
WHAT HAPPENS WHEN YOU EAT? (2)
 LPL
catalyzes release of FFAs from CM TG’s and
converts them to CM remnants
 FFAs are:
Stored in adipose tissue
 Oxidized as energy source
 Reutilized in hepatic lipoprotien TG synthesis (VLDL)

 Hepatic
lipase helps in final preparation of CMs for
uptake by hepatocytes
 CM remnants are rapidly cleared by the liver by
either LDL or LRP receptors, mediated by ApoE
ApoB-48
ApoA-1
ApoA-IV
ApoE, C1, CII, CIII from HDL
ApoB-48
ApoE
VLDL
 Synthesized
by the liver
 Production stimulated by increased delivery of FFA to
hepatocytes
 Microsomal triglyceride transfer protein (MTP)
Transfers TG and PL to nascent ApoB containing
lipoproteins (ApoB-100, and B48)
 Deficiency of MTP causes Abetalipoproteinemia

 VLDL
triglycerides are hydrolyzed by LPL and HL
 Converted to smaller particles that are increasingly
rich in cholesterol
IDL
 Metabolic
product of VLDL catabolism by LPL
 Primary proteins are ApoE and ApoB-100
 Fate:
Further processed by LPL and HL to LDL
 Removed from plasma by the LDLR (uptake mediated
by ApoE

LDL
 50%
of VLDL makes it
to LDL
 70% of total plasma
cholesterol is in LDL
 Major apolipoprotein is
ApoB-100
 Uptake by the LDLR is
mediated by ApoB-100
 Delivers cholesterol to
cells
B100, E, C1, CII, CIII
B100, E
B100
LIPID DISORDERS
 Previously
classified according to Fredrickson
phenotype
 Categorized by type of lipoprotein particle that
accumulated in the blood
 Does not include HDL
 Not take into account cause
 Not distinguish between primary and secondary causes
FREDRICKSON PHENOTYPES
Phenotype
Lipoprotein
Lipid Elevation
Type I
CMs
TG
Type IIa
LDL
TC
Type IIb
LDL and VLDL
TC and TG
Type III
IDL
TC and TG
Type IV
VLDL
TG
Type V
VLDL and CMs
TC and TG
PRIMARY DISORDERS OF HYPERLIPIDEMIA
 Increased
Cholesterol
 Increased
Cholesterol and Triglycerides
 Increased
Triglycerides
PRIMARY DISORDERS OF HYPERLIPIDEMIA
 Increased





Cholesterol
Familial Hypercholesterolemia (FH)
Familial Defective Apolipoprotein B100 (FDB)
Autosomal Recessive Hypercholesterolemia (ARH)
Sitosterolemia
Polygenic Hypercholesterolemia
FAMILIAL HYPERCHOLESTEROLEMIA (FH)
 Autosomal
dominant
 Caused by mutation in LDL receptor gene

>900 described mutations
 Markedly
elevated LDL (>95%ile)
 Heterozygous 1 in 500, homozygous 1 in 106
60-80, 000 Canadians
 French Canadian, Christian Lebanese, Dutch South
Afrikaners
 ~5% of men with MI age < 60

 High
Risk of CAD if untreated > 60% men, > 30%
women by age 60
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
WHEN TO CONSIDER FH
 Very
high LDL (typically > 5.0 mmol/L)
 Personal history of early cardiovascular disease
 Typical physical findings:
Xanthelasmas
 Arcus cornealis
 Tendon xanthomas

 Family
history:
Early cardiovascular disease
 Marked hyperlipidemia

XANTHALASMAS
ARCUS CORNEALIS
TENDON XANTHOMAS
HOMOZYGOUS FH
Very rare, 1 in 106
 Marked
hypercholesterolemia
from birth

TC 15 – 25 mmol/L,
 LDL 14 - 25 mmol/L


Symptomatic CHD
< 10 years of age, MI as
young as 18 months
 If untreated, usually die in
20’s of CHD

Xanthomas, xanthelasma
early in life
 Tuberous xanthomas

Katz P. 2014. Lipid metabolism & clinical lipid disorders.
SCREENING FOR FH
1.
Targeted screening to identify FH index cases
with at least 1 feature:
Personal or family history of clinical stigmata or
premature CVD
 Family history of significant hypercholesterolemia

2.
Cascade screening to detect affected members
 Opportunistic
screening should be done around time of
cardiovascular event
 Canadian-specific cascade screening
 www.fhcanada.net
CCS: Position Statement on FH. 2014
FH DIAGNOSIS
 Homozygous

Suspect in child with TC > 12.9 or xanthomas
 Heterozygotes
Primarily clinical diagnosis
 Family history very important
 Standard criteria have been suggested:

Simon-Broome Criteria
 Dutch Lipid Clinic Criteria


If family member has known FH and mutation can do
cascade testing in family members
Yuan G et al. 2006. CMAJ 17(8):1124
Yuan G et al. 2006. CMAJ 17(8):1124
FH DIAGNOSIS
Yuan G et al. 2006. CMAJ 17(8):1124
WHEN TO DO GENETIC TESTING?
 Cases
of diagnostic uncertainty
 Unavailable family history
 Borderline lipid levels
 Screened as possible or probable FH
 Will change management
CCS: Position Statement on FH. 2014
TREATMENT OF FH
 Global

risk factor assessment and management
HTN, DM, smoking, obesity
 Homozygotes
– plasmapharesis or LDL apheresis
 Heterozygotes – statins +/- other agents
Ezetimibe, bile acid sequestrants, niacin
 Newer agents PSCK9 monoclonal antibodies

 Treatment
goal is at least a 50% reduction in LDL
or less than 2.0 mmol/L
Feldman D et al. 2015. CurrAtherosclerRep 17(1):473.
TREATMENT OF FH
Feldman D et al. 2015. CurrAtherosclerRep 17(1):473.
CHOLESTEROL BIOSYNTHESIS
 Cholesterol
is either absorbed from diet or synthesized
by cells in the body
 3 molecules of acetate are condensed to form 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
 HMG-CoA is converted to mevalonic acid by
HMG-CoA reductase RATE LIMITING STEP
 Feedback


regulation:
 intracellular cholesterol  HMG-CoA reductase
Cholesterol deficiency upregulate enzyme
ENTEROHEPATIC CIRCULATION
 Either
excreted as free cholesterol (FC) in bile or
converted to bile acids (BA)
 50% of FC and 97% of secreted BA are reabsorbed
 Reabsorbed cholesterol and BA regulate de novo
cholesterol and bile acid synthesis in the liver
 7-αHydroxylase
RATE LIMITING STEP in
BA synthesis
 Feedback regulation by recirculating BA
 Closely coupled to HMG-CoA reductase activity
Statins:
inhibit HMG CoA reductase
decrease cholesterol
upregulate LDL-R expression
increased clearance of LDL-C
Bile acid sequestrants:
Decrease FC/BA reabsorption
Ezetimibe:
inhibit intestinal absorption
Niacin:
1. Direct inhibition of DGAT2
2. Decrease lipolysis and FFA
influx to liver
3. Increase ApoB catabolism
PCSK9
Mullard A. 2012. Nature Rev Drug Discovery 11:817
FAMILIAL DEFECTIVE APOLIPOPROTEIN B100
 Mutation
in ApoB-100 that impairs its ability to bind to
the LDL receptor
 Single mutation accounts for almost all cases

Substitution of glutamine for arginine at aa3500
 Phenotypically
similar to FH
Isolated elevated LDL
 Tendon xanthomas and xanthelasma
 Premature CVD

 Generally

less severe
Clear remnant particles through LDL receptor via ApoE
Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed
AUTOSOMAL RECESSIVE
HYPERCHOLESTEROLEMIA
 Mutation
in ARH which
encodes LDLR adaptor
protein 1
 Mediates endocytosis of
LDL receptor in
hepatocyte cells
 Very rare – described in
Sardinia, Lebanon
✕
Soutar A. 2010. IUBMB Life. 62(2):125.
SITOSTEROLEMIA
 Very
rare autosomal recessive
 Mutations in Adenosine triphosphate binding
cassette transporter (ABCG) 5 or 8
 Function to remove passively absorbed plant sterols
 Leads to elevations of sitosterol and campesterol
 Presentation:
Xanthomas
 Premature CHD
 Arthralgias, hemolysis, thrombocytopenia

 Requires
liquid or gas chromatography to identify
 Treatment – restriction of dietary plant sterols and
ezetimibe
Othman R et al. 2013. Atherosclerosis. 231(2):291.
POLYGENIC HYPERCHOLESTEROLEMIA
A
cholesterol value > 95th percentile for
population
 Exclude other primary genetic causes by absence
of tendon xanthomas and family history in ≤ 10%
of first degree relatives
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
PRIMARY DISORDERS OF HYPERLIPIDEMIA
 Increased
Cholesterol and Triglyceride
Familial Combined Hyperlipidemia
 Familial Dysbetalipoproteinemia

FAMILIAL COMBINED HYPERLIPIDEMIA (FCH)
 Autosomal
dominant
 Common disorder (5-7%)
 Unknown genetic cause, likely multiple genes
 Overproduction of ApoB VLDL, LDL or both
 Moderate elevations of cholesterol or TG or both
 Predominant lipid abnormality can vary among
affected family member or a single person over
time
Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed
FAMILIAL COMBINED HYPERLIPIDEMIA (FCH)
 Clinically

Overlapping features of metabolic syndrome
Insulin resistance
 Obesity
 Hyperuricemia
 Low HDL

No xanthomas
 Increased susceptibility to CHD


11% of male survivors of MI < age 60
 Treatment
Lifestyle – diet, exercise, weight loss
 Pharmacotherapy – targeted at specific lipid
abnormality

Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed
FAMILIAL
DYSBETALIPOPROTEINEMIA/TYPE III
HYPERLIPOPROTEINEMIA
 Mutations
in ApoE
 Results in impaired binding of ApoE to lipoprotein
receptors and accumulations of remnant particles (CM
remnants and IDL)
 Moderate to severe TG and TC
 LDL reduced (cleared by LDL receptor via ApoB-100)
Marais A et al. 2014.CritRevClinLabSci. 51(1):46.
ApoB-48
ApoE


B100, E
×
×
B100
FAMILIAL
DYSBETALIPOPROTEINEMIA/TYPE III
HYPERLIPOPROTEINEMIA
 Typically
autosomal recessive (rarely dominant)
 1 in 10, 000
 Majority are homozygous of ApoE-2 genotype
 ~ 1% population is ApoE2/E2, only 0.01% have type III


Requires 2nd exacerbating metabolic factor
Hypothyroidism, menopause, alcohol, diabetes
 Premature
vascular disease (including PVD)
 Treatment



Treat exacerbating factor
Diet
Fibrates +/- statins
Marais A et al. 2014.CritRevClinLabSci. 51(1):46.
PALMAR XANTHOMAS
 Yellowish
plaques on palms – especially creases
and flexural surface of fingers
PRIMARY DISORDERS OF HYPERLIPIDEMIA
 Increased
Triglceride
Lipoprotein Lipase Deficiency
 Apolipoprotein CII Deficiency
 Familial hypertriglyceridemia

LIPOPROTEIN LIPASE DEFICIENCY
 Autosomal
recessive
 Mutation in the LPL gene
Absence or inactivation of LPL protein
 Impaired clearance of TG-rich lipoproteins from
plasma
 Accumulation of CMs and VLDL

 Chylomicronemia
Syndrome
Marked hypertriglyceridemia (TG >22.6 mmol/L)
 Recurrent abdominal pain /pancreatitis

Rahalkar A et al. 2009.Can J Physiol Pharmacol. 87(3):151.
LIPOPROTEIN LIPASE DEFICIENCY
 Usually
present in infancy or childhood
 Clinically





Eruptive xanthomas
Lipemia retinalis
Hepatosplenomegaly
Neurological manifestations
Dyspnea
 Biochemically
Lipemic plasma
 Pseudohyponatremia

 Treatment
– diet, fibrates
Rahalkar A et al. 2009.Can J Physiol Pharmacol. 87(3):151.
ERUPTIVE XANTHOMA
LIPEMIA RETINALIS
LIPEMIC PLASMA
APOLIPOPROTEIN CII DEFICIENCY
 Rare
autosomal recessive disorder (< 1 in 106)
 ApoC-II necessary cofactor for LPL activity
 Chylomicronemic syndrome similar to LPL
deficiency
Severely elevated TG
 Lipemic serum
 Recurrent pancreatitis/abdominal pain
 Eruptive xanthmoas and lipemia retinalis

 Absent
ApoC-II on electrophoresis
 Treatment – diet, fibrates
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
FAMILIAL HYPERTRIGLYCERIDEMIA
 Overproduction
of VLDL with near normal ApoB
production
Typically TG 2.3-5.6
 Normal LDL
 Often low HDL

 Must
be present in half of 1st degree relatives to
diagnose
 Eruptive xanthomas usually not present
 Obesity, insulin resistance common

Exacerbating factors – hypothyroid, estrogen therapy,
alcohol
 Uncertain
if increase CHD risk
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
HIGH-DENSITY LIPOPROTEIN (HDL)
 Redistribution
of lipids among lipoproteins and cells
by REVERSE CHOLESTEROL TRANSPORT:

HDL acquires cholesterol from cells and transports it to
other cells that require cholesterol or to the liver for
excretion
ORIGIN OF HDL
1.
Liver makes ApoA-I phspholipid disc (nascent,
pre-beta HDL)
2.
Small intestine directly synthesizes small
ApoA-I containing HDL particles
3.
Derived from surface material (ApoA-I and PL)
that comes from CM and VLDL during lipolysis
by LPL
ACQUISITION OF CHOLESTEROL BY HDL
1.
Aqueous transfer from cells
Free cholesterol moves by passive desorption from high
concentration in membranes of cells with excess
cholesterol to low concentration on HDL surface

2.
Transport by a cell-surface binding proteins
SR-B1 – transfers CEs through hydrophilic channel
ABCA1




Binds ApoA-1 or a pre-beta HDL disc to the cell membrane and
facilitates transfer of FC and PL from cell to HDL precursor
ATP binding cassette transporters (ABCG1 and ABCG4)
stimulate cholesterol efflux to mature HDL (HDL2 and
HDL3)
MATURATION OF HDL
 Nascent
HDL particles (ApoA-I phospholipid discs) are
excellent acceptors of excess cholesterol from cells or other
lipoproteins
 Lecithin-cholesterol acyltransferase (LCAT)
Converts free cholesterol to cholesterol esters (CEs)
 LCAT is activated by ApoA-I

 CEs
are more hydrophobic, turn disc sphere (HDL3)
 HDL3 accepts and esterifies free cholesterol

increases in size  HDL2
FATE OF HDL2
1.
2.
3.
4.
Reconverted to HDL3 by hepatic lipase
Exchange CE for TG with VLDL, IDL, LDL and
remnants via CETP which are then indirectly
delivered to the liver and taken up by remnant
receptor (MAJOR)
Via SR-B1 receptor deposit CEs directly to
liver, adrenal, gonads
Is further enriched with CE and acquires ApoE
becoming HDL1 thereby allowing interaction
with LDL receptor allowing excretion of
cholesterol by the liver (MINOR)
PRIMARY DISORDERS OF HDL METABOLISM
Disorder
Mutant
Gene
AD vs
Frequency
AR
HDL
Corneal
opacification
Early
vascular
disease
Familial Hypoalphalipoproteinemia
Unknown
AD
~1/400
0.5-0.8
No
Yes
Familial ApoA-I and
ApoC-II deficiency
ApoA-I or
ApoC-II
AR
Rare
<0.1
Yes
Yes
ApoA-I Milano
ApoA-I
AD
Rare
~0.3
No
No
LCAT deficiency
LCAT
AR
Rare
<0.3
Yes
Yes
Fish-eye disease
LCAT
AR
Rare
<0.3
Yes
No
Tangier disease
ABCA1
AR
Rare
<0.1
Yes
Yes
CETP deficiency
CETP
AR
Rare
>2.6
No
No
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
FAMILIAL HYPOALPHALIPOPROTEINEMIA
 HDL
< 10% in men (<0.77 mmol/L), < 15% in
women (<1.04 mmol/L)
 Normal LDL and TG
 Increased risk of premature CHD
 No characteristic findings
 Often family history
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
APOLIPOPROTEIN A1 MUTATIONS
 Mutations
in ApoA-I results in poor LCAT
activation
 HDL < 0.3
 Corneal opacities
 Increased CHD
 ApoA-I Milano
rare variant of ApoA-I
 Autosomal dominant
 Low HDL
 Not associated with premature CHD

Katz P. 2014. Lipid metabolism & clinical lipid disorders.
LCAT DEFICIENCY
 Decreased
esterification of cholesterol to
cholesterol esters in HDL particles
 Free cholesterol accumulates on lipoprotein
particles and in peripheral tissues
 Features





Corneal opacities
Normochromic anemia
Renal failure
Decreased HDL
Increased free cholesterol
Saeedi R et al. 2014. Clin Biochem. Aug:Epub
FISH-EYE DISEASE
 Variant
of LCAT deficiency
 Phenotype is less severe

Able to esterfy cholesterol on ApoB-containing
lipoproteins just not HDL
 Low
HDL
 Corneal opacities
 No anemia, renal disease, or premature CHD
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
TANGIER DISEASE
 Mutations

in ABCA1
Loss of cholesterol efflux from cells such as
macrophages massive accumulation of CEs
 Hypolipidemia

Decreases in plasma HDL and LDL
 Features





Orange tonsils
Corneal opacities
Hepatosplenomegaly
Peripheral neuropathy
Premature CHD
Kolovou G et al. 2006. Curr Med Chem. 13(7):771.
CHOLESTERYL ESTER TRANSFER PROTEIN
(CETP) DEFICIENCY
 Diminished
CETP activity
 Decreased transfer of CE from HDL to ApoB
containing lipoproteins (VLDL, IDL, LDL)
 HDL increased
 More common in Japanese population
 Homozygotes have marked elevation of HDL
(> 2.6 mmol/L)
 Effect on CHD risk is unclear
Katz P. 2014. Lipid metabolism & clinical lipid disorders.
OBJECTIVES
 Review
lipid and lipoprotein classification and
nomenclature
 Understand the pathways of cholesterol
biosynthesis and metabolism
 Review primary disorders of hyper- and
hypolipidemia
Low-Density Lipoprotein (LDL)
 Triglycerides (TG)
 High-Density Lipoprotein (HDL)

QUESTIONS?
REFERENCES
CCS: Position Statement on FH. 2014
 Feldman D et al. 2015. CurrAtherosclerRep 17(1):473.
 Katz P. 2014. Lipid metabolism & clinical lipid
disorders. CSEM.
 Kolovou G et al. 2006. Curr Med Chem. 13(7):771.
 Kronenberg HM et al. Williams Textbook of
Endocrinology. 12th Ed
 Marais A et al. 2014.CritRevClinLabSci. 51(1):46.
 Mullard A. 2012. Nature Rev Drug Discovery 11:817.
 Othman R et al. 2013. Atherosclerosis. 231(2):291.
 Rahalkar A et al. 2009.Can J Physiol Pharmacol.
87(3):151.
 Saeedi R et al. 2014. Clin Biochem. Aug:Epub.
 Soutar A. 2010. IUBMB Life. 62(2):125.
 Yuan G et al. 2006. CMAJ 17(8):1124.
