Metabolism of Lipoproteins Hyperlipoproteinemia

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Metabolism of LipoproteinsHyperlipoproteinemia
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Cardiovascular diseases caused by atherosclerosis

• In Europe gt 4 million CVD deaths/year
• 43 men and 55 women die of CVD
• 2002 2557 CVD/100 000 hospitalized
• 2003 CVD treat. costs 168 757 mil.

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Lipoproteins

• Micels transporting cholesterol esters and
  triglycerides in plasma Lipoprotein classes
• CHYLOMICRONs (TG)
• VLDL (TG)
• IDL (TGCHE)
• LDL (CHE)
• HDL (CHE)

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Lipoprotein. class Density (g/ml) Diameter (nm) Protein Phospho-lipids Triglycerides
HDL 1.063-1.21 5 15 33 29 8
LDL 1.019 1.063 18 28 25 21 4
IDL 1.006-1.019 25 - 50 18 22 31
VLDL 0.95 1.006 30 - 80 10 18 50
CHYLO-MIKRONS lt 0.95 100 - 500 1 - 2 7 84
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Lipoprotein structure
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LDL molecule
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Apoproteins

• Protein moiety of Lp
• Classification A,B,C,D,E,H,M
• Function-hydrophilic properties
• -receptor ligands
• -enzyme cofactors

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Classification of lipoproteins

• Density EF
• Chylomicrons Chylomicrons
• VLDL pre-beta
• IDL slow pre-beta
• LDL beta
• HDL alpha

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Apoproteins

• A-I (28,300)- main apoprotein of HDL
• activates LCAT
• A-II (8,700) as a dimer namely in HDL
• enhances activity of hepatic lipase
• B-48 (240,000) only in chylomicrones
• coded by apo-B-100 gene, edited mRNA stop-codone
  at 48 length of the chain, binds to different
  receptors than B-100
• B-100 (500,000) main apoprotein of VLDL, IDL,
  LDL
• ligand of apoB100E receptor (LDL receptor)

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Apoproteins

• C-I (7,000) present in CHM, VLDL, HDL
• LCAT activation
• C-II (8,800) present in CHM, VLDL, HDL
• LPL activation
• C-III (8,800) present in CHM, VLDL, IDL, HDL
• LPL inhibition
• D (32,500) present in HDL
• equivalent - cholesterol ester transfer protein
  (CETP)
• E (34,100) present in CHM, VLDL, IDL HDL
• ligand of apo B100E receptoru ( LDL receptoru)
• H (50,000) present in CHM as b-2-glycoprotein I
  (TAG metabolism)
• M present in HDL (reverse cholesterol
  transport)

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Main lipoprotein classes

• Chylomicrones (intestine-dietary fat)
• density lt 1.006
• diameter 80 - 500 nm
• Dietary fat (esp. TAG)
• apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-III,
  apoE
• ELFO- on the start line

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Chylomicrones

• formed in enterocytes, resynthetised TG, less
  cholesterol-ester
• Transported in the lymph ductus thoracicus and v.
  subclavia (systemic circulation)
• TG hydrolized by lipoprotein lipase (LPL)
  present on capillary endothelium of peripheral
  tissues
• CHM remnants taken up by hepatocytes (CHM
  receptor binds apoE-III and apoE-IV isoforms)

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Cholesterol and lipid transport by lipoproteins
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Main lipoprotein classes

• VLDL
• density gt1.006
• diameter 30 - 80nm
• Formed in the liver, nascent VLDL contain mainly
  TG, less CHE
• apoB-100, apoE, apoC-II/C-III
• EF - pre-beta fraction

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VLDL

• nascent VLDL interaction with HDL, receive
  apoC-II and apoC-III, equimolar exchange of TG
  for CH-E with HDL)
• VLDL TG hydrolized by LPL in peripheral tissues
  resulting in formation ofVLDL remnants (IDL)
• IDL cca. 50 taken up in the liver by
• apoB100E receptor
• - cca. 50 degradation by HL
• resulting in LDL formation

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Main lipoprotein classes

• IDL (intermediate density lipoproteins)
• density 1.006 - 1.019
• diameter 25 - 35nm
• TG a CHE
• apoB-100, apoE, apoC-II/C-III
• EF slow pre-beta
• highly atherogenic

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Main lipoprotein classes

• LDL (low density lipoproteins)
• density 1.019 - 1.063
• diameter 18-25nm
• cholesterol esters
• apoB-100
• EF beta fraction
• highly atherogenic

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Cholesterol and lipid transport by lipoproteins
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Main lipoprotein classes

• HDL (high density lipoproteins)
• density 1.063-1.210
• diameter 5-12nm
• cholesterol esters
• apoA-I, apoA-II, apoC-II/C-III and apoE
• EF alpha fraction

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HDL

• formed in liver and enterocytes
• nascent discoid micels of PL monolayer, with
  apoA-I, apoA-II, apoE
• lecithin-cholesterol acyl transferase (LCAT) in
  periph. tissues transfers CHE into the HDL-core
  which becomes spheric - HDL3 (smaller HDL)

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HDL3

• HDL3
• Binds to the cell membranes of peripheral tissues
  and aquires free cholesterol from them
• LCAT esterification of free cholesterol to CHE
  and its storage in the core of the particle
• More CHE aquisition HDL3 becomes bigger and
  transforms to HDL2a
• HDL2a and VLDL exchange in equimolar ratio 11
  CHE za TG --- HDL2b

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Function of HDL

• REVERSE CHOLESTEROL TRANSPORT
• donor of apoproteins to other LPs

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Lp(a)

• independent Lp class (at least 19 polymorphisms
  described)
• structure similar to LDL
• apoB-100 binds apo(a)
• apo(a) primary structure asplasminogen
• highly atherogenic

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LDL receptor

• First described by Michael Brown a Joseph
  Goldstein (Nobelova cena v roce 1985)
• studies of familir hypercholesterolemia
• also named as apo B-100E receptor
• present in the liver and all peripheral tissues

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LDL receptor (839 aa) Extracellular domain
binds apo-B-100/apo-E Intracellular domain
responsible for LDL recpetors clustering in
coated pits of cellular membranes
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Atherosclerosis

• Most common cause of death in developed
  industrial countries
• High socioeconomic impact
• Multifactorial detrmination
• Fibroproliferative inflammation
• Hyperlipoproteinemia- important but modifiable RF

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Aterosklerotický plát
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PRIMARY HYPERLIPOPROTEINEMIAS

• Primary genetic precondition
• Phenotype determined also by exogenic factors
  (diet, physical in-activity)

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Primary HL-classification

• TG increased
• CHOL increased
• Both TG and CHOL increased

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Primary hypertriglyceridemia

• Fredrickson typ IV
• TG 3-12 mmol/l
• Frequency 1/500 ?
• Primary incr. VLDL synthesis, low LPL activity
  (identical phenotype in metabolic syndrom - IR)
• Clinical signs eruptive xanthomas
• R premature ATS, ac. pancreatitis (TGgt18,0)
• Th diet, fibrates, nacin

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Primary hyper-CHYLOMIKRON-emia rare

• Fredrickson typ I
• high chylomicrons, defect of LPL or
  apo CII
• autosomal recessive disorder,
  frequ. 1/1000 000
• TG 20-200 mmol/l
• Clin.signs. eruptive - tuberous xanthomas,
  hypersplenism, acute pancreatitis
• diet fat max. 15 of total calories

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Primary monogenic hypercholesterolemia (FH, ABD)

• Fredrickson typ II a
• Chol. gt9,0 mmol/l, (homozyg. 14,5-23 mmol/l)
• Gen. defect of LDL receptoru (FH)
  or gen. defect of Apo B100
  (ABD)
• autosomal dominant hered., frequency heterozyg.
  1/500-1/700, homozyg. 1/1000 000
• Clinical signs xanthelasmata, tendineous
  xanthomas, arcus lipoides corneae
• R very high risk of premature ATS
• Th statin, ezetimibe, resins, (niacin),
  in homozygous forms LDL-apheresis

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Primary monogenic hyperchol. type ARH (rare)

• SYN. Autosomal recessive hyperchol.
• Chol. 13,5-18 mmol/l
• Gen. defect of ARH protein, which binds the
  plasma-terminal of LDL receptor gtgtimpaired LDL-R
  internalization
• Autosomal recesssive disorder
• Clinical signs xanthelasmata, tendineous
  xanthomas, arcus lipoides corneae
• R very high risk of premature ATS
• Th LDL-apheresis

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Primary polygenic hypercholesterolemia

• Fredrickson type II a
• Chol. 5,5-9,0 mmol/l
• Down-regulation of LDL-R in liver (a/o periph.
  tissues) due to high dietary SFA and cholesterol
  (animal fat)
• Polygenic disease
• Clinical signs xanthelasmata
• R high risk of premature ATS
• Th statin, ezetimibe, resins, (niacin),
  

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Hyperlipidemia Lp(a)

• Lp(a) gt 0,3 g/l
• Chol. 5-6 mmol/l,
• normal HDL-chol. and TAG
• Dg direct estimation necessary !
• Et increased Lp(a) synthesis in the liver
• R premature ATS
• Th lower cholesterol, (niacin)

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Primary combined hyperlipidemia (common)

• Most frequent form of primary HL
• Fredrickson typ II b
• Increased VLDL and LDL concentrations
• Chol. 5,5-10 mmol/l, TG 2-9 mmol/l
• Clnical signs no xanthomas
• R premature ATS
• Th diet, statins, fibrates (combination)

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Primary dysbetalipoproteinemia

• Fredrickson typ III
• Increased VLDL remnants (IDL) and CHM remnants
• Chol. 7-20 mmol/l, TG 4,5-12 mmol/l
• Genotype E2/E2 other gen.factor?
• Severe xanthomas (tuberoeruptive, tuberose,
  palmar)
• R prematue ATS (CHD, PVD)
• Th diet, fibrats, statin, (niacin)

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SECONDARY HYPERLIPOPROTEINEMIAS

• Alcohol
• Hypothyroidism
• T2DM and decomp. T1DM
• Hypercorticalism, corticosteroid therapy
• Hormonal contraceptives
• Nephrotic syndrom
• Acute nonfulminant hepatitis
• Lymfomas, leukemias Plasmocytoma
• SLE Rheumatoid arthritis
• Anorexia neurosa
• Glycogenosis type I (Gierke)

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THERAPY

• DIET
• HYPOLIPIDEMIC DRUGS

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DIETARY PRINCIPLES

• Lower body weight (BMI lt 25.0)
• Increase physical activity-caloric balance !
• Dietary cholesterol lt 300 (200) mg/D
• Dietary fat 25-30 of total calories
• SFAMUFAPUFA71010 ()
• Fibres 20-30 g/D
• Phytosterols cca. 2 g/D
• Limit alcohol intake !
• Quit smoking !

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HYPOLIPIDEMIC DRUGS

• STATINS
• FIBRATES
• EZETIMIBE
• RESINS
• NIACIN

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STATINS

• Cholesterol lowering
• HMG-CoA reductase inhibitors
• Very potent
• Mild decrease of TG
• atorvastatin, simvastatin, cerivastatin,
  fluvastatin, pravastatin, lovastatin

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EZETIMIBE

• Cholesterol absorption inhibitor
• Block NPC1L1 channel
• Cholesterol lowering
• In combination with statin very effective

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Ezetimibe (Zetia)
This drug blocks the intestinal absorption of
cholesterol. A dose of 10 mg qd leads to a 19
reduction of LDL shows real promise in combo
product with statins (Schering- Plough and Merck)
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RESINS

• Cations binding bile acids in the gut
• Cholestyramine, colestipol, colesevelam

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Bile sequestering resins
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FIBRATES

• PPARs alpha agonists
• Lower TG, increase HDL-chol.
• Mild decrease of chol. (TC, LDL-C)
• Fenofibrate, bezafibrate, ciprofibrate

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NICOTINIC ACID (Niacin)
A water soluble vitamin of the B
family nicotinamide is not active
Cholesterol, TG and Lp(a) lowering HDL-chol.
increasing Severe side effects (flush, GI
symptoms, hyperglycemia, gout) TREDAPTIVE
(combination with laropiprant (PGD inhibitor)
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DIAGNOSTIC

• Total. chol., HDL-chol., TAG, Lp(a)
• LDL-chol. (Friedewalds equ.)-primární th. Cíl
• nonHDL-chl. (Total chol. - HDL-chol.) secondary
  th. goal.
• apo B event. , apo A1 (sec.th.goal)
• --------------------------------------------------
  -------------
• Other specialised diagnostic methods
• Calculation of atherogenic index of plasma
  (AIP)logTAG/HDL-ch
• Genotype LDL-R, apo-B, apo-E
• Ultracentrifugation-accurate estimation of chol.
  and TG in v CHM, VLDL, IDL, LDL, HDL
• Electrophoresis (unusual)

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nonHDL-cholesterol

• Cholesterol within all atherogenic lipoproteins
  (not only LDL, but also VLDL, IDL, chylomikronech
  i Lp(a) !

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FRIEDEWALDS FORMULAFOR LDL-chol.

• LDLchol. TCH HDLchol TAG/2,2
• TCH-total cholesterol
• TAG-triglycerides

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TREATMENT GOALS

• Depend on the risk level
• 4 levels
• SCORE tables in primary prevention only (w/o
  CVD, PVD or stroke)
• Secondary prevention patients reperesent the
  highest risk group
• New EAS guidelines 2011

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VERY HIGH RISK

• SEC. PREVENTION CVD, PVD, STROKE
• SCORE 10
• DM 2T
• DM 1T with organ complications (MAU)
• CRF moderate or severe (GFR 60 ml/min/1,73m2)
• Asymptomatic atherosclerosis (carotids, aorta,
  peripheral arteries, coron.calcium score,
  ankle/brachial index)

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HIGH RISK

• SCORE 5 - lt10
• Total.chol.gt 8,0 mmol/l, LDL-chol.gt 6,0 mmol/l
• BP 180/110, HT w.nephro-/retinopathy
• Positive family history ( Mlt55 y, Wlt65 y)

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MODERATE RISK

• SCORE 1 - lt 5
• Risk value may be underestimated if
• Positive family history
• Phisical inactivity
• Dyslipidemia high TG / lowHDL-chol
• Hyper Lp(a)
• Hyperfibrinogenemia
• Hyperhomocysteinemia (?)

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LOW RISK

• SCORE lt 1

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TREATMENT GOALS IN BASIC LIPID PARAMETERS
Low risk Modera risk High risk Very High risk
LDL cholestrol lt 3,0 mmol/l lt 3,0 mmol/l lt 2,5 mmol/l lt 1,8 mmol/l
Non HDL chol. lt 3,8 mmol/l lt 3,8 mmol/l lt 3,3 mmol/l lt 2,6 mmol/l
HDL chol/apoA1 muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l
Triglycerides lt 1,7 mmol/l lt 1,7 mmol/l lt 1,7 mmol/l
LDL-cholesterol is the primary therapeutical
goal In very high risk patients is lowering of
the LDL chol. by 50 an option
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GOAL for APO B
Low risk Moderate risk High risk Very high risk
Apo B lt 1,0 g/l lt 0,8 g/l
Apo B below 0,75 g/l may be of profitable
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The End