Hækkuð blóðfita
Gunnar Sigurðsson prófessor
Kennsla 4. árs læknanema
23. nóvember 2005
Hækkuð blóðfita (hyperlipoproteinemiur)
Áhersluatriði:
• Helstu lipoprotein og hlutverk þeirra.
• Megindrættir í lipoprotein physiology.
• Tengsl við sjúkdóma, sérstaklega æðakölkun.
• Undirliggjandi orsakir fyrir hækkaðri blóðfitu og
erfðaþættir.
• Hvenær er ástæða til að mæla blóðfitur?
• Hvenær er ástæða til að lækka blóðfitur?
• Helstu atriði í meðferð.
Structure of Lipoproteins
Free cholesterol
Phospholipid
Triglyceride
Apolipoprotein
Cholesteryl ester
Types of Lipoprotein Particles
• Triglyceride-rich lipoproteins
– Chylomicrons
– Very low-density lipoprotein (VLDL)
• Cholesterol-rich lipoproteins
– Low-density lipoprotein (LDL)
– High-density lipoprotein (HDL)
The Physiologic Role of Cholesterol
• Cholesterol is required for normal biologic function
– Component of all cell membranes
– Precursor of other steroids
• Cortisol
• Progesterone
• Estrogen
• Testosterone
• Bile acids
• Excess cholesterol can result in
– Coronary heart disease (CHD)
– Xanthomas
Adapted from Saladin KS. Anatomy and Physiology. 2nd ed. Boston: McGraw-Hill, 2001; Jones PH et al. In Hurst’s
The Heart. Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1553-1581; Ginsberg HN, Goldberg IJ. In
Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149.
Overview of Cholesterol Transport
Reiknað LDL-kólesteról (Friedewald’s formúla)
• mmol/L = heildarkól. – HDL-kól. – (þríglyseríðar)
2.2
• mg/dl = heildarkól. – HDL-kól. – (þríglyseríðar)
5
• kólesteról: 1 mmol/L = 38.7 mg/dl
• þríglyseríðar: 1 mmol/L = 88.5 mg/dl
Þessa nálgunaraðferð er ekki unnt að nota ef
þríglyseríðar eru mjög háir eða meir en 5 mmol/L
Samkvæmt rannsóknum á eineggja tvíburum ákvarðast kólesterólgildi
einstaklingsins nokkurn veginn að hálfu leyti af erfðaþáttum og að hálfu
af umhverfisþáttum.
Mismunandi mataræði skýrir að stórum hluta mismun á meðalgildi
heilla þjóða, t.d. Finna og Japana.
Heterozygotar hafa einungis helming eðlilegra LDL-viðtaka og þar af
leiðandi hækkar LDL-kólesteról utan frumna. Kólesteról þeirra er því
oftast verulega hækkað. Homozygotar hafa enga eðlilega LDL-viðtaka
og margfalda hækkun á kólesteróli í blóði.
Sérkennandi klínísk teikn í F.H. eru útfellingar á kólesteróli í sinar,
sérstaklega hásinar og handarsinar (tendinous xanthomata). Þær koma
þó ekki fyrr en á miðjum aldri og einungis ef kólesteról helst hátt. Þær
hverfa oft við meðferð.
Xanthelasmata palpebrarum sjást oft við hækkun á blóðfitu hver
sem undirliggjandi orsök er. Hverfur oftast við blóðfitulækkandi
meðferð eftir um það bil 12 mánuði.
Ef arcus senilis er til staðar fyrir fimmtugt er vert að mæla blóðfitur.
Tvær mikilvægustu gerðirnar af arfbundinni
hækkun á blóðfitu
Familial
hypercholesterolemia
Underlying defect
Inheritance
Lipoprotein
abnormality
Age at onset
Prevalence
Clinical signs
Response to diet
Drug therapy
LDL-receptor
Autosomal dominant
LDL (cholesterol) 
From birth
1/500
Xanthomata
±
ischaemic heart disease
±
Resins
statins
nicotinic acid
Familial combined
hyperlipidemia
? Overproduction of
VLDL and LDL
? Autosomal dominant
VLDL and or LDL 
(TG and or cholesterol )
After age 20-30
1/100-200
0
±
ischaemic heart disease
**
Fibrates
nicotinic acid
statins
Selective screening for hyperlipidemia
• First-degree relatives of patients with
hyperlipidemia
• Precence of xanthomas or xanthelasma in
patient of first-degree relative
• Family history of coronary artery disease
before age 50 (men) or 60 (women)
• Corneal arcus before age 50
Skimun fyrir kólesteróli, HDL-kólesteróli og þríglyseríðum er alla vega
réttlætanleg og mikilvæg þegar þessir þættir eru til staðar.
GENERAL CLASSIFICATION OF HYPERLIPIDAEMIAS
Hyperlipidaemia Detected at
initial Examination
Repeat Serum Lipid
Determination
Hypercholesterolaemia:
Triglyceride Normal
Hypercholesterolaemia:
Hypertriglyceridaemia
Cholesterol Normal to
Severely Elevated:
Hypertriglyceridaemia
Vert er að gera sér grein fyrir hvort bæði kólesteról og þríglyseríðar sé
hækkað eða einungis kólesteról. Það skiptir máli upp á meðferð.
Undirliggjandi orsakir einnig oft aðrar.
Útiloka verður aðrar
(secunderar) ástæður
fyrir hækkun á
blóðfitu, sérstaklega
TSH við
kólesterólhækkun
(hypothyr.), diabetes
og alkóhól við
hækkun á
þríglyseríðum.
Elevated Cholesterol Is a Risk Factor
for Cardiovascular Disease
– CHD and MI
– Re-infarction
– Stroke
– CVD Mortality
CVD mortality rate*
• Elevated serum cholesterol is
Multiple Risk Factor Intervention
associated with increased risk50of
Trial (n=350,977)
40
30
20
10
• All-cause
• CHD
• Stroke
0
<160
160–199 200–239 >240
Serum cholesterol
(mg/dl)
*Crude death rate (per 10,000 persons/years)
CVD = cardiovascular disease
Adapted from Kannel WB Am J Cardiol 1995;76:69C-77C; Anderson KM et al JAMA 1987;257:2176-2180; Kannel WB et al
Ann Intern Med 1971;74:1-12; Neaton JD et al Arch Intern Med 1992;152:1490-1500.
Vert er fyrir lækna að
kunna almennar og
einfaldar ráðleggingar um
mataræði sem lækkar
kólesterólgildi að jafnaði
um 10%, sumir svara betur,
en aðrir síður, sérstaklega
þeir sem hafa LDLviðtakagalla (F.H.).
LDL-C Lowering With Statins:
Reduced CHD Events
Secondary Prevention
4S-PL
Primary Prevention
25
LIPID-PL
20
4S-Rx
15
CARE-PL
CARE-Rx
10
LIPID-Rx
5
WOSCOPS-Rx
WOSCOPS-PL
AFCAPS-Rx
AFCAPS-PL
0
50
70
90
110
130
150
170
LDL Cholesterol (mg/dL)
Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.
190
210
Benefits of Cholesterol Lowering
Meta-analysis of 38 primary and secondary intervention trials
Mortality log odds ratio
-0.0
-0.2
-0.4
-0.6
Total mortality (p=0.004)
CHD mortality (p=0.012)
-0.8
-1.0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
% in cholesterol reduction
(Adapted from Gould AL, et al.,1998)
European Guidelines for CVD Prevention:
Lipid Management
Treatment Goals
Patient group
LDL-C
Total-C
General population
<115 mg/dl
(3 mmol/L)
<190 mg/dl
(5 mmol/L)
Clinical CVD
<100 mg/dl
<175 mg/dl
(2.5 mmol/L)
(4.5 mmol/L)
<100 mg/dl
<175 mg/dl
(2.5 mmol/L)
(4.5 mmol/L)
Diabetes
Adapted from DeBacker C et al Eur Heart J 2003;24:1601–1610.
Mechanism of Action of Statins:
Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA reductase
HMG-CoA
X Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones
farnesyl pyrophosphate
Squalene synthase
squalene
cholesterol
dolichols
Statin-lyfin eru tekin upp í lifur og þar er aðalverkun
þeirra á LDL-kólesteról.
Effects of Statins on Lipids
LDL cholesterol HDL cholesterol
% change
% change
Triglycerides
% change
atorvastatin
-50
+6
-29
simvastatin
-41
+12
-18
pravastatin
-34
+12
-24
lovastatin
-34
+8.6
-16
fluvastatin
-24
+8
-10
Daily dose of 40 mg of each drug
(Adapted from Knopp 1999)
Currently Available Pharmacologic Agents
• HMG-CoA reductase
inhibitors
– Inhibit cholesterol
synthesis
– Increase LDL
receptors
– Decrease LDL-C
by 25–40%
– Decrease VLDL-C
• Bile acid–binding resins
– Interrupt enterohepatic
bile acid circulation
– Increase LDL-C
receptors
– Decrease LDL-C
by 20–30%
– Decrease VLDL-C
– Increase HDL-C
Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill,
1998:2138-2149.
Cholesterol Management: Other Agents
• Bile acid–binding resins
– Interrupt enterohepatic bile acid circulation
–  LDL-C by 20–30%,  VLDL-C,  HDL-C,  TG
• Nicotinic acid (niacin)
– Inhibits lipoprotein secretion
–  LDL-C by 15–25%,  VLDL-C by 25–35%,  HDL-C
• Fibric acid derivatives
– Induce lipoprotein lipolysis,  LDL-C removal,
 HDL production and reverse cholesterol transport
–  TG by 25–40%,  HDL-C,  or  LDL-C
VLDL-C = very-low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides
Adapted from Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill,
1998:2138-2149; Illingworth DR Med Clin North Am 2000;84:23-42;Staels B et al Circulation 1998;98:2088-2093.
Two Sources of Cholesterol
Dietary
cholesterol
Intestine
(~300–700 mg/day)
Biliary
cholesterol
Fecal bile
acids
and neutral
sterols
~700 mg/day
(~1000 mg/day)
Liver
Synthesis
(~800 mg/day)
Extrahepatic
tissues
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In
Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg
IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart
J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: WileyLiss, 2002:1082-1150.
Biochemical Targets for Cholesterol
Control: Absorption
Dietary
cholesterol
Biliary
cholesterol
ABCA1
MTP
inhibitor
ACAT
inhibitor
Stanols
Sterols
Synthetic saponins
Neomycin
Surformer
Sucrose polyester
Ezetimibe
MTP=microsomal triglyceride transfer protein
Adapted from Champe PC, Harvey RA Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven,
1994; Miettinen TA Int J Clin Pract 2001;55(10):710-716; Brown WV Am J Cardiol 2001;87(suppl 5A):23B-27B.
Ezetimibe: A New Cholesterol
Absorption Inhibitor
• First of a new class of drugs with unique mechanism of action
– Targets intestinal absorption of dietary and biliary cholesterol
– Inhibits absorption of dietary and biliary cholesterol
– Reduces plasma LDL-C
• May be useful as monotherapy for patients intolerant or
nonresponsive to statins
• In co-administration therapy with statins
– Inhibits cholesterol absorption in the intestine and biosynthesis
in the liver (dual inhibition)
– Achieves lipid reductions greater than those with statins alone
• Favorable safety profile shown in clinical trials
• May reduce need for dosage adjustments of the statin
Adapted from Leitersdorf E Eur Heart J Suppl 2001;3(suppl E):E17-E23; Miettinen TA Int J Clin Pract 2001;55:710-716;
Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
Ezetimibe Co-administered with Statins:
Easier Control of LDL-C
0
Statin 10 mg
20 40 80
mg mg mg
Three-step titration
Statin 10 mg
+ Ezetimibe
10 mg
One-step co-administration
10
20
30
40
50
60
% reduction in LDL-C
• One-step co-administration of ezetimibe
equivalent to three-step statin titration
Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
HDL Cholesterol
• Low HDL cholesterol is a strong independent
predictor of CHD1
• The lower the HDL cholesterol level the higher
the risk for atherosclerosis and CHD2
• Low HDL is defined categorically as a level < 40
mg/dL (a change from < 35 mg/dL in ATP II)1
• HDL cholesterol tends to be low when triglycerides
are high2
1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
2. Wood D, et al. Atherosclerosis. 1998;140:199-270.
Lipoproteins: HDL
Nascent HDL
Liver
C
HDL
recept
or
Cholesterol
ester
Lecithin:
cholesterol
acyltransferase
Apo
PERIPHERA
L
TISSUES
+
HDL
HDL=high-density lipoprotein
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.
Triglycerides
• Recent data suggest that elevated triglycerides
are an independent risk factor for CHD
• Normal triglyceride levels: <150 mg/dL
• Borderline-high triglycerides: 150 to 199 mg/dL
• High triglycerides: 200 to 499 mg/dL
• Very high triglycerides: (500 mg/dL) increase
pancreatitis risk
– Initial aim of therapy is prevention of acute
pancreatitis
NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
Þríglyseríðar
Æskileg gildi <2 mmol/L. Hækkaðir þríglyseríðar eru sjálfstæður áhættuþáttur
fyrir æðakölkun enda þótt sú áhætta sé minni en af kólesteróli.
VLDL og chylomicron eru það stór mólekúl að þau valda gruggugu
sermi sem hækkun á LDL-kólesteróli gerir ekki. Þríglyseríðar þessa
sjúklings voru meir en 20 mmol/L. Hann kom inn vegna acute
abdomen. Hver er líklegasta orsökin?
Veruleg hækkun á þríglyseríðum í blóði getur leitt til fituútfellinga í
húð (tuberous xanthomata). Hverfa fljótt við meðferð.
Meðferð við hækkun á þríglyseríðum
• Útiloka og meðhöndla sekunder orsakir:
– Alkóhól
– Sykursýki
– Lyf o.fl.
• Meðferð:
– Megrun
– Statín-lyf
– Fibrate-lyf (pparagonists)
Lipoprotein - (a) er undirflokkur á
LDL. (a) er skylt plasminogeni en
hlutverk óþekkt. Virðist vera
atherogent. Magn ákvarðast af
erfðum. Lækkar ekki við statinlyfjagjöf.