Hækkuð blóðfitaHækkuð blóðfitaHækkuð blóðfitaHækkuð blóðfita

Gunnar Sigurðsson prófessorGunnar Sigurðsson prófessor

Kennsla 4. árs læknanemaKennsla 4. árs læknanema

23. nóvember 200523. nóvember 2005

Hækkuð blóðfita (hyperlipoproteinemiur)Hækkuð blóðfita (hyperlipoproteinemiur)

Áhersluatriði: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

PhospholipidTriglyceride

Cholesteryl esterApolipoprotein

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

Familial combined hyperlipidemia

Underlying defect LDL-receptor ? Overproduction of VLDL and LDL

Inheritance Autosomal dominant ? Autosomal dominant

Lipoprotein abnormality LDL (cholesterol) VLDL and or LDL

(TG and or cholesterol )Age at onset From birth After age 20-30

Prevalence 1/500 1/100-200

Clinical signsXanthomata

±ischaemic heart disease

0 ±

ischaemic heart diseaseResponse to diet ± **

Drug therapyResinsstatins

nicotinic acid

Fibratesnicotinic acid

statins

Selective screening for hyperlipidemiaSelective 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

• Elevated serum cholesterol is associated with increased risk of

– CHD and MI

– Re-infarction

– Stroke

– CVD Mortality

• All-cause

• CHD

• Stroke

*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.

0

10

20

30

40

50

<160 160–199 200–239 >240

CV

D m

ort

alit

y r

ate*

Multiple Risk Factor InterventionTrial (n=350,977)

Serum cholesterol(mg/dl)

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 LDL-viðtakagalla (F.H.).

50

Secondary Prevention

Primary Prevention

CARE-Rx

4S-Rx

LIPID-Rx

CARE-PL

LIPID-PL

4S-PL

AFCAPS-Rx

AFCAPS-PL

WOSCOPS-RxWOSCOPS-PL

70 90 110 130 150 170 190 210

0

5

10

15

20

25

LDL-C Lowering With Statins: Reduced CHD Events

Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.

LDL Cholesterol (mg/dL)

Even

ts (

%)

Meta-analysis of 38 primary and Meta-analysis of 38 primary and secondary intervention trials intervention trials

Benefits of Cholesterol Lowering

Total mortality (Total mortality (pp=0.004)=0.004)

CHD mortality (CHD mortality (pp=0.012)=0.012)

% in cholesterol reduction% in cholesterol reduction

Mor

talit

y lo

g od

ds r

atio

Mor

talit

y lo

g od

ds r

atio

(Adapted from Gould AL, et al.,1998)

00 44 88 1212 1616 2020 2424 2828 3232 3636-1.0-1.0

-0.8-0.8

-0.6-0.6

-0.4-0.4

-0.2-0.2

-0.0-0.0

4040 4444 4848 5252

European Guidelines for CVD Prevention: Lipid Management

Treatment Goals

Patient group LDL-C Total-C

General population <115 mg/dl <190 mg/dl(3 mmol/L) (5 mmol/L)

Clinical CVD <100 mg/dl <175 mg/dl

(2.5 mmol/L) (4.5 mmol/L)

Diabetes <100 mg/dl <175 mg/dl

(2.5 mmol/L) (4.5 mmol/L)

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

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

X Statins

Statin-lyfin eru tekin upp í lifur og þar er aðalverkun þeirra á LDL-kólesteról.

Effects of Statins on Lipids

atorvastatin

simvastatin

pravastatin

lovastatin

fluvastatin

LDL cholesterol% change

-50

-41

-34

-34

-24

HDL cholesterol% change

+6

+12

+12

+8.6

+8

Triglycerides% change

-29

-18

-24

-16

-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.

LiverLiver

Two Sources of Cholesterol

Fecal bile acids and neutral sterols

Extrahepatictissues

DietaryDietarycholesterolcholesterol

(~300–700 mg/day)(~300–700 mg/day) Intestine

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: Wiley-Liss, 2002:1082-1150.

BiliaryBiliarycholesterolcholesterol(~1000 mg/day)(~1000 mg/day)

~700 mg/day

Synthesis(~800 mg/day)

Biochemical Targets for Cholesterol Control: Absorption

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.

StanolsStanolsSterolsSterolsSynthetic saponinsSynthetic saponinsNeomycinNeomycinSurformerSurformerSucrose polyesterSucrose polyesterEzetimibeEzetimibe

MTP inhibitor

Dietarycholesterol

Biliarycholesterol

ACAT inhibitor

ABCA1ABCA1

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

• 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.

0 60

Three-step titration

One-step co-administrationStatin 10 mg

Statin 10 mg

+ Ezetimibe10 mg

5040302010

20mg

40mg

80mg

% reduction in LDL-C

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

HDL=high-density lipoprotein

Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

HDLrecept

or Lecithin:cholesterolacyltransferase

LiverLiver

Cholesterolester

HDL

+

C

Nascent HDL

PERIPHERAL

TISSUES

Apo

Free

cholesterol

(C)

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 (pparagonists)

Lipoprotein - (a) er undirflokkur á LDL. (a) er skylt plasminogeni en hlutverk óþekkt. Virðist vera atherogent. Magn ákvarðast af erfðum. Lækkar ekki við statin-lyfjagjöf.