Jan Borén lipider T3 2012 rev 3.ppt [Kompatibilitetsläge]

10/4/2012

1

Lipidmetabolism & blodfetter

Jan Borén

Sahlgrenska Center for Cardiovascular and Metabolic Research Wallenberg Laboratory for Cardiovascular Research

University of Gothenburg, Sweden

Jan BorénTel. 0733‐764264

[email protected]

10/4/2012

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Vad är lipider?

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Ett lipoprotein består av en central kärna av neutrallipid(triglycerider och cholesterol-estrar).Denna kärna är omgiven av ettmonolager av amfipatisk lipid(fosfolipider och cholesterol)

I det amfipatiska Monolagret “flyter” Proteindelen det s.k. apolipoproteinet

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Exogenous Lipid Transport

ApoB

apo

E

apoC-II

Fettsyror

Kapillär

Adipocyt(fettcell)

Chylomikron

ApoB

apoC-II

LDL-receptorn

LRP

Levern

Chylomikronremnant

Chylomikronen bildas i tarmen transporteras via lymfan till blodet. Ikapillärer i framförallt fettväv bryts en stor del av triglyceriderna icylomikronerna ner (katalys: lipoproteinlipas). En remnant partikel bildassom anrikas med apoE och tas upp i levern med LRP och LDL-receptorn.

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9

Adipocytes

Triglyceride-rich lipoproteins:size, structure and composition

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ENDOGENOUS LIPIDS

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(Adapted from Verschuren et al, 1995)

35

30

25

20

15

10

5

0

Dea

th r

ate

fro

m C

HD

/100

0 m

en

2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05

Serum total cholesterol (m m ol/L)

Northern Europe

United States

Southern Europe, inland

Southern Europe, M editerranean

Japan

Serbia

Relationship of serum cholesterol to m ortality

(Seven Countries Study)

Relationship of Serum Cholesterol to Mortality

GI TractLiver

Remnant

Chylomicron

VLDL IDLLDL

Oxidation

Arterial WallMacrophage

NascentPreBHDL

Lipid poorApoA-1

-HDL

TG

CE

CETP

Bile AcidsFC + PL

HL

LPL

HLPLTP

LCAT

Lipoprotein Metabolism

LPL

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Slide SourceLipids Online Slide Librarywww.lipidsonline.org

HDL MetabolismNascent HDL (lipid-poor apolipoprotein A1 [Apo A1]) is produced by the liver and intestine

intestine

peripheral cells

kidney

PLTP

LCAT

ABC1

particleuptake

liver

TGRLselectiveuptake

surfaceremnantscubilin

apo A1

HDL3

HDL2

pre-HDL

CETPSR-BIHL, EL

LPL

Von Eckardstein A et al. Curr Opin Lipidol 2000;11:627–637.

HDL Formation

Liver

ApoA

Pre--HDL

Discoidal/lipid poor

Cholesterol fromLiver and intestinal Cells via ABCA1

Pre--HDL

A A

Unesterified cholesterol-rich

Lecithin-cholesterol acyltransferase (LCAT)

HDL

1. Cholesterolto liver

Steroidogeniccells

2. Cholesterolfor steroid synthesis

Cholesterolto otherlipoproteins

3. Cholesterol-estertransfer protein(CETP)

A

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CETPLCAT

Free cholesterol

hydrolysis

Reverse Cholesterol Transport: Indirect

Extrahepatic tissues

Cholesterol esters

Pre--HDL

A

HDLACholesterol to VLDL, IDL,LDL

LiverCholesterol is reusedor excreted in bile

ABCA1

Direct

Reverse Cholesterol Transport : Direct

SR-BI (scavenger receptor, class B, type 2)

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PROCAM StudyMI-Incidence according to LDL-cholesterol and triglycerides

Endogenous lipoprotein metabolism

Atherosclerosis

LDL-receptorAdipose tissue

LDLLDL

IDL

LargeVLDL

SmallVLDL

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Retention of LDL in Aortic Intima from a Rabbit 2 h after Injection with Human LDL

Nievelstein et al. (1991) Arterio and Thromb.

Freeze-etch electron photomicrograph

Cholesterol Functions Membrane

component Precurser to

Bile acids Vitamin D Steroid hormones

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Sources of Cholesterol

Diet De novo synthesisCholesterol synthesizedin extrahepatic tissues

Liver cholesterolpool

Free cholesterolIn bile

Conversion to bile salts/acidsSecretion of HDLand VLDL

De novo Synthesis of Cholesterol Primary site: liver (80%) (~1g/d)

Secondary sites: intestine (10%), skin (5%), adrenal cortex, ovaries, testes

Overall equation:

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Dietary Cholesterol

• Assume 400 mg intake / day

• 200 mg is absorbed

• 1000 mg is excreted

• 800 mg from de novo synthesis

Lowering cholesterol in diet has very little effect on blood cholesterol !!!

CAD26 C

N

ER-lumen

• In cholesterol loaded cells– Unprocessed SREBP resides in Endoplasmatic Reticulum (ER)– SREBP is tightly complexed with sterol sensor SREBP-cleavage activating

protein (SCAP)– SCAP is attached via its sterol-sensing domain (SSD) to Insulin-induced

gene (INSIG) retention protein– (INSIG-1 and -2)

N

C

SCAP SREBPINSIG

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CAD27

ER-lumen

N

C

• In cholesterol depleted cells– Conformation of SCAP is altered due alteration in

conformation of SSD (sterol sensitive domaine)

C

N

SCAP SREBPINSIG

CAD28

ER-lumen

N

C

C

N

SCAP


conformation of SSD (sterol sensitive domaine)

SREBPINSIG

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CAD29

ER-lumen

N

C

C

N

SCAP SREBPINSIG


conformation of SSD (sterol sensitive domaine)– Which enables the dissociation of INSIG

CAD30

Golgi-lumen

N

C

C

N

SCAP SREBP


conformation of SSD (sterol sensitive domaine)– Which enables the dissociation of INSIG– SREBP is escorted to the Golgi apparatus

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CAD31

SREBP

Golgi-lumen

N

C

C

N

SCAP

• SREBP is cleaved in the Golgi apparatus– In Golgi apparatus SREBP is sequentially cleaved by two

proteases

– Site-1 protease (S1P) and Site-2 protease (S2P), respectively

– S1P is cholesterol sensitive (inhibited by cholesterol and SREBP is retained in Golgi if the content of cholesterol is high)

S1P

CAD32

SREBP

Golgi-lumen

C

C

N

SCAP

S1P

N

S2P

• SREBP is cleaved in the Golgi apparatus– In Golgi apparatus SREBP is sequentially cleaved by two

proteases

– Site-1 protease (S1P) and Site-2 protease (S2P), respectively

– S1P is cholesterol sensitive - low cholesterol content --> cleavage by S1P, followed by S2P cleavage

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CAD33

SREBP

Golgi-lumen

C

C

N

SCAP

S1P

S2P

• SREBP is cleaved in the Golgi apparatus– In Golgi apparatus SREBP is sequentially cleaved by

two membrane-bound proteases Site-1 protease (S1P) and Site-2 protease (S2P), respectively

– S1P is a serine protease– S2P is a zinc metalloproteinase

CAD34

Summary of SREBP maturation

CC

ER

C

Nucleus

N

N

Golgi

C

NCHOLESTEROL

125 kB65 kB

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CAD35

3 different SREBPsOsborne TF. J Biol Chem. 2000, 275, 32379–82

• Belong to the helix-loop-helix family of transcription factors

• First identified through their ability to bind to a sterol response element (SRE) on genes of cholesterolgenesis

• SREBP-1a and SREBP-1c regulate lipid synthetic genes

• SREBP-1a and SREBP-1c are transcribed from the same gene locus and differ only at their N-termini

• SREBP-2 is encoded by a separate gene

• SREBP-1a is dominant isoform in sterol-depleted cell lines

• SREBP-1c is the major isoform in rodent and human liver and is a key regulator of fatty acid and triglyceride synthesis

• SREBP-2 controls cholesterol synthesis at the cleavage site

• SREBP-1c regulates lipogenesis mainly by SREBP-1c mRNA level

Xanthomas Raised, waxy

appearing, often yellow skin lesions (shown here on knee) Associated with

hyperlipidemia Tendon xanthomas

common on Achilles and hand extensor tendons

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Xanthomasraised lesions related to hyperlipidemia

Eruptive Xanthomas-generally associated withhypertriglyceridemia

Xanthomas of the eyelid-generally associated withhypercholesterolemia

-80000

-60000

-40000

-20000

0

20021986Björck L, et al. Eur Heart J. 2009 Jan 13

13 180färre döda

56% förklaras av riskfaktorer:

Lägre kolesterol (39%)

Färre rökare (9%)

Lägre blodtryck (7%)

Mer motion (6%)

Mer diabetes (-5%)

Mer fetma (-2%)

35% förklaras av förbättrad behandling:

Hjärtinfarkt (6%)

Sekundär prevention (9%)

Hjärtsvikt (7%)

Angina (4%)

Hypertoni (4%)

Varför har antalet döda i kranskärlssjukdom halverats i Sverige 1986-2002?

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The Mevanolate Pathway2

The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)

+ HSCoA

H2CC

CH3HO

CH2

CO O

C SCoA

O

H2CC

CH3HO

CH2

CO O

H2C OH

2NADP+

2NADPH

HMG-CoA

mevalonate

HMG-CoA Reductase

5-pyrophosphomevalonate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

2,3-oxidosqualene

HO HO

lanosterol cholesterol

19 steps

In 1976…….. ML-236A, ML-236B, ML-236C: metabolites isolated from a

fungus (Penicillium citrinum) were found to reduce serum cholesterol levels in rats.

This work was done by Akira Endo, Masao Kuroda and Yoshio Tsujita at the Fermentation Research Laboratories, Tokyo, Japan.3

Preliminary experiments showed that these fungal metabolites had no effect on mevanolate or other steps in the biosynthetic pathway.

This led to the speculation that their action was somewhere between the mevanolate and the HMG-CoA

β

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Target: HMG-CoA Reductase (HMGR)

The enzyme that catalyzes the conversion of HMG-CoA to mevanolate.

This reaction is the rate-determining step in the synthetic pathway.

+ HSCoA

H2CC

CH3HO

CH2

CO O

C SCoA

O

H2CC

CH3HO

CH2

CO O

H2C OH

2NADP+

2NADPH

HMG-CoA

mevalonate

HMG-CoA Reductase

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)

Cholesterol and Bile Acid/Salt Metabolism Major excretory form of cholesterol

Steroid ring is not degraded in humans Occurs in liver

Bile acid/salts involved in dietary lipid digestion as emulsifiers

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Recycling of Bile Acids Enterohepatic

circulation 98% recycling of

bile acids Cholestyramine

Treatment Resin binds bile

acids Prevents recycling Increased uptake of

LDL-C for bile acid synthesis

CAD44

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CAD45

Genes activated by SREBP (Shimano. Vitam Horm. 2002;65:167-94)

CAD46

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ApoB and LpA-I, LpA-I:A-II Kinetics with Rosuvastatin

LDLrLiver

31%

IDL

VLDLApoB36%

LDL

47%

89%

58%

55%

TG 42%Apo C-III 23%HDL-C 10%CETPa 11%

LpAI

22%LpAI:AII

19%

Ooi et al Atherosclerosis 2008; 197: 139-46 Ooi et al J Clin Endo Metab 2008; 93: 430-37

20%

24%

LpAI

22%LpAI:AII

19%

20%

24%22%22%

-80000

-60000

-40000

-20000

0


13 180färre döda



Färre rökare (9%)


Mer motion (6%)

Mer diabetes (-5%)

Mer fetma (-2%)


Hjärtinfarkt (6%)


Hjärtsvikt (7%)

Angina (4%)

Hypertoni (4%)


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En liten bulle gör väl ingenting?

100 g choklad = 555 kcal

200 g chips = 1094 kcal

1 daimstrut = 337 kcal

33 cl coca-cola = 137 kcal

100 gram lösgodis = 400 kcal

1 kanelbulle = 280 kcal

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Pojke 11 år, 40 kg, som springer 8 km/h förbrukar ca 270 kcal/h

100 g choklad = 2 h200 g chips = 4 h1 daimstrut = 1,5 h33 cl coca-cola = 30 min100 gram lösgodis = 1 h 45 min1 kanelbulle = 1 h lek och skutt

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Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or Older

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% 26.0%

No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

2010

2010

There’s no such thing as a sudden heart attack. It requires years of

preparation.

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Secretion and Metabolism of VLDL1 and VLDL2

apoB

TG

Small, dense LDL

IDL

IDL

VLDL1

VLDL2

VLDL2

LDL

LDL

VLDL1 Triglycerides are the Major Determinant of Plasma Triglycerides

0 1 2 3 4 50

1

2

3

VLDL1 TG

VLDL2 TG

Total TG [mmol/l]

Tri

glyc

erie

s [m

mol

/l]

VLDL1 TG or VLDL2 TG in Type 2 DM patients

Hiukka A et al. Diabetologia 2005;48:1207

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What Forces Drive the Overproduction of VLDL1 Particles in

Type 2 Diabetes and Insulin Resistance?

Liver Fat and Plasma Glucose Determine VLDL1 TG Production

Variable Beta SE Significance

Liver fat 0.22 0.092 0.025Plasma glucose 0.80 0.38 0.050Insulin 0.49Adiponectin 0.86Total abdominal fat 0.86Subcutaneous fat 0.50Intra-abdominal fat 0.57

Multivariate regression

Adiels M et al. Diabetologia 2006;49:755

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Magnetic Resonance Imaging

Intraperitoneal Fat Compartments

Apo E, MTP, ApoB SP, HL, CETP genotypes, etcRyys et al Diabetes 2000; 49:749

39% liver fat

Liver Fat content

Proton Spectroscopy

Sources of Fatty Acids for Liver and VLDL TG

GlucoseInsulin

CM

PlasmaNEFA

TG

DNL

FA

β-OX

VLDLTG

apoBLIVER

TG

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Hypothesis:

Acute suppression of VLDL1

production by insulin is regulated by liver fat

Low Liver Fat: Normal Production and Regulation of VLDL1 Particles

apoB

TG

Insulin

Low Liver Fat

VLDL1

VLDL2

VLDL2

Adiels M et al. Diabetologia 2007; In Press

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High Liver Fat: Overproduction and Dysregulation of VLDL1 Particles

apoB

TG

Insulin

VLDL1

VLDL2

VLDL2

High Liver Fat

Adiels M et al. Diabetologia 2007; In Press

Metabolic Syndrome: Dysregulation of ApoB and ApoAI Lipoproteins

LDLrLiver18%

IDL

VLDL

ApoB85%

LDL

54%

37%

85%

45%HDL AI16%

48%

25%

TG 200%45%

Riches et al Int J Obesity 1998;22:414 /Chan et al Metabolism 2002;51:1041/ Watts et al Diabetes 2003;53:803

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Proposed Mechanisms for Generation of Small, Dense LDL

CETP = cholesterol ester transfer protein, HL = hepatic lipase

Secretion and Metabolism of VLDL1 and VLDL2

Residence time

Small, dense LDL

apoB

TG

Small, dense LDL

IDL

IDL

VLDL1

VLDL2

VLDL2

LDL

LDL

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LDL Size by Diabetic Status and Gender

Adapted from Gray RS et al Arterioscler Thromb Vasc Biol 1997;17-2713-2720.

The Strong Heart Study

262.8

260.8

257.5

260.5

258.6

256.3

Women Men

Normal glucose tolerance

Impaired glucose tolerance

Diabetes

263

261

259

257

255

Atherogenic Lipoprotein Profile

LargeVLDL

Small denseLDL

HDL

Metabolic SyndromeType 2 Diabetes

IncreasedCAD Risk

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Large, buoyantparticles

Small, denseparticles

Apo-B 25% more apo-B "Normal" concentrationof LDL-C can bemisleading

The number of LDLparticles is increased

The concentration ofapo-B is increased

Why is Small dense LDL Associated with Increased ApoB?

Metabolic Syndrome: Dysregulation of ApoB and ApoAI Lipoproteins

LDLrLiver18%

IDL

VLDL

ApoB85%

LDL

54%

37%

85%

45%HDL AI16%

48%

25%

TG 200%45%

Riches et al Int J Obesity 1998;22:414 /Chan et al Metabolism 2002;51:1041/ Watts et al Diabetes 2003;53:803

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Therapeutic Interventions

Lifestyle– Weight loss

– Diet-Exercise

Pharmacotherapy– Statins

– Ezetimibe

– Fish oils

– PPARs (, , )– Niacin

– CETP inhibitors “Did you say I should start dieting?”

Watts, Barrett, Chan. Curr Opin Lipidol 2008; 19: 395-404 . Watts, Ooi, Chan. Pharmacol Ther 2009; 123: 231-91

ApoB and ApoAI Kinetics with Weight Loss

LDLrLiver

IDL

VLDL

ApoB

LDL

34%

24%

42%

24%

24%

27%

Riches et al J Clin Endocrinol Metab 1999; 84: 2854-61, Ng et al Diabetes Care 2007 30:2945-50, Ng et al Clin Sci 2009;118: 79-85.

Chol 12% TG 43%Insulin 34%Adiponectin 18%

HDL AIHDL AII 9%

AI 13%AII 23%

AI 13%AII 12%

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Effect of Weight Loss on Liver Fat Content and VLDL Secretion in Obese Men

Chan et al 2009

ApoB and LpA-I, LpA-I:A-II Kinetics with Rosuvastatin

LDLrLiver

31%

IDL

VLDLApoB36%

LDL

47%

89%

58%

55%

TG 42%Apo C-III 23%HDL-C 10%CETPa 11%

LpAI

22%LpAI:AII

19%

Ooi et al Atherosclerosis 2008; 197: 139-46 Ooi et al J Clin Endo Metab 2008; 93: 430-37

20%

24%

LpAI

22%LpAI:AII

19%

20%

24%22%22%

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-80000

-60000

-40000

-20000

0


13 180färre döda



Färre rökare (9%)


Mer motion (6%)

Mer diabetes (-5%)

Mer fetma (-2%)


Hjärtinfarkt (6%)


Hjärtsvikt (7%)

Angina (4%)

Hypertoni (4%)


ApoB and ApoAI Kinetics with Fish Oils

LDLrLiver

IDL

VLDL

ApoB

LDL

28%

HDL AIHDL AII 9%

13%

30%

49%

Chan et al Am J Clin Nutr 2003; 77: 300 / Chan et al Am J Clin Nutr 2006; 84: 37-43

TG 25%

AI 9%AII 23%

AI 9%AII 12%

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Summary: Interventions – VLDL ApoBIntervention Secretion Catabolism Concentration

Wt loss

Fish Oils

Statin -

CETPi

Ezetimibe -

Niacin -

PPAR -

PPAR -

PPAR

Proportions of lipid levels at recommended targets among US adults with dyslipidemia on treatment

LDL-C Non-HDL-C HDL-C Triglyceride% % % %

Total cohort

Male

Female

Diabetes

MetS

CVD

61.0

57.4

65.4

40.4

68.5

50.4

57.7

53.5

62.9

46.5

42.6

63.5

73.3

74.3

71.9

64.1

57.9

73.9

60.6

61.6

59.7

56.0

43.8

71.6

Ghandehari H et al. Am Heart J 2008;156;112-119

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The proportions at recommended level of all lipids among US adults on treatment

60

40

20

0All Men Women DM Mets CVD

Less than 20% of people with diabetes, Mets and CVDwere at recommended goal for all lipids

Ghandehari H et al. Am Heart J 2008;156;112-119

Behandling med lipidsänkande läkemedel

Bedömning av lipidvärden

Indikatorer för ökad risk

Triglycerider

>2,0 mmol/L

HDL kolesterol

<1,0 mmol/L

Triglycerider >2 mmol/L och HDL-kolesterol <1,0 mmol/L kan stärka indikationerna för behandling.

* Hos patienter med mycket hög risk kan behandlingsindikation föreligga även vid lägre värden

Önskvärd nivå

Kolesterol

<5,0 mmol/L *

LDL kolesterol

<3,0 mmol/L *

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Motiverade lipidanalyser

• Totalkolesterol

• HDL-kolesterol

• LDL-kolesterol

• Triglycerider

Upprepat prov efter fasta önskvärt

Lipidanalyser

Apolipoprotein B och A I kan tillföra ytterligare information för den specialintresserade


Befolkningsinriktad screening saknar vetenskapligt underlag!

Målgrupper för mätning av blodlipider

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Målgrupper för mätning av blodlipider

• Vid: manifest kranskärlssjukdom/annan aterosklerotisk kärlsjukdom

• Personer med ökad risk - diabetes mellitus, rökning, hypertoni, övervikt, kronisk njursjukdom

• Förekomst av aterosklerotisk hjärt-kärl sjukdom/ uttalad hyperkolesterolemi i familjen


Patienter med diabetes

• Kardiovaskulär sjukdom är den viktigaste orsaken till morbiditet och mortalitet vid diabetes.

• Diabetiker klassas därför i Riskgrupp 1

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Bedömning av lipidvärden

Indikatorer för ökad risk

Triglycerider

>2,0 mmol/L

HDL kolesterol

<1,0 mmol/L

Triglycerider >2 mmol/L och HDL-kolesterol <1,0 mmol/L kan stärka indikationerna för behandling.

* Hos patienter med mycket hög risk kan behandlingsindikation föreligga även vid lägre värden

Önskvärd nivå

Kolesterol

<5,0 mmol/L *

LDL kolesterol

<3,0 mmol/L *


Läkemedelsval

Lipidrubbning Rekommenderat

läkemedel

Alternativt

läkemedel

Kombinations-

behandling

Isolerad

hyperkolesterolemi

Statin Resin Statin + Resin

Alt. Statin +

ezetimib

Kombinerad

hyperlipidemi

Statin Fibrat Statin + Fibrat

Uttalad isolerad

hypertriglyceridemi

Fibrat Nikotinsyra

Omega-3

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Hälsoekonomi

Statinbehandling oavsett ålder och kön är kostnadseffektiv vid behandling efter hjärtinfarkt, koronarkärlsingrepp och angina pectoris.

Primärprevention:– acceptabel kostnadseffektivitet endast vid behandling av personer

med särskilt hög risk

– Statinbehandling vid diabetes och familjär hyperkolesterolemi synes vara kostnadseffektiv

Fall beskrivning 1

Man 42 år kommer till vårdcentral med lätt reumatiska problem (ont i leder). Mamman har RA. Oklart på pappans sida då pappan dog tidigt i ”hjärt-problem”. Vid undersökning känns knutor över leder och förtjockad akillessena.

Utredning? Vad tänka på?

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Fall beskrivning 2

Kvinna kommer till läkare efter att hälsoundersökning påvisat förhöjda blodfetter:

S-kol 6.1 mmol/LS-Tg 4.2 mmol/LS-HDL 0.7 mmol/L

Vad tänka på – vad fråga – vilka råd och/eller behandling?

Fall beskrivning 3

Barn med flera utvecklingsskador skall opereras. Barnet står på Intralipid. Vid operation påvisas ”vit vätska i buk och lungor”. Misstanke på felaktig sond med Intralipid?

Vad tänka på – vad analysera?

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Fall beskrivning 4

Man kommer till distriktsläkaren. Berättar att familjen har ”tidig hjärtdöd” med lågt HDL kolesterol. För att förbättra detta dricker han en halv flaska vin per dag.

Vad säger Du?

Alcohol Increases HDL-C Level

• Alcohol increases HDL-C level in a dose-dependent manner.

• Half bottle of wine per day (39 g alcohol) for 6 weeks significantly increased mean HDL-C level by 7 mg/dL in 12 healthy subjects.1

– Wine intake did not significantly affect Total-C, Total-TG, or LDL-C.1

• One beer per day (13.5 g alcohol) for 6 weeks significantly increased mean HDL-C level by 2 mg/dL in 20 healthy subjects.2

– Beer intake did not significantly affect LDL-C, VLDL-C, TG, or apolipoproteins.

1. Thornton J et al. Lancet 1983;ii:819–8222. McConnell MV et al. Am J Cardiol 1997;80:1226–1228

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Fall beskrivning 4

Man kommer till distriktsläkaren. Berättar att familjen har ”tidig hjärtdöd” med lågt HDL kolesterol. För att förbättra detta dricker han en halv flaska vin per dag.

Vad säger Du?

Jan Borén lipider T3 2012 rev 3.ppt [Kompatibilitetsläge]

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Transcript of Jan Borén lipider T3 2012 rev 3.ppt [Kompatibilitetsläge]