Lipoprotein Disorders

, Jorge Plutzky2 and Jorge Plutzky3



(1)
Harvard Medical School Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

(2)
Harvard Medical School, Boston, USA

(3)
Vascular Disease Prevention Program, Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

 



Introduction

Overview of Lipoprotein Metabolism

Lipoprotein Disorders and CHD Risk

Diagnosis and Screening

Management of Lipoprotein Disorders

Drugs that Modulate Lipid Metabolism

Management of Genetic Dyslipidemias

Quick Review

References


Abstract

Disorders of serum lipid and lipoproteins account for approximately 50 % of population-attributable risk for myocardial infarction (MI) [1, 2]. Randomized control trial (RCT) data demonstrate that treating elevated levels of low density lipoprotein (LDL) cholesterol results in substantial reductions in cardiovascular events and death [3]. Evidence-based guidelines identify serum lipids and lipoprotein disorders as important targets in primary and secondary prevention of coronary heart disease (CHD) [4, 5].


Abbreviations


ABCA

ATP-binding cassette transporter A

ABCG

ATP-binding cassette transporter G

ACS

Acute Coronary Syndrome

ATPIII

Adult Treatment Panel III

CAD

Coronary artery disease

CE

Cholesterol esters

CETP

Cholesterol ester transfer protein

CHD

Coronary Heart Disease

CK

Creatine kinase

CKD

Chronic kidney disease

CM

Chylomicron

CV

Cardiovascular

DM

Diabetes Mellitus

FA

Fatty acid

FC

Free cholesterol

FCH

Familial combined hyperlipidemia

FDB

Familial defective apolipoprotein B

FFA

Free fatty acids

FH

Familial hypercholesterolemia

FRS

Framingham Risk Score

GFR

Glomerular Filtration Rate

GI

Gastrointestinal

HDL

High density lipoprotein

HDL-C

High density lipoprotein cholesterol

IDL

Intermediate density lipoprotein

LCAT

Lecithin cholesterolacyl transferase

LDL

Low density lipoprotein

LDL-C

Low density lipoprotein cholesterol

LDL-R

LDL receptor

LFTs

Liver function tests

LPL

Lipoprotein lipase

MetS

Metabolic syndrome

MI

Myocardial Infarction

Non-HDL-C

Non high density lipoprotein cholesterol

NCEP

National Cholesterol Education Program

PCI

Percutaneous intervention

PL

Phospholipids

PPARα

Peroxisome proliferator-activated receptor alpha

RCT

Randomized control trial

RF

Risk factors

TC

Total cholesterol

TLC

Therapeutic lifestyle changes

TG

Triglycerides

T2D

Type 2 diabetes mellitus

VLDL

Very low density lipoprotein



Introduction


Disorders of serum lipid and lipoproteins account for approximately 50 % of population-attributable risk for myocardial infarction (MI) [1, 2]. Randomized control trial (RCT) data demonstrate that treating elevated levels of low density lipoprotein (LDL) cholesterol results in substantial reductions in cardiovascular events and death [3]. Evidence-based guidelines identify serum lipids and lipoprotein disorders as important targets in primary and secondary prevention of coronary heart disease (CHD) [4, 5].


Overview of Lipoprotein Metabolism






  • Three major types of lipids circulate in the serum:



    • Cholesterol-essential component of cell membranes and substrate for synthesis of steroid hormones and bile acids


    • Triglycerides (TG)-macromolecules consisting of glycerol backbone connected to three fatty acids (FA)


    • Phospholipids (PL)-important constituents of cell membranes


  • Serum lipids are packaged and transported in lipoproteins (Fig. 6-1), which consist of a hydrophobic lipid core of TG, and a polar shell consisting of hydrophilic PL, free cholesterol (FC), and specialized apolipoproteins.

    A306999_1_En_6_Fig1_HTML.gif


    Figure 6-1
    Schematic of a lipoprotein


  • Lipoproteins are classified according to their density in plasma (Table 6-1)


    Table 6-1
    Plasma lipoproteins












































    Lipoprotein
    Density (g/mL)
    Primary lipid component
    Major apolipoprotein

    Chylomicron (CM)
    <0.95
    TG
    B48

    CM remnant
    0.95–1.006
    TG
    B48, E

    Very low density lipoprotein (VLDL)
    <1.006
    TG
    B100

    Intermediate density lipoprotein (IDL)
    1.006–1.019
    TG, CE
    B100, E

    LDL
    1.019–1.063
    CE
    B100

    High density lipoprotein (HDL)
    1.063–1.210
    CE, TG
    A-I, A-II


  • Lipoprotein(a) or Lp(a) is an LDL-like lipoprotein that confers a modest increased risk of CHD independent of LDL-C


  • Lp(a) contains the Apo(a) apolipoprotein, which has structural homology to plasminogen but lacks any fibrinolytic activity


  • Apo(a) may interfere with plasminogen activity and contribute to the pro-thrombotic state associated with Lp(a)


  • Routine measurement of Lp(a) is not recommended as a part of risk factor assessment


  • Apolipoproteins (Apo; Table 6-2) participate in:


    Table 6-2
    Major apolipoproteins












































    Apolipoprotein
    Predominant lipoprotein
    Role

    A (A-I, A-II, A-IV, A-V)
    HDL
    ACAT activation (A-I)

    VLDL (A-V)
    Structural integrity (A-II, A-IV)

    TG metabolism (A-V)

    B48
    CM, CM remnants
    Structural integrity

    B100
    VLDL, IDL, LDL
    Structural integrity

    LDL-R binding

    C (C-I, C-II, C-III)
    CM (C-I, C-II, C-III)
    TG Metabolism (C-I)

    VLDL (C-II, C-III)
    LPL activation (C-II)

    LPL Inhibition (C-III)

    E
    CM remnants, IDL
    LDL-R, Apo E-Receptor binding


    ACAT acetyl-coenzyme A acetyltransferase, LDL-R LDL receptor, LPL lipoprotein lipase




    • lipoprotein assembly and secretion (Apo A-I, Apo B100, Apo B48)


    • catalysis (Apo A-I, Apo A-V, Apo C-II) or inhibition (Apo C-III) of enzymes


    • lipoprotein binding to receptors (Apo B48, B100)


  • Lipoprotein transport serves two important functions:



    • Transport of TG from the intestine to the liver and sites of TG uptake (muscle & fat)


    • Transport of cholesterol to peripheral tissues


  • Two important pathways coordinate lipoprotein transport:


  • Intestinal pathway (Fig. 6-2 ):

    A306999_1_En_6_Fig2_HTML.jpg


    Figure 6-2
    Schematic of intestinal pathway. Chylomicrons (CM) are assembled in intestinal epithelial cells and secreted into the circulation, where they undergo lipolysis by lipoprotein lipase (LPL). CM-remnants are taken up by the liver. LRP lipoprotein receptor-related protein




    • Coordinates transfer of dietary TG to the liver and peripheral tissues


    • Dietary TG in intestinal epithelial cells are packaged with Apo B48 and a small amount of cholesterol to form chylomicron (CM) lipoproteins


    • CM are secreted into the circulation and acquire Apo C and E from HDL


    • CM undergo hydrolysis by lipoprotein lipase (LPL) on endothelial cells


    • Free fatty acids (FFA) released by TG hydrolysis are taken up for energy storage


  • Hepatic Pathway (Fig. 6-3 ):

    A306999_1_En_6_Fig3_HTML.jpg


    Figure 6-3
    Schematic of hepatic pathway. TG-rich VLDL are assembled in the liver and secreted into the circulation. Cholesteryl ester transfer protein (CETP) facilitates transfer of TG from VLDL to HDL in exchange for cholesterol. VLDL is hydrolyzed by LPL to release FFA that are taken up by peripheral tissues (fat, muscle). LDL generated from LPL action can enter the vessel wall, where its oxidation and uptake by macrophages leads to foam cell formation, a key step in atherogenesis. Nascent HDL secreted from the liver play an important role in reverse cholesterol transport




    • Coordinates the transport of TG and cholesterol between the liver and target peripheral tissues


    • Hepatocytes package TG with Apo B100 to form VLDL


    • In the circulation, VLDL interacts with HDL to [1]: acquire additional lipoproteins (Apo C and E), and [2] exchange TG for CE


    • Like CM, VLDL undergoes lipolysis by LPL to produce FFA


    • VLDL hydrolysis yields IDL, which undergoes further hydrolysis by hepatic lipase to form LDL, the main courier of FC and CE


    • LDL is taken by the liver, a process mediated by the LDL receptor (LDL-R)


    • LDL modification in the vessel wall and uptake by macrophages leads to foam cell formation, a key step in atherogenesis


Lipoprotein Disorders and CHD Risk






  • Several lipid and lipoprotein variables have been reported to confer an increased risk of CHD:



    • Elevated total cholesterol (TC) and LDL cholesterol (LDL-C) [6, 7]


    • Low HDL-C and high TG [6, 8]


    • Elevated non-HDL cholesterol (a measure of the total burden of Apo-B containing atherogenic lipoprotein particles) [9]


    • Apo B lipoprotein levels [9]


    • Elevated Lp(a) [10]


    • Small, dense LDL particles [11]


  • NCEP-ATPIII guidelines identify LDL-C as the primary lipid target for intervention [4, 5]


  • A continuous log-linear relationship exists between LDL-C and CHD risk [5]:



    • a decrease of 1 mg/dL in LDL-C results in a 1 % decrease in CHD relative risk


    • a given mg/dL change in LDL-C produces the same change in relative risk of CHD at any level of LDL-C


  • Although LDL-C is the primary lipid target, other parameters such as low HDL-C, non-HDL-C, and Apo B appear to be stronger predictors of CHD risk [9, 12, 13]


  • An increase of 1 mg/dL in HDL-C is associated with a 2–3 % decrease in CHD risk [8], but to date there is no RCT to support targeting HDL-C


  • ATPIII identified non-HDL-C, a surrogate marker of Apo B levels, as a secondary target in patients with TG  >  200 mg/dL (Non-HDL-C  =  TC – HDL-C)


  • NCEP ATPIII guidelines did not recommend routine testing for emerging lipid risk markers


Diagnosis and Screening






  • The most common lipoprotein disorders encountered clinically are related to age, physical inactivity, diet, obesity, and lifestyle factors (smoking)


  • Recent classification systems from WHO and NCEP focus on thresholds and cut points for serum lipoprotein lipids to diagnose and treat lipoprotein disorders (Table 6-3)


    Table 6-3
    Serum lipid concentrations





































    Lipid
    Optimal (mg/dL)
    Borderline elevation (mg/dL)
    Elevated/high risk (mg/dL)

    TC
    <200
    200–239
    >240

    LDL-C
    <100 (100–129-near optimal)
    130–159
    >160

    HDL-C
    ≥60
    40–59 (men)
    <40 (men)

    50–59 (women)
    <50 (women)

    TG
    <150
    150–199
    >200


  • Plasma levels of lipids (cholesterol and triglycerides) and lipoprotein cholesterol (LDL-C and HDL-C) define three general patterns of lipoprotein disorders commonly encountered in clinical settings:



    • Hyperlipidemia refers to an elevation in LDL-C (and TC)


    • Hypertriglyceridemia refers to an elevation in TG


    • Dyslipidemia refers to a combination of hypertriglyceridemia and low HDL-C with either a normal or elevated TC or LDL-C (commonly seen in insulin resistant states)


  • Fasting lipid profile (FLP), which provides direct measurement of TC, TG, HDL-C and calculated LDL-C, is the preferred initial test, rather than measurement of non-fasting TC and HDL-C alone.


  • The Friedewald formula [14] (below) is used to calculate LDL-C, because direct measurement of LDL-C is time consuming and costly


    $$ \text{LDL-C}=\text{TC}-(\text{HDL}+\text{TG}/5)$$


  • The LDL-C calculated from the Friedewald formula is inaccurate at higher TG levels [15], and direct measurement of LDL should be considered if TG  >  400 mg/dL [4, 15]


  • ATP III screening guidelines: FLP at least once every 5 years for individuals older than 20 years of age, with consideration for more frequent testing in older individuals with risk factors [4]


  • Significant elevations in LDL-C (> 190 mg/dL) can indicate a genetic disorder that warrants further consideration and family testing


  • Patients admitted with MI should have a FLP within 24 h of admission (levels drawn later will be spuriously low due to hepatic stress response or medications)


Management of Lipoprotein Disorders



Drugs that Modulate Lipid Metabolism






  • Hyroxymethylglutaryl-Coenzyme A Reductase Inhibitors (Statins)



    • Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in sterol synthesis


    • Statins increase expression of LDL-R and decrease CE formation, leading to enhanced LDL-C clearance from plasma and reduced VLDL production


    • Statins are the drugs of choice for reducing LDL-C (20–55 % reduction)


    • Statins also modestly decrease TG (5–30 %) and increase HDL-C (2–10 %)


    • Data support efficacy of statins in primary and secondary prevention across age groups, in men and women, and in type 2 diabetes (T2D) [3, 4]


    • Starting statin dose should be sufficient to decrease the LDL-C by 30–40 % [4] (Table 6-4)


      Table 6-4
      Doses of available statins required to attain 30–40 % reduction in LDL-C














      Statin
      Dose (mg/dL)
      LDL-C reduction (%)

      Fluvastatin
      < div class='tao-gold-member'>

      Only gold members can continue reading. Log In or Register to continue

      Related posts:

      1. Diseases of the Aorta
      2. Perioperative Cardiovascular Management
      3. Nuclear Cardiology and Exercise Stress Testing
      4. Imaging Studies Section (Echocardiograms, Ventriculograms, Aortograms and Angiograms)

      Stay updated, free articles. Join our Telegram channel
      Tags:
      Jul 13, 2016 | Posted by in CARDIOLOGY | Comments Off on Lipoprotein Disorders

      Full access? Get Clinical Tree

       Get Clinical Tree app for offline access