Hyperlipidemia (Hyperlipoproteinaemia) (Dyslipidemia) By Ahmed M Hyperlipidemia (Hyperlipoproteinaemia) (Dyslipidemia) By Ahmed M. Ali, PhD. 2019

Hyperlipidemia 2019 Part One

Learning Objectives Definition of hyperlipidemia Etiology and clinical types of hyperlipidemia Risk factors of hyperlipidemia Lipid profile in hyperlipidemia Management of hyperlipidemia Lipid-lowering drugs ACC/AHA Guidelines on the Management of Blood Cholesterol (2018).

 Hyperlipidemia is an abnormally high level of fatty substances (lipids) in the blood.  The major plasma lipids include cholesterol (C) and triglycerides (TGs).  Plasma lipids do not circulate freely in the blood, but are bound to proteins (apoproteins) and transported as macromolecules known as lipoproteins.

Lipoproteins Lipoproteins are spherical particles that have a hydrophobic core wrapped in a hydrophilic coat. The core contains cholesterol esters and triglycerides and the surface coat contains cholesterol, phospholipids and proteins ( apoproteins). Lipoproteins circulate in the blood and function to transport cholesterol and cholesterol esters either from or to the liver.

There are several forms of lipoproteins, depending on their size, density and electrophoretic mobility.

The larger the size of lipoproteins, the lower the density (1) Chylomicrons (TG-rich particles) (2) Very low density (pre-β) lipoproteins (VLDL). (3) Low density (β-) lipoproteins (LDL). (4) Intermediate density lipoproteins (IDL) (5) High density (α-) lipoproteins (HDL). The larger the size of lipoproteins, the lower the density

Functions of Lipoproteins

(1) Chylomicrons : transport of dietary (exogenous) TG from the intestine to the liver. (2) VLDL: transport of endogenous TG & cholesterol from the liver to the peripheral tissues (adipocytes & muscle cells) for storage and/or energy production. (3) LDL: transports cholesterol to peripheral tissues. (4) HDL: transports cholesterol from peripheral tissues to the liver (Reverse cholesterol transport).

Etiology and Clinical Types of Hyperlipidemia

I. Primary Hyperlipoproteinemia

- It results from genetic predisposition, excessive fat intake or obesity. - Primary hyperlipoproteinemia may lead to: (a) Hypercholesterolaemia ( blood TC). (b) Hypertriglyceridemia ( blood TGs). (c) A combination of (a) & (b).

II. Secondary Hyperlipoproteinemia

It develops secondary to: (1) Pathological conditions such as: -Diabetes mellitus       - Nephrotic syndrome - Renal failure - Hypothyroidism - Cholestasis - Cushing syndrome  

Nephrotic Syndrome An inflammatory renal disease characterized by: - Low plasma albumin. - Albuminuria. - Oedema. - Hyperlipidemia. It may be associated with DM (diabetic nephropathy).

(2) Drug therapy: - Thiazide diuretics (2) Drug therapy: - Thiazide diuretics. - β-adrenergic blockers - Oral contraceptives. - Corticosteroids. - Isotretinoin (vitamin A derivative).

Risk Factors of hyperlipidemia Advancing age Adult men (at any age) Postmenopause Lack of exercise Smoking Stress Excessive alcohol intake

Depending on the chief lipoprotein raised, primary hyperlipoproteinemia may be classified according to Fredrickson into 6 types.  

Type I (Familial hyperchylomicronmia). Type IIa (Familial hypercholesterolemia). Type IIb (Familial mixed hyperlipidemia). Type III (Familial dysbetalipoproteinemia). Type IV (Familial hypertriglyceridemia). Type V (Familial mixed hypertriglyceridemia).

Fredrickson Classification of Hyperlipidemia Risk of Atherosclerosis Triglyceride Cholesterol Lipoprotein Elevated Type Not elevated +++ + Chylomicrons I High Normal ++ LDL IIa LDL + VLDL IIb Moderate IDL III VLDL IV Chylomicrons + VLDL V

 Hyperlipidemia is usually asymptomatic.  Very high levels of cholesterol in the blood may cause yellow fat deposits in the skin or tendons (xanthomas).  Extremely high levels of triglycerides in the blood may cause pain, enlargement, or swelling (inflammation) of abdominal organs such as the liver, spleen, or pancreas (pancreatitis).

 The most significant consequence of hyperlipidemia involves partial or complete obstruction of blood vessels throughout the body, particularly those supplying the heart and brain.  Individuals with hyperlipidemia are at increased risk of: - Atherosclerosis. - Heart attack (myocardial infarction) - Stroke (sudden loss of consciousness due to cerebrovascular thrombosis, embolism or hemorrhage with varying degrees of hemiplegia).

Diagnosis

 The National Cholesterol Education Program (NCEP) advises that adults have their blood lipids checked at least once every five years, starting at age 20.  Earlier or more frequent blood lipid testing is indicated in persons with: (1) Family history of hyperlipidemia. (2) Risk factors for hyperlipidemia. (3) Medical conditions that may cause or result from hyperlipidemia.

Risk Factors of hyperlipidemia Advancing age Adult men (at any age) Postmenopause Lack of exercise Smoking Stress Excessive alcohol intake

Lipid Profile

Total Cholesterol (TC) Levels - Normal range : 150-200 mg/dl. - Borderline range: 200-250 mg/dl. - Hypercholesterolaemia: > 250 mg/dl. High TC requires dietary and/or medical management. However, most decisions about treatment are made based upon the LDL-C or HDL-C, rather than TC.

LDL-cholesterol (Bad cholesterol) The LDL-C is a more accurate predictor of Atherosclerotic cardiovascular disease (ASCVD) than TC. Higher LDL-C concentrations have been associated with an increased incidence of CHD in a large number of studies. Ideally, LDL-C levels should be less than 130 mg/dl.

The level of LDL-C should not exceed 100mg/dl in patients with past history of CHD. People with LDL-C levels of  160 mg/dl have a high risk of CHD. Intermediate LDL-C levels (130-159 mg/dl) predict an intermediate risk of CHD.

VLDL-Cholesterol - Elevated VLDL level is associated with a moderate risk of atherosclerosis. - The ideal VLDL level should be < 20 mg/dl.

Triglycerides (TG) Elevated levels of blood TG are also associated with an increased risk of CHD. Like LDL-C, TG should only be measured on a blood specimen obtained after fasting for 12 to 14 hours.

TG concentrations are graded as follows: Level Grade < 200 mg/dl Normal < 150 mg/dl Desirable 200 to 400 mg/dl Borderline high 400 to 1000 mg/dl High > 1000 mg/dl Very high

HDL-cholesterol (Good cholesterol) Elevated levels of HDL-C actually lower the risk of CHD. A plasma HDL-C of > 60 mg/dl is considered a "negative" risk factor for CHD. Similar to total cholesterol, the HDL-C can be measured on any blood specimen, no need to be fasting

LDL/HDL Ratio The normal LDL/HDL ratio is about 3.22. The higher the ratio, the higher the atherosclerotic risk.

Management of Hyperlipidemia

 Diet and lifestyle changes can help treat hyperlipidemia  Diet and lifestyle changes can help treat hyperlipidemia.  A combination of diet, lifestyle changes and medication may be required in some cases.

Dietary Changes The chief dietary measures are: (1) Restriction of caloric intake (35% as fats, 50% as carbohydrates and 15% as proteins). (2) Restriction of cholesterol to < 300 mg/day (equivalent to 11/2 eggs). (3) Replace animal fats with polyunsaturated fats (corn oil). (4) Increase in dietary fibres (fruits & vegetables).

Lifestyle Changes (1) Weight reduction (for overweight and obese persons). (2) Exercise. (3) Cessation of smoking. (4) Avoidance of alcohol intake.

Drug Therapy

Lipid-lowering Drug Classes HMG-CoA reductase inhibitors (Statins). Cholesterol absorption inhibitors. PCSK9 inhibitors. Bile Acid-Binding Resins (Bile acid sequestrants). Niacin (Nicotinic acid, Vitamin B3). Fibric acid derivatives (Fibrates or PPAR activators). Probucol. Fish oils. Other anti-hyperlipidemics.

HMG-CoA Reductase Inhibitors (Statins)

HMG-CoA Reductase Inhibitors (Statins) Statins are competitive inhibitors of the enzyme 3-Hydroxy-3-MethylGlutaryl (HMG) Coenzyme A (CoA) reductase that catalyzes an early rate-limiting step in cholesterol synthesis. Statins are the most effective and best-tolerated agents for treating elevated LDL-C. They effectively reduce fatal and non-fatal CAD events, strokes and mortality rates.

Beneficial effects of statins (1) Inhibition of HMG-CoA reductase (2) Increase in LDL receptor (3) Reduction of plasma TGs (4) Elevation of HDL-C

STATINS Lovastatin (Lovastan®) Pravastatin (Lipostat®) Simvastatin (Zocor®) Atorvastatin (Lipitor®, Ator®) Fluvastatin (Lescol®) Rosuvastatin (Crestor®)

LDL Cholesterol-lowering potency of Different Statins High-potency (density) statins: Rosuvastatin and Atorvastatin. Intermediate-potency (density) statins: Simvastatin, and Pravastatin. Low-potency (density) statins: Lovastatin and Fluvastatin.

Therapeutic Benefits of Statins The marked reduction in LDL-C levels decreases the risk of CAD by 50-60% Atheromatus plaque stabilization (no rupture!). Improvement of coronary endothelial function. Inhibition of platelet thrombus formation. Anti-inflammatory activity.

Indications of Statins Treatment of elevated LDL-C plasma levels either as monotherapy or with ezetimibe, bile acid-binding resins or niacin. Treatment of severe hypercholesterolemia of familial origin such as types IIa and IIb. Reduction of LDL-C and TGs and elevation of HDL-C in dyslipidemic diabetic patients. Statins are less effective in patients with homozygous familial hypercholesterolemia who lack LDL receptors.

Fredrickson Classification of Hyperlipidemia Risk of Atherosclerosis Triglyceride Cholesterol Lipoprotein Elevated Type Not elevated +++ + Chylomicrons I High Normal ++ LDL IIa LDL + VLDL IIb Moderate IDL III VLDL IV Chylomicrons + VLDL V

ADRs Transient elevation of serum transaminases. Myopathy (muscle weakness). Rhabdomyolysis (disintegration of muscle tissue) with elevated serum creatine kinase level may rarely occur (0.01%) especially in patients with renal insufficiency or in those taking cyclosporin, azole antifungals (itraconazole), macrolides (erythromycin), gemfibrozil (38% of cases) or digoxin, warfarin, amiodarone and niacin (rare) Creatine kinase (CK) level should be monitored regularly.

Factors increasing the risk of Statin-induced myopathy High-dose statin. Advanced age (> 80 years). Drugs that inhibit statin catabolism (50% of cases). Hepatic or renal dysfunction. Diabetes mellitus. Hypothyroidism.

- Gemfibrozil enhances statin-induced myopathy by: (1) Inhibition of OATP2-mediated hepatic uptake of the active β-hydroxy acid forms of statins. (2) Inhibition of CYP-dependent statin catabolism. (3) Inhibition of statin glucuronidation. - Macrolides, azole antifungals, cyclosporin, HIV protease inhibitors and the antidepressant nefazodone can enhance myopathy caused by atorvastatin, simvastatin and lovastatin by interfering with their hepatic CYP3A4-mediated catabolism. These drugs can be safely given with pravastatin (excreted unchanged in urine) or fluvastatin (catabolized mainly by CYP2C9).

Contraindications Pregnancy and lactation. Women willing to be pregnant Children and teenagers. Homozygous familial hypercholesterolemia