Disorders of Plasma Lipids and Lipoproteins

Introduction

• Plasma lipids include cholesterol, triglycerides, phospholipids, and free fatty acids, which are essential for energy metabolism, membrane structure, and hormone synthesis.

• Because lipids are insoluble in water, they circulate in blood as lipoproteins, composed of lipids and specific apolipoproteins.

• Disorders of plasma lipids and lipoproteins arise due to abnormal synthesis, transport, or clearance of lipoproteins.

• These disorders lead to either decreased lipid levels (hypolipoproteinemia) or increased lipid levels (hyperlipoproteinemia / dyslipidemia).

• Lipoprotein disorders may be primary (genetic) or secondary (acquired), with secondary causes being more common in clinical practice.

• Dyslipidemias are major biochemical risk factors for atherosclerosis, cardiovascular disease, metabolic syndrome, and diabetes mellitus.

• Altered lipid metabolism also affects oral and periodontal health, influencing wound healing, alveolar bone health, and outcomes of dental procedures.

• A sound understanding of these disorders helps students correlate biochemical mechanisms with clinical and dental manifestations.

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Normal Plasma Lipids

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Major plasma lipids include:

• Triglycerides (TAG)

• Cholesterol

• Cholesteryl esters

• Phospholipids

• Free fatty acids

Normal lipid transport occurs via:

• Chylomicrons

• VLDL

• IDL

• LDL

• HDL

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Lipoproteins – Composition & Function 

 

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Classification of Disorders of Plasma Lipids

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Broad Classification

1. Hypolipoproteinemia – ↓ plasma lipoproteins

2. Hyperlipoproteinemia – ↑ plasma lipoproteins

Each is further divided into:

• Primary (genetic)

• Secondary (acquired)

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I. Hypolipoproteinemia

(Decreased plasma lipids/lipoproteins)

Hypolipoproteinemia is characterized by abnormally low levels of LDL, HDL, or both, leading to impaired lipid transport and deficiency of fat-soluble vitamins.

A. Primary Hypolipoproteinemia (Genetic)

1. Disorders with Low LDL Cholesterol

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2. Disorders with Low HDL Cholesterol

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B. Secondary Hypolipoproteinemia (Acquired)

Common Causes

• Anemia

• Chronic inflammation

• Chronic liver disease

• Hyperthyroidism

• Chronic infections

• Malabsorption syndromes

• Malignancy

• Critical illness

Mechanism: Reduced hepatic synthesis or increased catabolism of lipoproteins.

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II. Hyperlipoproteinemia

(Increased plasma lipids/lipoproteins)

Hyperlipoproteinemia refers to elevated cholesterol, triglycerides, or both, due to impaired clearance or overproduction of lipoproteins.

A. Primary Hyperlipoproteinemia (Genetic)

Fredrickson Classification

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Important Primary Disorders

Type IIa – Familial Hypercholesterolemia

• Defect: LDL receptor mutation

• Biochemistry: ↑ LDL-cholesterol

• Clinical: Tendon xanthomas, premature CAD

Type IIb – Familial Combined Hyperlipidemia

• Most common genetic dyslipidemia

• ↑ LDL + VLDL

• Strongly associated with cardiovascular disease

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B. Secondary Hyperlipoproteinemia 

Causes

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Pathophysiology of Atherosclerosis

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Step 1: Endothelial Dysfunction (Initiating Event)

• Normal endothelium maintains vascular tone and antithrombotic state.

• Risk factors cause endothelial injury:

  • Hyperlipidemia (↑ LDL)

  • Smoking

  • Diabetes mellitus

  • Hypertension

• Endothelial damage leads to:

  • ↑ Vascular permeability to lipoproteins

  • ↑ Adhesion of monocytes

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Step 2: Entry and Oxidation of LDL

• LDL particles enter the subendothelial space (intima).

• LDL undergoes oxidation by:

  • Reactive oxygen species (ROS)

  • Endothelial and macrophage enzymes

• Oxidized LDL (oxLDL) is highly atherogenic.

  Biochemical importance: Oxidized LDL is not recognized by normal LDL receptors.

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Step 3: Monocyte Migration and Foam Cell Formation

• Monocytes migrate into the intima and differentiate into macrophages.

• Macrophages engulf oxidized LDL via scavenger receptors.

• Lipid-laden macrophages are called foam cells.

   Accumulation of foam cells forms fatty streaks (earliest lesion).

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Step 4: Smooth Muscle Cell Proliferation

• Growth factors released by:

  • Activated macrophages

  • Damaged endothelium

• Cause:

  • Migration of smooth muscle cells from media to intima

  • Proliferation of smooth muscle cells

• Smooth muscle cells synthesize:

  • Collagen

  • Proteoglycans

  • Elastin

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Step 5: Formation of Fibrous Atherosclerotic Plaque

• Lipid core composed of:

  • Cholesterol

  • Cholesteryl esters

  • Dead foam cells

• Covered by a fibrous cap (collagen-rich)

• Results in:

  • Narrowing of arterial lumen

  • Reduced blood flow (ischemia)

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Step 6: Plaque Complications

• Plaque rupture or erosion exposes thrombogenic material

• Leads to:

  • Platelet aggregation

  • Thrombus formation

• Can cause:

  • Myocardial infarction

  • Stroke

  • Peripheral vascular disease

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Role of Lipoproteins in Atherosclerosis

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Biochemical Risk Factors

• ↑ LDL cholesterol

• ↓ HDL cholesterol

• ↑ Triglycerides

• Oxidative stress

• Chronic inflammation

 

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Laboratory Evaluation of Lipid Disorders

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1. Specimen and Pre-analytical Requirements

• Sample: Venous blood (serum preferred)

• Fasting state:

  • 9–12 hours fasting required

  • Only water allowed

• Reason for fasting:

  • To eliminate post-prandial lipemia

  • To obtain accurate triglyceride and VLDL values

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2. Fasting Lipid Profile (Primary Test)

The fasting lipid profile is the first-line and most important investigation.

Parameters Measured

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Diagnostic Significance

• ↑ Total cholesterol → Hypercholesterolemia

• ↑ Triglycerides → Hypertriglyceridemia

• ↑ LDL-C → Increased atherogenic risk

• ↓ HDL-C → Loss of cardioprotective effect

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3. Calculation of Lipoprotein Fractions

Friedewald Formula (Very Important for Exams)

• VLDL-C = TG / 5

• LDL-C = TC − (HDL-C + VLDL-C)

Limitations:

• Not valid when:

  • TG > 400 mg/dL

  • Non-fasting sample

  • Type I hyperlipoproteinemia

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4. Atherogenic Indices (Risk Assessment)

Atherogenic ratios give better cardiovascular risk prediction than individual lipid values.

   High-risk TC/HDL ratio: > 5

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5. Apolipoprotein Estimation

 Especially useful when LDL-C is misleading (e.g., high TG states)

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6. Lipoprotein

• LDL-like particle containing apolipoprotein(a)

• Genetically determined

• Highly atherogenic and thrombogenic

• Indicated in:

  • Premature cardiovascular disease

  • Strong family history of CAD

  • Normal lipid profile with high risk

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7. Specialized Lipoprotein Tests

• Lipoprotein electrophoresis

  • Identifies Fredrickson types

• Ultracentrifugation

  • Gold standard for lipoprotein separation

• Genetic testing

  • Familial hypercholesterolemia

  • Apo-E polymorphism

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8. Evaluation of Secondary Causes 

Whenever dyslipidemia is detected, secondary causes must be ruled out.

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9. Typical Laboratory Patterns 

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Management of Lipid Disorders

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Principles of Management

• Identify whether dyslipidemia is primary (genetic) or secondary (acquired)

• Assess overall cardiovascular risk

• Correct modifiable risk factors

• Combine lifestyle modification with pharmacotherapy when required

• Monitor lipid levels and treatment response regularly

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I. Lifestyle Modification (First-Line for All Patients)

1. Dietary Management

Goals: Reduce LDL and triglycerides, increase HDL

• Reduce saturated fats and trans fats

• Limit dietary cholesterol

• Increase intake of:

  • Fruits and vegetables

  • Whole grains

  • Dietary fiber

• Prefer:

  • Polyunsaturated and monounsaturated fats

• Avoid:

  • Excess sugar

  • Refined carbohydrates

  • Alcohol (especially in hypertriglyceridemia)

Diet alone can reduce LDL by 10–15%

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2. Physical Activity

• Regular aerobic exercise (≥150 minutes/week)

• Effects:

  • ↑ HDL cholesterol

  • ↓ Triglycerides

  • Improves insulin sensitivity

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3. Weight Reduction

• Essential in obese individuals

• Even 5–10% weight loss significantly improves lipid profile

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4. Smoking Cessation

• Smoking lowers HDL and accelerates atherosclerosis

• Cessation improves HDL and vascular health

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II. Management of Secondary Causes 

Secondary dyslipidemia must be corrected before drug therapy.

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III. Pharmacological Therapy

Drug therapy is indicated when:

• Lifestyle measures fail

• High cardiovascular risk is present

• Genetic dyslipidemia exists

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1. Statins (First-Line Drugs)

Examples: Atorvastatin, Rosuvastatin

Mechanism:

• Inhibit HMG-CoA reductase

• ↓ Cholesterol synthesis

• ↑ LDL receptor expression → ↓ LDL

Effects:

• ↓ LDL (major effect)

• Mild ↓ TG

• Mild ↑ HDL

 Most effective drugs for cardiovascular risk reduction

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2. Fibrates

Examples: Fenofibrate, Gemfibrozil

Mechanism:

• Activate PPAR-α

• ↑ Lipoprotein lipase activity

Effects:

• ↓ Triglycerides (major effect)

• ↑ HDL

Indication:

• Severe hypertriglyceridemia

• Prevention of pancreatitis

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3. Niacin (Nicotinic Acid)

Effects:

• ↓ LDL

• ↓ Triglycerides

• ↑ HDL (best drug to raise HDL)

Limitations:

• Flushing

• Hepatotoxicity

• Insulin resistance

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4. Ezetimibe

Mechanism:

• Inhibits intestinal cholesterol absorption

Use:

• Combined with statins when LDL targets not achieved

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5. Bile Acid Sequestrants

Examples: Cholestyramine

Mechanism:

• Bind bile acids → increased cholesterol excretion

Effect:

• ↓ LDL

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6. PCSK9 Inhibitors

• Increase LDL receptor availability

• Used in familial hypercholesterolemia

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IV. Management According to Lipid Abnormality

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V. Monitoring of Therapy

• Lipid profile repeated:

  • 6–12 weeks after starting treatment

  • Every 6 months once stable

• Monitor for:

  • Liver enzymes (statins)

  • Muscle symptoms

• Adjust dose based on response

 

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MCQs

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1. Plasma lipids are transported in blood mainly as:

A. Free fatty acids
B. Micelles
C. Lipoproteins
D. Phospholipid bilayers

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2. Major lipid carried by LDL is:

A. Triglyceride
B. Phospholipid
C. Cholesterol
D. Free fatty acid

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3. HDL is primarily involved in:

A. Cholesterol delivery to tissues
B. Triglyceride transport
C. Reverse cholesterol transport
D. Fat digestion

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4. Hyperlipoproteinemia refers to:

A. Low lipid levels
B. High lipoprotein levels
C. Normal lipid metabolism
D. Fat malabsorption

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5. Hypolipoproteinemia is characterized by:

A. Increased LDL
B. Decreased lipoproteins
C. Increased triglycerides
D. Increased cholesterol

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6. Primary lipid disorders are caused by:

A. Diet
B. Drugs
C. Genetic defects
D. Liver disease

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7. Secondary lipid disorders are most commonly due to:

A. Apo-B mutation
B. PCSK9 mutation
C. Diabetes mellitus
D. LDL receptor defect

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8. Fredrickson classification is based on:

A. Clinical features
B. Genetic mutations
C. Lipoprotein pattern
D. Enzyme levels

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9. Type I hyperlipoproteinemia shows increase in:

A. LDL
B. VLDL
C. Chylomicrons
D. HDL

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10. Type IIa hyperlipoproteinemia is characterized by:

A. ↑ VLDL
B. ↑ LDL
C. ↑ Chylomicrons
D. ↑ HDL

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11. Most common primary hyperlipoproteinemia is:

A. Type I
B. Type IIa
C. Type IIb
D. Type V

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12. Type III hyperlipoproteinemia is also called:

A. Familial hypercholesterolemia
B. Dysbetalipoproteinemia
C. Hyperchylomicronemia
D. Hypoalphalipoproteinemia

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13. Palmar xanthomas are characteristic of:

A. Type I
B. Type IIa
C. Type III
D. Type IV

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14. Type IV hyperlipoproteinemia shows increase in:

A. LDL
B. HDL
C. VLDL
D. Chylomicrons

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15. High risk of pancreatitis is seen in:

A. Type IIa
B. Type IIb
C. Type I and Type V
D. Type III

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16. Abetalipoproteinemia is associated with absence of:

A. Apo-A1
B. Apo-B
C. Apo-CII
D. Apo-E

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17. Tangier disease is characterized by:

A. High LDL
B. High HDL
C. Very low HDL
D. High triglycerides

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18. LCAT deficiency mainly affects:

A. LDL formation
B. Cholesterol esterification
C. Triglyceride synthesis
D. Fat absorption

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19. Atherogenic lipoprotein is:

A. HDL
B. LDL
C. Chylomicron
D. VLDL only

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20. Protective lipoprotein is:

A. LDL
B. IDL
C. HDL
D. VLDL

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21. First step in atherosclerosis is:

A. Foam cell formation
B. Plaque rupture
C. Endothelial dysfunction
D. Thrombosis

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22. Oxidized LDL leads to formation of:

A. Smooth muscle cells
B. Fibrous cap
C. Foam cells
D. Platelets

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23. Earliest lesion of atherosclerosis is:

A. Fibrous plaque
B. Fatty streak
C. Calcified plaque
D. Thrombus

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24. Foam cells are:

A. Smooth muscle cells
B. Lipid-laden macrophages
C. Endothelial cells
D. Fibroblasts

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25. HDL protects against atherosclerosis by:

A. Increasing LDL
B. Oxidizing cholesterol
C. Reverse cholesterol transport
D. Increasing triglycerides

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26. Basic test for lipid disorder evaluation is:

A. Apolipoprotein assay
B. Lipoprotein electrophoresis
C. Fasting lipid profile
D. Genetic testing

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27. Fasting required for lipid profile is:

A. 4–6 hours
B. 6–8 hours
C. 9–12 hours
D. 24 hours

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28. LDL-cholesterol is calculated using:

A. Friedewald formula
B. Beer–Lambert law
C. Michaelis–Menten equation
D. Henderson–Hasselbalch equation

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29. Friedewald formula is invalid when triglycerides are:

A. <150 mg/dL
B. >200 mg/dL
C. >400 mg/dL
D. <100 mg/dL

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30. VLDL-cholesterol is calculated as:

A. TC − HDL
B. TG ÷ 2
C. TG ÷ 5
D. HDL ÷ 5

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31. Best predictor of cardiovascular risk is:

A. Total cholesterol
B. LDL alone
C. Apo-B / Apo-A1 ratio
D. Triglycerides

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32. Lipoprotein(a) is:

A. Diet dependent
B. Drug induced
C. Genetically determined
D. Vitamin dependent

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33. Secondary hyperlipidemia is commonly seen in:

A. Hyperthyroidism
B. Diabetes mellitus
C. Anemia
D. Malnutrition

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34. Hypothyroidism causes increase in:

A. HDL
B. LDL
C. Chylomicrons
D. Apo-A1

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35. Primary aim of lipid disorder management is:

A. Cosmetic improvement
B. Weight gain
C. Cardiovascular risk reduction
D. Fat absorption

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36. First-line management of dyslipidemia is:

A. Statins
B. Fibrates
C. Lifestyle modification
D. PCSK9 inhibitors

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37. Statins act by inhibiting:

A. Lipoprotein lipase
B. HMG-CoA reductase
C. ACAT
D. CETP

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38. Best drugs for lowering LDL are:

A. Fibrates
B. Niacin
C. Statins
D. Bile acids

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39. Fibrates are mainly used to treat:

A. Hypercholesterolemia
B. Hypertriglyceridemia
C. Low HDL
D. Tangier disease

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40. Niacin is best known for:

A. Lowering LDL only
B. Raising HDL
C. Lowering Lp(a) only
D. Increasing triglycerides

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41. Ezetimibe reduces cholesterol by:

A. Increasing LDL receptors
B. Inhibiting intestinal absorption
C. Increasing bile acid excretion
D. Increasing HDL synthesis

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42. PCSK9 inhibitors are used mainly in:

A. Type I hyperlipoproteinemia
B. Familial hypercholesterolemia
C. Tangier disease
D. Abetalipoproteinemia

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43. Monitoring lipid therapy is usually done after:

A. 1 week
B. 2 weeks
C. 6–12 weeks
D. 1 year

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44. High TG with low HDL is commonly seen in:

A. Hypothyroidism
B. Diabetes mellitus
C. Anemia
D. Liver failure

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45. Secondary causes of dyslipidemia must be:

A. Ignored
B. Treated first
C. Treated later
D. Never evaluated

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46. Atherogenic index is calculated using:

A. LDL only
B. HDL only
C. Lipid ratios
D. Triglycerides only

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47. Low HDL is associated with:

A. Reduced CV risk
B. Increased CV risk
C. No risk
D. Improved prognosis

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48. Major complication of severe hypertriglyceridemia is:

A. Stroke
B. Pancreatitis
C. Hypertension
D. Anemia

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49. Dyslipidemia affects dental practice mainly by:

A. Increasing caries
B. Delaying wound healing
C. Causing tooth discoloration
D. Increasing saliva

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50. Most important lipid abnormality in atherosclerosis is:

A. High HDL
B. Low triglycerides
C. High LDL
D. Low VLDL

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Answer Key

1. C

2. C

3. C

4. B

5. B

6. C

7. C

8. C

9. C

10. B

11. C

12. B

13. C

14. C

15. C

16. B

17. C

18. B

19. B

20. C

21. C

22. C

23. B

24. B

25. C

26. C

27. C

28. A

29. C

30. C

31. C

32. C

33. B

34. B

35. C

36. C

37. B

38. C

39. B

40. B

41. B

42. B

43. C

44. B

45. B

46. C

47. B

48. B

49. B

50. C