Disorders of Lipoprotein Metabolism¶
Chapter 419 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 419
Key Clinical Points¶
- Lipoproteins are complexes of lipids (TGs, cholesterol) and proteins (apolipoproteins) essential for the transport of lipids and fat-soluble vitamins.
- Lipoproteins are classified by density: Chylomicrons (least dense, largest) to HDL (most dense, smallest).
- Severe Hypertriglyceridemia (HTG) is defined as fasting TG >500 mg/dL and carries a significant risk of acute pancreatitis.
- Familial Hypercholesterolemia (FH) results from mutations in LDLR, APOB, or PCSK9, leading to elevated LDL-C and premature ASCVD.
- Lp(a) is an independent, heritable risk factor for ASCVD and aortic stenosis; elevated levels require aggressive management.
- The Friedewald formula (LDL-C = total cholesterol - (TG/5) - HDL-C) is only reliable if TG < 200 mg/dL and cannot be used if TG > 400 mg/dL.
- ApoB levels may provide a more accurate assessment of cardiovascular risk than LDL-C alone as it reflects the number of atherogenic particles.
- Chylomicron remnants are cleared by the liver via ApoE as a ligand; ApoB-48 lacks the region required to bind to the LDLR.
- Reverse Cholesterol Transport (RCT) is mediated by HDL and involves LCAT for esterification, CETP for lipid exchange, and SR-BI for liver uptake.
- Primary dyslipidemias are often monogenic (e.g., FCS, FH), while many cases of HTG are polygenic or secondary to conditions like obesity, diabetes, or alcohol use.
DEFINITION & OVERVIEW¶
• Lipoproteins: Complexes of lipids and proteins essential for transporting cholesterol, triglycerides (TGs), and fat-soluble vitamins. • Structure: ◦ Core: Hydrophobic lipids (TGs and cholesteryl esters). ◦ Shell: Hydrophilic lipids (phospholipids, unesterified cholesterol) and apolipoproteins. • Classification by Density/Size: ◦ Chylomicrons: Largest, most lipid-rich, least dense. ◦ VLDL: Very-low-density; intermediate size. ◦ IDL: Intermediate-density; transition between VLDL and LDL. ◦ LDL: Low-density; small, high-density particles. ◦ HDL: High-density; smallest, most dense particles. • Apolipoproteins: Required for assembly, structure, function, metabolism, and catabolism. ◦ ApoB: Major structural protein of chylomicrons (ApoB-48), VLDL, IDL, and LDL (ApoB-100). ◦ ApoA-I: Core structural protein for HDL; promotes cellular lipid efflux via ABCA1; activates LCAT. ◦ ApoC-II & ApoA-V: Regulate TG-rich lipoprotein metabolism; ApoC-II is a required cofactor for LPL. ◦ ApoE: Critical for clearance of TG-rich particles (remnants and IDL) by the liver. ◦ Apo(a): Distinctive apolipoprotein that results in the formation of Lp(a).
Table 419-1 summarizes major apolipoproteins: • ApoA-I: Intestine/Liver; HDL, chylomicrons; promotes efflux via ABCA1, activates LCAT. • ApoA-II: Liver; HDL, chylomicrons; structural protein. • ApoA-V: Liver; VLDL, chylomicrons; promotes LPL-mediated triglyceride lipolysis. • Apo(a): Liver; Lp(a); structural protein. • ApoB-48: Intestine; Chylomicrons, chylomicron remnants; core structural protein. • ApoB-100: Liver; VLDL, IDL, LDL, Lp(a); ligand for LDLR (except for Lp(a)). • ApoC-II: Liver; Chylomicrons, VLDL, HDL; cofactor for LPL. • ApoC-III: Liver/Intestine; Chylomicrons, VLDL, HDL; inhibitor of LPL activity and remnant binding. • ApoE: Liver; Chylomicron remnants, IDL, HDL; ligand for LDLR and other receptors.
EPIDEMIOLOGY¶
• Screening: All adults (and many children) should be screened for plasma lipids. • Measurement Methods: ◦ Total Cholesterol & TGs: Measured enzymatically. ◦ HDL-C: Determined after precipitation of apoB-containing lipoproteins. ◦ LDL-C Calculation (Friedewald): LDL-C = total cholesterol - (TG/5) - HDL-C. → Valid if: Fasted plasma and TG ≤ 200 mg/dL. → Invalid if: TG > 400 mg/dL. ◦ Non-HDL-C: Total cholesterol - HDL-C; includes VLDL and IDL (both atherogenic). • Risk Markers: ◦ ApoB: May provide a better assessment of cardiovascular risk than LDL-C or non-HDL-C. ◦ Lp(a): Independent, highly heritable risk factor for ASCVD and aortic stenosis. • Prevalence of Specific Disorders: ◦ Familial chylomicronemia syndrome (FCS): ~1/200,000–300,000. ◦ Familial hypercholesterolemia (FH): ~1/250 (heterozygous). ◦ Familial dysbetalipoproteinemia (FDBL): ~1/10,000. ◦ Multifactorial severe hypertriglyceridemia: ~1 in 1,000.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Metabolic Pathways: ◦ Exogenous Pathway (Chylomicrons): Chylomicrons → Capillary system → LPL action → Chylomicron remnants → Liver clearance via ApoE. ◦ Endogenous Pathway (VLDL/LDL): VLDL → IDL → LDL → Capillary system → LPL action → FFA release to Muscle/Adipose tissue. ◦ Reverse Cholesterol Transport (HDL): Peripheral cells → Free cholesterol → Nascent HDL (ApoA-I) → Mature HDL (via LCAT) → Liver (via SR-BI).
• Key Metabolic Nodes: 1. Lipolysis of TG-rich lipoproteins by LPL. 2. Receptor-mediated uptake of apoB-containing lipoproteins by the liver. 3. Cellular cholesterol metabolism in the hepatocyte and enterocyte. 4. Assembly and secretion of VLDLs by the liver. 5. Neutral lipid transfer and phospholipid hydrolysis in the plasma.
• Genetic vs. Secondary Factors: ◦ Primary (Monogenic): → FCS: Mutations in LPL, APOC2, APOA5, GPIHBP1, LMF1. → FPLD: Mutations in LMNA, PPARG, PLIN1, AKT2, ADRA2A. → FH: Mutations in LDLR, APOB (receptor binding region), PCSK9 (GoF), LDLRAP1. → Sitosterolemia: ABCG5, ABCG8. → FDBL: APOE2 variant, LIPC. ◦ Secondary (Multifactorial): → Obesity, Type 2 diabetes, insulin resistance, high-carbohydrate diet, alcohol use.
Figure 419-1 illustrates the inverse relationship between size and density. Figure 419-2 maps the exogenous and endogenous pathways. Figure 419-3 details HDL metabolism and reverse cholesterol transport.
CLINICAL FEATURES¶
• Severe Hypertriglyceridemia (HTG): ◦ Definition: Fasting TG >500 mg/dL. ◦ Clinical Findings: → Eruptive xanthomas. → Hepatosplenomegaly. ◦ Risk: Acute pancreatitis; potential for increased ASCVD risk if exacerbated by other factors. • Elevated LDL-C: ◦ Associated with Atherosclerotic Cardiovascular Disease (ASCVD). ◦ Clinical signs in FH: Tendon xanthomas, premature ASCVD. • Mixed Dyslipidemia and Low HDL: ◦ Characterized by elevated chylomicron remnants and IDL. ◦ Clinical signs in FDBL: Palmar and tuberoeruptive xanthomas, premature ASCVD.
DIFFERENTIAL DIAGNOSIS¶
• Primary vs. Secondary Dyslipidemia: ◦ Primary: Genetic mutations (e.g., LPL, ApoC-II, ApoA-V, GPIHBP1, LMF1). ◦ Secondary: Induced by lifestyle or medical conditions.
Table 419-3 lists secondary causes of altered lipid levels: • TG Elevated: High-carbohydrate diet, Alcohol, Obesity, Insulin resistance, Type 2 diabetes, Lipodystrophy, Chronic kidney disease, Nephrotic syndrome, Viral hepatitis, Sepsis, Cushing’s syndrome. • LDL-C Elevated: Obesity, Type 2 diabetes, Lipodystrophy, Chronic kidney disease, Nephrotic syndrome, Viral hepatitis, Sepsis, Cushing’s syndrome. • HDL-C Reduced: High-carbohydrate diet, Alcohol, Obesity, Insulin resistance, Type 2 diabetes, Lipodystrophy, Chronic kidney disease, Nephrotic syndrome, Viral hepatitis, Sepsis, Cushing’s syndrome. • Lp(a) Elevated: Chronic kidney disease, Nephrotic syndrome, Inflammation, Menopause, Orchidectomy, Hypothyroidism, Acromegaly.
DIAGNOSTIC APPROACH¶
- Initial Screening: Obtain a lipid panel (preferably after an overnight fast).
- Calculation of LDL-C:
- If TG < 200 mg/dL → Use Friedewald formula (LDL = TC - [TG/5] - HDL).
- If TG > 200 mg/dL → Direct measurement of LDL-C.
- Assessment of Non-HDL-C:
- Calculate by subtracting HDL-C from total cholesterol to include VLDL and IDL.
- Identification of Secondary Causes:
- Evaluate for alcohol, obesity, diabetes, and renal disease (Table 419-3).
- Clinical Correlation for Specific Syndromes:
- Presence of eruptive xanthomas → suspect FCS.
- Presence of tendon xanthomas → suspect FH.
- Presence of palmar/tuberoeruptive xanthomas → suspect FDBL.
MANAGEMENT & TREATMENT¶
- Lifestyle Modifications:
- Implement dietary changes and exercise to manage lipids.
- LDL-Lowering Therapy (HMG-CoA reductase inhibitors/Statins):
- Lovastatin: 20–40 mg daily (Max 80).
- Pravastatin: 40–80 mg daily (Max 80).
- Simvastatin: 20–40 mg daily (Max 80).
- Fluvastatin: 20–40 mg daily (Max 80).
- Atorvastatin: 20–40 mg daily (Max 80).
- Rosuvastatin: 5–20 mg daily (Max 40).
- Pitavastatin: 1–2 mg daily (Max 4).
- Bile Acid Sequestrants (for elevated LDL-C):
- Cholestyramine: 4 g daily (Max 32 g).
- Colestipol: 5 g daily (Max 40 g).
- Colesevelam: 3750 mg daily (Max 4375 mg).
- Bempedoic Acid (ATP citrate lyase inhibitor):
- Dose: 180 mg daily.
- Mipomersen (ApoB inhibitor):
- Use in HoFH; Dose: 200 mg SC weekly.
- ANGPTL3 Inhibitor:
- Dose: 15 mg/kg IV q 4 weeks.
- TG-Lowering Therapy (for elevated TG):
- Fibrates (Gemfibrozil, Fenofibrate).
- Fish oil (e.g., 4 g daily).
- Escalation for High Risk:
- Patients with TG >500 mg/dL after trial of diet/exercise → initiate fibrate or fish oil to prevent pancreatitis.
PROGNOSIS & COMPLICATIONS¶
• Acute Pancreatitis: Risk in patients with severe hypertriglyceridemia (TG >500 mg/dL). • Atherosclerotic Cardiovascular Disease (ASCVD): Primary risk for elevated LDL-C, high Lp(a), and chylomicron remnants. • Aortic Stenosis: Associated with elevated Lp(a) levels.
KEY PEARLS & CLINICAL TRAPS¶
• Friedewald Rule: Only use if TG < 200 mg/dL; never use if TG > 400 mg/dL. • ApoB vs. LDL-C: ApoB may be a superior marker for cardiovascular risk as it reflects the total number of atherogenic particles. • Lp(a) Significance: It is an independent, heritable risk factor; high levels require aggressive therapy to lower LDL-C. • Chylomicron Clearance: Requires ApoE as a ligand for liver receptors (ApoB-48 lacks the LDLR binding site). • HDL Function: Reverse cholesterol transport involves LCAT (esterification), CETP (lipid exchange), and SR-BI (liver uptake).
Reference Tables¶
TABLE 419-1 Major Apolipoproteins APOLIPOPROTEIN ApoA-I ApoA-II ApoA-V Apo(a) ApoB-48 ApoB-100 ApoC-II ApoC-III ApoE…¶
Harrison's 22e, p.3237
| APOLIPOPROTEIN | PRIMARY SOURCE | LIPOPROTEIN ASSOCIATION | FUNCTION |
|---|---|---|---|
| ApoA-I | Intestine, liver | HDL, chylomicrons | Core structural protein for HDL, promotes cellular lipid efflux via ABCA1, activates LCAT |
| Liver | HDL, chylomicrons | ||
| ApoA-V | Liver | VLDL, chylomicrons | Promotes LPL-mediated triglyceride lipolysis |
| Liver | Lp(a) | ||
| ApoB-48 | Intestine | Chylomicrons, chylomicron remnants | Core structural protein for chylomicrons |
| Liver | VLDL, IDL, LDL, Lp(a) | ||
| ApoC-II | Liver | Chylomicrons, VLDL, HDL | Cofactor for LPL |
| Liver, intestine | Chylomicrons, VLDL, HDL | ||
| ApoE | Liver | Chylomicron remnants, IDL, HDL | Ligand for binding to LDL receptor and other receptors |
TABLE 419-2 Primary Dyslipoproteinemias Caused by Known Single-Gene Mutations¶
Harrison's 22e, p.3241
| GENETIC DISORDER | GENES MUTATED | LIPOPROTEINS AFFECTED | CLINICAL FINDINGS | GENETIC TRANSMISSION | ESTIMATED PREVALENCE |
|---|---|---|---|---|---|
| Severe Hypertriglyceridemia | |||||
| Familial chylomicronemia syndrome (FCS) |
Biallelic LoF mutations in: LPL, APOC2, APOA5, GPIHBP1, LMF1 |
Elevated: Chylomicrons, VLDL Reduced: HDL |
Pancreatitis, eruptive xanthomas, hepatosplenomegaly |
AR | ~1/200,000–300,000 |
| Heterozygous LoF mutations in: LMNA, PPARG, PLIN1, AKT2, ADRA2A |
Elevated: Chylomicrons, VLDL, LDL Reduced: HDL |
Insulin resistance, fatty liver disease, pancreatitis, central obesity, lack of subcutaneous adipose in extremities |
AD | ||
| Hypercholesterolemia | |||||
| Familial hypercholesterolemia (FH) |
Heterozygous LoF mutations in LDLR |
Elevated: LDL | Tendon xanthomas, premature atherosclerotic cardiovascular disease (ASCVD) |
AD | ~1/250 |
| Heterozygous LoF receptor binding region mutations in APOB |
Elevated: LDL | Tendon xanthomas, premature ASCVD |
AD | ||
| Autosomal dominant hypercholesterolemia (ADH), type 3 |
Heterozygous GoF mutations in PCSK9 |
Elevated: LDL | Tendon xanthomas, premature ASCVD |
AD | <1/1,000,000 |
| Biallelic LoF mutations in LDLRAP1 |
Elevated: LDL | Tendon xanthomas, premature ASCVD |
AR | ||
| Sitosterolemia | Biallelic LoF mutations in ABCG5, ABCG8 |
Elevated: LDL | Tendon xanthomas, premature ASCVD |
AR | <1/1,000,000 |
| Biallelic LoF mutations in LIPA |
Elevated: LDL Reduced: HDL |
Fatty liver disease, micronodular cirrhosis |
AR | ||
| Mixed Dyslipidemia | |||||
| Familial dysbetalipoproteinemia (FDBL) |
Biallelic carriers of the APOE2 variant |
Elevated: Chylomicron remnants, IDL |
Palmar and tuberoeruptive xanthomas, premature ASCVD |
AR | ~1/10,000 |
| Biallelic LoF mutations in LIPC |
Elevated: Chylomicron remnants, IDL, HDL |
Premature ASCVD | AR | ||
| Familial Hypolipidemia Syndromes | |||||
| Abetalipoproteinemia | Biallelic LoF mutations in MTTP |
Absent: LDL Reduced: TG, HDL |
Spinocerebellar degeneration, retinal degeneration |
AR | <1/1,000,000 |
| Heterozygous truncating mutations in APOB |
Reduced: LDL | Fatty liver, reduced risk of ASCVD |
AD | ||
| Familial PCSK9 deficiency | Heterozygous LoF mutations in PCSK9 |
Reduced: LDL | Reduced risk of ASCVD | AD | ~1/1,000 |
| Heterozygous LoF mutations in ANGPTL3 |
Reduced: TG, LDL, HDL | Reduced risk of ASCVD | AD | ||
| Primary Low HDL Cholesterol Syndromes | |||||
| ApoA-I deletions/ mutations |
Heterozygous structural mutations in APOA1 |
Reduced: HDL | Variable depending on mutation: premature ASCVD, systemic amyloidosis |
AD | <1/1,000,000 |
| Biallelic LoF mutations in ABCA1 |
Nearly absent: HDL Reduced: LDL Elevated: TG |
Peripheral neuropathy, hepatosplenomegaly |
AR | ||
| Familial LCAT deficiency (FLD); fish eye disease (FED) |
Biallelic LoF mutations in LCAT |
Markedly reduced: HDL | Corneal opacities (both FLD and FED), progressive chronic kidney disease (FLD only) |
AR | <1/1,000,000 |
TABLE 419-3 Secondary Causes of Altered Lipid and Lipoprotein Levels TG ELEVATED High-carbohydrate diet Alcohol Obesity…¶
Harrison's 22e, p.3242
| LDL-C | HDL-C | LP(a) ELEVATED | |||
|---|---|---|---|---|---|
| TG ELEVATED | ELEVATED | REDUCED | ELEVATED | REDUCED | |
| High-carbohydrate diet Alcohol Obesity Insulin resistance Type 2 diabetes Lipodystrophy Chronic kidney disease Nephrotic syndrome Viral hepatitis Sepsis Cushing’s syndrome Acromegaly Glycogen storage disease Pregnancy Drugs: estrogen, glucocorticoids, isotretinoin, bexarotene, other retinoids, beta blockers, bile acid binding resins |
Hypothyroidism Cholestasis Nephrotic syndrome Cushing’s syndrome Acute intermittent porphyria Drugs: corticosteroids, cyclosporin, sirolimus, carbamazepine |
Vegan diet Malabsorption Malnutrition Severe liver disease Gaucher’s disease Chronic infectious disease Hyperthyroidism |
High-fat diet Alcohol Exercise Drugs: estrogen, phenytoin |
Hypertriglyceridemia Vegan diet Malabsorption Malnutrition Sedentary lifestyle Smoking Obesity Gaucher’s disease LAL deficiency Drugs: anabolic steroids, testosterone, beta blockers |
Chronic kidney disease Nephrotic syndrome Inflammation Menopause Orchidectomy Hypothyroidism Acromegaly Drugs: growth hormone, isotretinoin |
TABLE 419-4 Drugs Used to Treat Dyslipidemia DRUG LDL-Lowering Drugs HMG-CoA reductase inhibitors (statins)¶
Harrison's 22e, p.3244
| DRUG | MAJOR INDICATIONS |
STARTING DOSE | MAXIMAL DOSE | MECHANISM | ADVERSE EFFECTS |
|---|---|---|---|---|---|
| LDL-Lowering Drugs | |||||
| HMG-CoA reductase inhibitors (statins) |
Elevated LDL-C; increased CV risk |
↓ Inhibition of cholesterol synthesis → ↑ Hepatic LDL receptors |
Myalgias and myopathy, ↑ transaminases, ↑ diabetes risk |
||
| Lovastatin | 20–40 mg daily | 80 mg daily | |||
| Pravastatin | 40–80 mg daily | 80 mg daily | |||
| Simvastatin | 20–40 mg daily | 80 mg daily | |||
| Fluvastatin | 20–40 mg daily | 80 mg daily | |||
| Atorvastatin | 20–40 mg daily | 80 mg daily | |||
| Rosuvastatin | 5–20 mg daily | 40 mg daily | |||
| Pitavastatin | 1–2 mg daily | 4 mg daily | |||
| Elevated LDL-C | 10 mg daily | 10 mg daily | ↓ Cholesterol absorption→ ↑ LDL receptors |
||
| Bile acid sequestrants | Elevated LDL-C | ↑ Bile acid excretion → ↑ LDL receptors |
Bloating, constipation, elevated triglycerides |
||
| Cholestyramine | 4 g daily | 32 g daily | |||
| Colestipol | 5 g daily | 40 g daily | |||
| Colesevelam | 3750 mg daily | 4375 mg daily | |||
| Elevated LDL-C | 140 mg SC every 2 weeks 75 mg SC every 2 weeks 300 mg SC every 6 months |
420 mg SC every 1 month (HoFH) 150 mg SC every 2 weeks 300 mg SC every 6 months |
↓ PCSK9 activity due to Ab inhibition → ↑ LDL receptors ↓ PCSK9 synthesis due to siRNA silencing → ↑ LDL receptors |
||
| ATP citrate lyase inhibitor Bempedoic acid |
Elevated LDL-C | 180 mg daily | 180 mg daily | ↓ Inhibition of cholesterol synthesis → ↑ LDL receptors |
↑ uric acid and gout ↑ cholelithiasis |
| HoFH | 5 mg daily | 60 mg daily | MTP inhibition → ↓ VLDL assembly and secretion |
||
| ApoB inhibitor (ASO) Mipomersen |
HoFH | 200 mg SC weekly | 200 mg SC weekly | ↓ ApoB synthesis due to ASO silencing → ↓ ApoB/VLDL secretion |
Injection site reactions, flu-like symptoms, increased hepatic fat |
| HoFH | 15 mg/kg IV q 4 weeks | 15 mg/kg IV q 4 weeks | ↓ ANGPTL3 activity due to Ab inhibition → ↑ LPL and EL activity, ↑ LDL catabolism |
||
| TG-Lowering Drugs | |||||
| Fibric acid derivatives (fibrates) Gemfibrozil Fenofibrate |
Elevated TG | 600 mg bid 40–160 mg daily depending on product |
600 mg bid 40–160 mg daily depending on product |
↑ LPL, ↓ VLDL synthesis | Dyspepsia, myalgia, cholelithiasis, elevated transaminases |
| Elevated TG | 4 g daily 4 g daily |
4 g daily 4 g daily |
↑ TG catabolism |