DYSLIPIDEMIAS


Note

Lipid physiology and pathophysiology
Secondary causes of dyslipidemias
Diagnosis/Monitoring
Treatment of Dyslipidemias

I. Lipid physiology and pathophysiology

  1. Normal functions of cholesterol include structural role in cell membrane and as a precursor of bile acids and steroid hormones
  2. Also as a component of serum lipoproteins--Total level of serum cholesterol is correlated w/risk for coronary heart disease (CHD) and with higher mortality rates (the latter association less clearly demonstrated in women than in men); Higher overall mortality ass'd with very low tot. chol. levels, e.g. < 140
  1. Low-density lipoprotein (LDL)
  1. Contains 60-70% of total serum cholesterol
  2. Directly correlated w/risk for CHD-"The major atherogenic lipoprotein"
  3. Low LDL is associated with diabetes mellitus, lack of exercise, obesity, very high carbohydrate intake (> 60% tot. calories) and cigarette smoking; also some drugs (beta-blockers, anabolic steroids, progestins)
  1. High-density lipoprotein (HDL)
  1. Contains 20-30% of total serum cholesterol
  2. Inversely correlated w/CHD risk
  3. "HDL should be measured at initial cholesterol testing" (NCEP)
  1. Very low-density lipoprotein (VLDL) & Triglycerides
  1. VLDL is a precursor of LDL; contains 10-15% of total serum cholesterol
  2. Also contains most of the triglyceride in fasting serum; after eating, there is also TG in chylomicrons
  3. Risk factors for hypertriglyceridemia: obesity, physical inactivity, cigarette smoking, excess alcohol intake, high carbohydrate intake (> 60% caolries), DM, chronic renal failure, nephrotic syndrome, certain drugs (corticosteroids, estrogens, retinoids, beta-blockers), and genetic dyslipidemias
  4. Triglyceride levels & CHD risk
    1. Population data (e.g. from Helsinki Heart Study) have shown elevated triglycerides levels to be correlated with elevated CHD risk (particularly among pts with high total chol. and low HDL) but the question of causation is controversial
    2. Some forms of VLDL, particularly "remnant" VLDL, may contribute to CHD-can't tell by triglyceride level, i.e. not all cases of hypertriglyceridemia impart the same degree of risk
    3. One prospective trial in 2,900 white males followed x 8y found that triglyceride level was an independent risk factor for ischemic heart disease; adjusted for HDL, LDL, and other potential confounders (Circ. 97:1029, 1998--JW)
    4. Studies of treatment focused specifically on reducing triglycerides have not shown benefit in reduced incidence of CHD events (see Helsinki Heart Study)
  1. The "Metabolic Syndrome"--Identified by the NCEP as a "secondary target of therapy" for dyslipidemics. A constellation of phenomena which increase CHD risk independent of LDL levels and may include any of the following (defined as 3 or more):
    1. Abdominal obesity (waist circumference > 102cm in men, 88cm in women)
    2. Hypertriglyceridemia (> 150 mg/dL)
    3. Low HDL (< 40mg/dL for men, < 50mg/dL for women)
    4. Hypertension (> 130/85)
    5. Impaired fasting glucose (> 100 mg/dL)
  1. Primary dyslipidemia syndromes
  1. Type I: excess chylomicrons; elevated TG
  2. Type IIA: excess LDL
  3. Type IIB: excess LDL and VLDL
  4. Type III: excess IDL; elevated total Chol and TG
  5. Type IV: excess VLDL; elevated TG
  6. Type V: excess chylomicrons and VLDL; elevated tot chol and TG
  1. Hereditary dyslipidemias
  1. Familial hypercholesterolemia
  1. Autosomal dominant disorder (frequency about 1:500) characterized by abnormally low # or absence of LDL receptors, which normally remove LDL from circulation
  2. Homozygous form is quite rare (about 1:1,000,000) & is ass'd w/LDL levels 500-1,000, CHD developing in first 2 decades of life, and cutaneous xanthomas appearing within the first few months or years of life
  3. Heterozygous form ass'd w/LDL levels about twice normal, CHD appearing in 4th or 5th decades in men, about 10y later in women, and tendon xanthomas, esp. in achilles tendons & extensor tendons of hands
  4. Both homozygotes and heterozygotes will us. require both dietary and drug therapy; homozygotes will often be resistant to drugs and are sometimes tx'd with plasmapheresis or liver transplantation.
  1. Familial defective apolipoprotein B-100
  1. Autosomal dominant genetic abnormality caused by a single nucleotide substitution in gene for apolipoprotein B, causing reduced affinity of LDL particles for the LDL receptor
  2. Ass'd w/premature atherosclerosis and tendon xanthomas
  1. Familial combined hyperlipidemia
  1. Unknown genetic abnormality resulting in high tot. chol., high TG, or both, in familial clusters
  2. No unique clinical features; many have high levels of apo B-100
  3. Increased risk for CHD
  1. Familial dysbetalipoproteinemia
  1. Caused by an homozygosity for an abnormal form of apolipoprotein E (apo E-2), which mediates binding of remnants of VLDL and chylomicrons, though other factors are probably responsible for the syndrome since penetrance is about 1 in 50
  2. Characterized by elevated chylomicrons and VLDL remnants, with elevated tot. chol. and TG (us. 300-600 and 400-800, respectively)
  3. Get palmar xanthomas of creases of palms and fingers
  4. Get premature atherosclerotic disease, us. not until adulthood

II. Secondary causes of dyslipidemias

  1. Dietary: saturated fats, "trans" fatty acids (see NEJM 340:1933, 1999--JW), cholesterol, excess calories, alcohol
  1. Nurses's Health Study in 1997 looked at 80,000 women 34-59yo with no known CHD, CVA, Ca, hyperlipidemia, or DM at intake. Diet analyzed by questionnaire; f/u x 14y. 939 cases of MI or death from CHD documented.
  1. Each increase of 5% of energy intake from sat'd fat ass'd with 17% increase in risk of CHD (p = 0.10)
  2. RR 1.93 for CHD for 2% increase in energy intake from trans unsaturated fat (p < 0.001)
  3. RR 0.81 for CHD for 5% increase from monounsaturated fat (p = 0.05)
  4. RR 0.62 for CHD for 5% increase in polyunsaturated fat (p = 0.003)
  5. RR 1.02 for CHD for 5% increase in energy from fat
  6. Est'd that replacing 5% of energy from saturated fat w/energy from unsaturated fats would reduce risk for CHD by 42% (p < 0.001) and replacement of 2% of energy from trans fat w/energy from unhydrogenated, unsaturated fats would reduce risk by 53% (p < 0.001)
  1. Drugs
  1. Steroid hormones (inc. glucococorticoids, progesterone, and anabolic steroids)
  2. Diuretics (thiazides and loop diuretics can increase LDL and TG by 5-10mg/dl, often transiently)
  3. Beta-blockers (those without ISA or alpha-blocking properties tend to rreduce HDL and increase TG; labetalol and those w/ISA don't change lipid levels significantly)
  4. Cyclosporine and amiodarone, can raise LDL and/or lower HDL
  5. Olanzapine (though not risperdone--Arch. Gen. Psychiat. 59:1021, 2002--AFP)
  1. Hypothyroidism
  2. Diabetes Mellitus (us. low HDL, high TG)
  3. Hepatobiliary obstruction
  4. Nephrotic syndrome and chronic renal failure (us. high LDL, sometimes also high TG)
  5. Systemic diseases
  1. Porphyrias
  2. Systemic Lupus Erythematosuss
  3. Lymphoma

III. Diagnosis/Monitoring of Dyslipidemias

  1. Screening recommendations
  1. NCEP recommends screening fasting lipoprotein analysis (tot. chol., LDL, HDL, TG) Q5y starting age 20
  2. USPSTF recommends checking tot. chol. & HDL "periodically" starting age 35 in men and age 45 in women; start @ age 20 if risk factors present (DM, family h/o early-onset CHD or familial dyslipidemias, HTN, tobacco use)(2001)
  3. AAP recommends screening in kids with the following risk factors; Also says optional for kids who are at risk b/c of other factors, e.g. smoking, high-fat diet, DM, HTN, overweight (Pediatrics 1/98):
    1. Parents or grandparents with dx of CHD, angina, MI, PVD, cerebrovascular disease, or sudden cardiac death at age 55 or younger--fasting lipid profile
    2. Parent with total chol > 239--check total chol. and fasting lipid profile if > 200
  1. Lipoprotein analysis details
  1. Measurements should be taken post 12-14h fast
  2. LDL is typically calculated (LDL = Total - HDL - TG/5); can't calculate accurately if TG > 400 mg/dl
  3. Don't check in pts w/recent trauma, surgery, acute infection, change in usual diet, or pregnancy, because these may alter levels significantly
  4. Lipid levels may drop starting about 24h after acute MI so if checking in that setting, the earlier the better
  1. Followup lipid testing
  1. NCEP recommends followup lipoprotein analysis at 6wk intervals after initiating lifestyle or drug therapy until regimen is stable then "monitoring for response" Q4-6mos but doesn't specify recommended interval for repeat lipoprotein analysis in those situations.
  2. NCEP II (1993) recommended 1y intervals if LDL 130-159 and < 2 risk factors