Are You Confident of the Diagnosis?
The diagnosis of hyperlipoproteinemia is confirmed by laboratory measurement of lipoproteins in the blood. Although a family history of a lipid disorder, multiple non-lipid risk factors and certain physical examination findings are helpful, the disorder may only truly be characterized by assessing the composition of plasma lipoproteins in the laboratory.
The major reason there is clinical concern regarding hyperlipoproteinemia is because of the strong association with atherosclerosis and, more specifically, coronary artery atherosclerosis, which is directly responsible for coronary heart disease (CHD), the leading cause of death in adult patients in the United States. Thus, making the diagnosis of a specific lipid disorder early is essential to modifying the natural history of atherosclerosis. In addition to atherosclerosis, there is also clinical concern regarding the development of pancreatitis in patients with the specific lipid disorder of hypertriglyceridemia.
What you should be alert for in the history
The diagnosis of hyperlipoproteinemia should be suspected when a patient has a family history of premature atherosclerosis as defined by coronary heart disease in a first-degree male relative less than 55 years of age or a first degree female relative less than 65 years of age.
Physical examination should includes careful inspection of the skin, tendons, and eyes looking for xanthoma, xanthelasma, corneal arcus, and lipemia retinalis, which directly suggest a lipid disorder. In addition, evaluation of the blood pressure and peripheral pulses may provide evidence for existing atherosclerosis, raising the probability of finding a lipid disorder upon laboratory testing.
Patients with hyperlipoproteinemia have been studied extensively and divided into types I – V (Table I).
|Type||Electrophoretic Profile||Laboratory Findings|
|I||Chylomicron band at origin||Fasting chylomicronemia|
|II||Increased beta band||Elevated LDL-C|
|IIa||Increased beta band||Elevated LDL-C; normal triglycerides|
|IIb||Increased beta, prebeta bands||Elevated LDL-C; elevated triglycerides|
|III||Floating beta band||Abnormal VLDL|
|IV||Increased prebeta band||Elevated VLDL-C|
|V||Increased prebeta, chylomicron bands||Elevated VLDL-C; fasting chylomicronemia|
Characteristic findings on physical examination
The various hyperlipoprotein disorders produce different physical examination findings that have been well described.
Tendinous xanthomas are pathognomonic of familial hypercholesterolemia (FH), which is one of the type II hyperlipoproteinemias. FH patients, characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C), above 400mg/dL in heterozygotes and 600 mg/dL in homozygotes, are prone to recurrent migratory polyarthritis typically involving large joints such as knees, elbows, and ankles.
This joint inflammation often extends to the tendons and following repeated episodes results in nodules known as tendinous xanthomas. These xanthomas are detected by running your fingers along extensor tendons of the knee, elbow, or ankle joint and feel like a “string of beads.”
Tuberous xanthomas are firm, nodular excrescences that typically occur in clusters on the skin located along the extensor surfaces of the elbows and knees. These raised lesions may be sensitive to touch when first formed but become painless in their chronic phase. Tuberous xanthomas are associated with types II, III, and IV hyperlipoproteinemia.
The differential diagnosis of xanthomas includes: Types IIa, IIb, III, and IV hyperlipoproteinemia; low HDL-C; uncontrolled diabetes mellitus with hypertriglyceridemia; cerebrotendinous xanthomatosis; systemic amyloidosis; sarcoidosis; Wegener granulomatosis; atypical lymphoid infiltrates; necrobiotic xanthogranuloma; juvenile xanthogranuloma; lipoid proteinosis; necrobiosis lipoidica; Erdheim-Chester disease, and sitosterolemia.
Sitosterolemia is a particularly rare but interesting autosomal recessive disorder of childhood involving abnormal intestinal absorption of plant sterols leading to xanthomas in the setting of relatively normal serum cholesterol levels. This condition should be suspected in any patient with xanthomas but a normal to only moderately elevated lipid profile as plant sterols are not measured as part of plasma cholesterol. A separate measure of the plant sterols (sitosterol, campesterol, etc) would confirm the marked abnormality. The condition leads to premature atherosclerosis and death if untreated by dietary modification and blocking dietary plant sterol uptake.
Xanthelasma palpebrum (commonly called “xanthelasma”) is a yellowish generally raised lesion located on the upper eyelid near the inner canthus (Figure). These lesions are almost always bilateral; 50% of xanthelasma are associated with types II or III hyperlipoproteinemia. Not all xanthelasma represent systemic disease, and up to 50% may simply be due to a a localized process.
The differential diagnosis of xanthelasma includes: Types IIa, IIb, III, and IV hyperlipoproteinemia; low HDL-C; uncontrolled diabetes mellitus with hypertriglyceridemia; primary biliary cirrhosis; necrobiotic xanthogranuloma; orbital lipogranulomata; Erdheim-Chester disease; Wegener granulomatosis; lipoid proteinosis; systemic amyloidosis; necrobiosis lipoidica; sarcoidosis.
Corneal arcus decribes a gray or white deposit of lipid in the form of a ring located just inside the outer margin of the cornea. Corneal arcus may be a normal finding in neonates and in people over age 60 (arcus senilis) and does not suggest a lipid disorder. The term arcus juvenilis is specific to children over age 1 and adults less than age 50 in whom corneal arcus is much more likely associated with a disorder of lipid metabolism. When observed in this age group, formal lipid evaluation is warranted.
Lipemia retinalis is observed as a discoloration of the usually crimson red blood vessels observed in the periphery of the retina on fundoscopic examination. As serum triglycerides rise above 2000mg/dL, the vessels turn pink and as triglycerides rise further, eventually these vessels appear milky white. These fundoscopic observations continually fluctuate with triglyceride levels and may serve as a guide to success of therapy.
The differential diagnosis for lipemia retinalis includes types I, III, V hyperlipoproteinemia; hepatic necrosis; Zieve’s syndrome (metabolic syndrome following acute withdrawal from alcohol abuse manifested by hemolytic anemia, hyperlipoproteinemia, jaundice and abdominal pain).
Once a lipid disorder is expected by history or physical examination, a fasting lipid profile should be obtained. This requires a 12-hour fast and yields information about total cholesterol, triglycerides, and HDL cholesterol (HDL-C). The Friedewald equation permits an estimation of the LDL cholesterol (LDL-C) level by subtracting the HDL-C level and 1/5 of the triglyceride level from the total cholesterol value. This estimation is reasonable as long as the triglyceride concentration is less than 400mg/dL.
An alternative measure when the triglycerides are elevated is to measure the LDL-C directly via a process called beta quantitation, which is more expensive than a fasting lipid profile. Another less expensive means of evaluating the atherogenic potential of a standard lipid profile when triglycerides are above 200mg/dL is to calculate non–HDL-C, which is an approximation of all the atherogenic (apoB containing) lipoproteins. Non-HDL-C is simply the total cholesterol minus the HDL-C.
The National Cholesterol Education Program has well-established guidelines for desirable levels of total cholesterol, triglyceride, HDL-C, LDL-C and non-HDL-C. Clinicians should refer to these easily accessible guidelines for details (http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf).
Who is at Risk for Developing this Disease?
An estimated 102 million adults in the United States have total cholesterol levels above 200mg/dL and are considered at borderline high risk for cardiovascular events. An additional 36 million adults have total cholesterol levels above 240mg/dL, placing them at high risk for cardiovascular events.
Additional risk factors for cardiovascular events includes diabetes mellitus (considered by some as a risk equivalent), cigarette smoking, hypertension (BP >140/90mmHg or on antihypertensive medication), low HDL cholesterol (< 40mg/dL), family history of premature atherosclerosis (first-degree male relative < age 55 or first-degree female relative < age 65), and age (men >45 years or women >55 years).
Cardiovascular disease was responsible for 831,372 deaths in the United States in 2006.
What is the Cause of the Disease?
Hyperlipoproteinemias cause elevations in the plasma levels of cholesterol and triglycerides. Dietary fat in the form of triglyceride undergoes hydrolysis by pancreatic lipase in the presence of bile salts in the intestinal lumen to form monoglyceride and unesterified fatty acids. Dietary cholesterol is also present in this milieu and together with the bile salts forms a lipid solution known as a micelle, which is actively absorbed by the brush border of intestinal cells (enterocytes) in the small bowel. Once inside the enterocyte, the lipid must be “packaged” within a spherical protein structure to become soluble in water.
Part of the protein structure contains a 48-amino-acid apoprotein known as B-48. This apo B-48 protein/lipid complex is known as a chylomicron. Chylomicrons are extruded by the basolateral surface of the cell and enter the lymphatic circulation. Then, via the thoracic duct, these chylomicrons enter the bloodstream where they may be quantified.
The triglyceride of chylomicrons is rapidly hydrolyzed by lipoprotein lipase (LPL), which resides on the surface of capillary endothelium. This produces smaller particles with a higher cholesterol content known as chylomicron remnants. These remnants are rapidly removed by the liver.
Endogenously produced triglyceride is packaged in the liver into proteins containing a 100-amino-acid apoprotein known as apoB-100. This triglyceride rich lipoprotein is known as very low density lipoprotein (VLDL). VLDL in the presence of LPL in the capillary beds undergoes hydrolysis and becomes a smaller, cholesterol rich, apo B containing intermediate density lipoprotein (IDL). IDL is efficiently removed from the circulation by the liver. Approximately 70% of VLDL undergoes further hydrolysis to an even smaller, cholesterol rich, apoB-containing particle known as low density lipoprotein (LDL).
LDL is the major lipoprotein carrying cholesterol to the peripheral blood vessels such as the coronary arteries; 50% of the body’s pool of LDL is cleared daily by a receptor-mediated uptake in the liver. This LDL receptor recognizes apo B-100 but not apo B-48. The activity of the LDL receptors is regulated by genetic factors, hormonal factors, as well as cellular requirements for cholesterol; 15% of LDL may be removed from circulation by a different receptor that recognizes only modified LDL such as oxidized LDL. This receptor is known as scavenger receptor B-1 (SRB-1).
HDL is produced by both the liver and intestines as a disc shaped complex of phospholipid, unesterified cholesterol and apoprotein A-1 (apo A-1). This essentially underfilled particle is able to extract cholesterol from peripheral tissues in the presence of a protein present on the peripheral cell known as ATP binding casette protein A-1 (ABCA-1). It is believed that ABCA-1 is expressed by cholesterol loading of cells. This off-loading of cholesterol from the peripheral cell to an immature HDL particle results in enlargement of the HDL and formation of mature HDL.
The HDL may directly return cholesterol to the liver via SRB-1, resulting in reverse cholesterol transport (RCT). However, HDL may also transfer cholesterol to an apo B-containing lipoprotein catabolite of VLDL via cholesterol ester transfer protein (CETP). This apo B-containing cholesterol rich lipoprotein may now unload its cholesterol content to the liver via the previously described LDL receptor pathway.
The processes described above results in a very tightly controlled regulation of lipid levels in the body. However, genetic factors and dietary factors can cause dramatic alterations in normal lipid homeostasis, resulting in pathology. The most notable genetic cause is the complete absence of the LDL receptor as is seen in homozygous FH, which results in LDL-C levels of 600mg/dL with associated tendon xanthomas and premature death from CHD.
Systemic Implications and Complications
The importance of recognizing hyperlipoproteinemia is to reduce the cardiovascular complications by instituting dietary and sytemic pharmacotherapy early in the course of the disorder. In some individuals, the diagnosis is first suspected by skin findings leading to a presumptive diagnosis, which may be easily confirmed by a fasting lipid profile laboratory test. This may ultimately result in a life-saving intervention by reducing CHD events. In addition, early identification of the specific disorder of hypertriglyceridemia may prevent resultant pancreatitis with rapid intervention.
Table II. Treatment options for hyperlipoproteinemia
|Lifestyle modification||Pharmacologic therapy||Surgical therapy|
|–Low fat, low cholesterol American Heart Association Step II diet
–Low carbohydrate diet
–Aerobic and strength training exercise for 30 to 90 minutes most days of the week
–Bile-acid binding resins
–Plant sterols/ stanols
| –Locally destructive modalities for medically unresponsive xanthomas
–Topical trichloroacetic acid, electrodessication, laser therapy, excision for medically unresponsive xanthelasma
–Bariatric surgery for weight loss and lipid reduction
Optimal Therapeutic Approach for this Disease
Hyperlipoproteinemia (hyperlipidemia) is associated with hereditary as well as environmental factors. Accordingly, the approach to therapy must address both lifestyle issues (nurture) and biochemical maladaptation (nature). Before the development of medications to reduce lipid levels, the only available therapy was improved diet and exercise. There is much data to support the benefit of dietary therapy and increased physical activity on reducing morbidity and mortality.
Thus, the initial management strategy in essentially all patients with a lipid disorder is to invoke a therapeutic lifestyle modification. The National Cholesterol Education Program Adult Treatment Panel III guidelines recommend the American Heart Association Step II Diet. This diet consists of adjusting nutrient intake as follows:
–Restrict total calories to maintain a desirable weight.
–Consume less than 200mg/day of cholesterol.
–Total fat consumption should be 25% to 30% of total calories.
–Saturated fat should be less than 7% of total calories.
–Polyunsaturated fat should be 10% or less of total calories.
–Monounsaturated fat should be 20% or less of total calories.
–Carbohydrate should be predominantly of the complex variety and provide 50% to 60% of total calories
–Fiber should be 20 to 30g/day
–Protein should account for approximately 15% of total calories
In addition to dietary modification, a therapeutic lifestyle change must include regular exercise. The Surgeon General and the American Heart Association have promoted physical activity guidelines for maintenance of health.
–Surgeon General recommends Americans accumulate at least 30 minutes (adults) or 60 minutes (children) of moderate physical activity most days of the week.
–American Heart Association advocates moderate-to-vigorous-intensity aerobic activity for at least 30 minutes on most days of the week at 50% to 85% of maximum heart rate.
Once the therapeutic lifestyle interventions have been instituted, the fasting lipid panel should be re-evaluated in approximately 3 months. At that point, if the lipid values are not within desirable limits based upon the published National Cholesterol Education Program (NCEP) guidelines, then pharmacologic therapy is advised. (Please note that in high risk patient groups [as defined by NCEP] it is acceptable to institute therapeutic lifestyle change and pharmacologic therapy simultaneously.)
Pharmacologic therapy consists of alteration of essentially three mechanisms of action.
1) Drugs that enhance LDL-C clearance via the LDL receptor include bile-acid sequestrants, HMG-CoA reductase inhibitors, plant stanols, and ezetimibe. The bile-acid sequestrants, plant sterols/stanols, and ezetimibe interfere with lipid absorption in the intestine leading to decreased intracellular cholesterol, which triggers enhanced activity of the LDL receptor, removing LDL-C from the circulation. HMG-CoA reductase inhibitors directly reduce cholesterol production in the cell, which similarly triggers upregulation of the LDL receptor leading to LDL-C removal from the circulation.
2) Drugs that reduce lipoprotein synthesis or secretion such as nicotinic acid and fish oils.
3) Drugs that affect lipoprotein metabolism such as the congeners of fenofibric acid (“fibrates”).
HMG-CoA reductase inhibitors, known as statins, are the most potent of the lipid-lowering medications and have been the most proven to reduce mortality in clinical trials. Accordingly, this class of drugs should be the first used to reduce elevated total cholesterol and triglycerides and to raise HDL in patients not meeting NCEP guidelines despite a therapeutic lifestyle intervention. Statins reduce LDL-C 20% to 60% depending upon their dose. They reduce triglycerides 15% to 30% and raise HDL-C 5% to 10%.
Table III. HMG-Co-A Reductase Inhibitors (Statins)
|Generic name (Trade name)||How supplied||Usual starting dose||Dose range|
|Atorvastatin (Lipitor)||Tablet: 10, 20, 40, 80mg||10mg daily||10 to 80mg daily|
|Capsule: 20, 40mg
Tablet: extended release 80mg
|20 to 40mg in evening
80mg in evening
|20 to 40mg in evening
80mg in evening
|Lovastatin (Mevacor)||Tablet: 10. 20, 40mg||20mg in evening||10 to 40mg in evening;
maximum dose 40mg BID
|Pitavastatin (Livalo)||Tablet: 1, 2, 4 mg||2mg daily||1 to 4mg daily|
|Pravastatin (Pravachol)||Tablet: 10, 20, 40, 80mg||40mg in evening||10 to 80mg in evening|
|Rosuvastatin (Crestor)||Tablet: 5, 10, 20, 40mg||5 to 20mg daily||5 to 40mg daily|
|Simvastatin (Zocor)||Tablet: 5, 10, 20, 40, 80*mg||10 to 20mg in evening||5 to 40mg daily (*80mg dose not advised)|
Nicotinic acid (niacin) at relatively high doses of 3 to 4g/day has the potential to reduce LDL-C by 20% to 25%, reduce triglyceride levels by 20% to 50%, and raise HDL-C levels by 25% to 50%.
Bile-acid binding resins have been in use since the 1960s and were the mainstay of lipid-lowering therapy until the arrival of the statins. They reduce LDL-C levels by 10% to 20% and raise HDL-C levels by 2% to 5%. Unfortunately they may raise triglyceride levels by 10% to 15%.
Table IV. Bile Acid Binding Resins
|Generic name (Trade name)||How supplied||Usual starting dose||Dose range|
|Cholestyramine (Questran, Questran Light)||Powder for oral suspension: single-dose (4g) packets or cans with dosing scoop (1 scoop= 1dose)||4g daily||4-12g twice a day|
|Colestipol (Colestid)||Granules: single-dose (5g) packets or bottles with dosing scoop (1scoop=1dose)
|5g daily||5-15g twice a day|
|Colesevalam (WelChol)||Tablet 625mg||6 tablets daily||6 to 7 tablets daily|
Fibric acid derivatives (“fibrates”) are primarily triglyceride lowering drugs. They lower triglycerides by 30% to 70%, raise HDL-C by 5% to 10%, and may lower or raise LDL-C up to 10%.
Table V. Fibrates
|Generic name (Trade name)||How supplied||Usual starting dose||Dose range|
|Tablet: 48, 145mg
Capsule: 43, 130mg
43 to 130mg daily
43 to 130mg daily
|Fenofibric acid (Trilipix)||Capsule: 45, 135mg||45 to 135mg daily||45 to 135mg daily|
|Gemfibrozil (Lopid)||Tablet: 600mg||600mg twice a day||600mg twice a day|
Fish oils (omega-3 polyunsaturated fatty acids) are relatively potent agents to lower triglycerides (particularly when the triglycerides are above 500mg/dL). At a dose of 6g/day, the efficacy of triglyceride lowering approaches 50%. HDL-C may rise slightly as triglycerides fall. LDL-C may rise or fall similar to what is seen with fibrates.
Fish oil can be obtained from eating fish or by taking supplements. Fish that are especially rich in the beneficial oils known as omega-3 fatty acids include mackerel, tuna, salmon, sturgeon, mullet, bluefish, anchovy, sardines, herring, trout, and menhaden. They provide about 1g of omega-3 fatty acids in about 3.5 ounces of fish. Typical fish oil supplements contain approximately 1g of fish oils per capsule.
Ezetimibe (Zetia 10mg/day) inhibits the absorption of lipid micelles in the small intestine. LDL-C levels may fall by 15% to 20%, HDL-C may rise by 1%, and triglycerides are generally unaffected.
Plant sterols/stanols work in the intestine by competing for absorption with cholesterol. A dosage of 2 to 3g/day may reduce LDL-C by 5% to 15% with minimal effects on HDL-C or triglycedrides. Plant sterols/stanols are available as over-the-counter supplements as well as in commercial products. Perhaps best known are the buttery spreads sold as Benecol and Smart Balance.
Surgical therapy of skin/tendon lesions related to hyperlipoproteinemia is reserved for cosmesis and does not change the natural history of the disorder.
Bariatric surgery via gastric bypass or modification is an aggressive technique for weight loss. Interestingly, studies do confirm that this type of surgery reduces lipid levels within 6 months and overall lipid levels continue to improve for as long as 6 years.
Patient’s with a confirmed diagnosis of hyperlipoproteinemia (hyperlipidemia) must be counselled that the elevation in lipids is a major risk factor for cardiovasular disease, which is the leading cause of death in adults in the United States. The natural history of hyperlipidemia is that it remains throughout life unless major and lasting lifestyle changes are made and/or medication is taken daily.
Thus, this is a chronic disease requiring lifelong therapy. Transient use of diet or medication results in temporary improvement in lipid numbers, but the values go right back to baseline within days to a few weeks of stopping therapy. There are some reports of a rebound effect of increased cardiovascular events in patients stopping therapy abruptly.
Lipid-lowering therapy requires close laboratory monitoring and regular patient follow-up. Since essentially all lipid-lowering medications have effects in the liver, hepatic enzymes should be measured prior to starting therapy and followed periodically thereafter. In general, liver function panels are checked 6 to 12 weeks after starting a drug or increasing the dose of a drug.
This is particularly true of the statins. Medications should be stopped if the liver enzymes rise 2 to 3 times above the upper limit of normal. In addition, statins may inflame skeletal muscles causing myositis and possible rhabdomyolysis, which may be life-threatening. Thus, it is imperative to instruct patients to seek immediate medical attention for unusual muscle aches. If the serum creatine phosphokinase (CPK) level rises above 10 times the upper limit of normal, the medication must also be stopped.
It is not unusual for patients to experience side effects of the various lipid-lowering medications. As above, care needs to be taken to evaluate possible myositis. In the absence of frank myositis, patients may experience non–life-threatening muscle aches and pains, which make them unwilling to continue therapy. This is a particularly common clinical finding with statins.
In general, switching to an alternate member of the statin class is a realistic approach as each statin is biochemically different and the tolerability may be different. Since statins have the most abundant clinical trial evidence of benefit, it is best to try to keep the patient on a statin if possible.
One of the most common clinical scenarios in the United States is the patient with central obesity and the resultant metabolic syndrome. These patients will have modestly elevated total and LDL cholesterol with high triglycerides and low HDL cholesterol. Treatment should start with therapeutic lifestyle change as described in the previous section. Then, if LDL-C remains above the NCEP goal, the patient should be started on a statin at a dose consistent with achieving the goal (statin package inserts will tell you the percentage of LDL-C lowering anticipated with each dosage strength).
Once the LDL-C goal is attained, then turn attention to optimizing HDL-C and triglycerides with add-on therapy (usually nicotinic acid, fibrate, or fish oil). Remember to re-check labs for safety after each additional medication or dosage increase. Continue this process until all NCEP goals are achieved. Monitor laboratory tests for efficacy and safety periodically thereafter (approximately every 6 months).
Unusual Clinical Scenarios to Consider in Patient Management
There are several lipid disorders that are particularly difficult to treat. True homozygous familial hypercholesterolemia (FH) results from the congenital absence of LDL receptors. As a consequence, these patients cannot clear LDL-C from the systemic circulation and will have LDL-C levels in the 400 to 600 mg/dL range. They generally do have marked tendon and eruptive xanthomas and premature atherosclerosis. Management requires the specialized therapy of LDL apheresis. These patients should be immediately referred to a specialized lipid clinic.
Another challenge is the patient with marked hypertriglyceridemia. Triglyceride levels exceeding 500 mg/dL place the patient at immediate risk of pancreatitis. Statins, bile-acid binding resins, ezetimibe, and plant sterols/stanols will not be helpful. These patients require aggressive dietary restriction of carbohydrates including alcohol and management of glucose abnormalities. Fibrates are particularly useful in this situation to reduce the triglycerides by greater than 50% and prevent pancreatitis. Fish oil may also be helpful.
Once the triglycerides are brought under 400 mg/dL there is less concern for pancreatitis and time may be taken to fine tune the adjustment of total, LDL, and HDL cholesterol with add-on therapy. Recall that LDL-C may not be estimated using the Friedewald equation when the triglycerides are above 400 mg/dL. Thus, non–HDL-C or a direct beta quantification of LDL-C via ultacentrifugation may be used to guide therapy.
Finally, it is important to recognize that hyperlipoproteinemia may be secondary to diet, drugs, disorders of metabolism and diseases. It is difficult to correct a secondary dyslipidemia unless the primary problem is addressed. Thus, the first step in analysis is always a detailed history including evaluation of diet, medications (prescription or over-the-counter), family history, and personal history of thyroid disease, diabetes, or kidney disease.
Medications such as diuretics, beta blockers and amiodarone may have subtle effects on lipid levels. Steroids, retinoids (as in isotretinoin used for acne, acitretin for psoriasis, bexarotene for cutaneous T cell lymphoma), and anti-retroviral therapy may have profound effects on lipids, primarily elevating triglycerides. As with all medications, benefits must be weighed against risks. Monitoring of lipids is required.
Primary endocrine disorders such as hypothyroidism and diabetes mellitus will directly contribute to secondary hyperlipoproteinemia and can be treated with correction of the endocrine abnormality. Chronic kidney disease also may have profound effects on lipoproteins and is associated with advanced atheroclerosis and death from cardiovascular disease. Accordingly, the National Kidney Foundation advocates particularly aggressive lipid management in these patients.
What is the Evidence?
Genest, J, Libby, P, Libby, P, Bonow , RO, Mann, DL, Zipes, DP, Braunwald, E. “Braunwald’s heart hisease”. A textbook of cardiovascular medicine. 2008. pp. 1071-92. (An outstanding review of lipoprotein metabolism, lipoprotein disorders, drugs that affect lipid metabolism, clinical trials of lipoprotein modification, and an overview of the global approach to treatment of lipoprotein disorders.)
Libby, P, Fauci, AS, Braunwald, E, Kasper, DL, Hauser, SL, Longo, DL, Jameson, JL. “The pathogenesis, prevention, and treatment of atherosclerosis (Chapter 235)”. Harrison’s principles of internal medicine. (A detailed review of the pathogenesis of atherosclerosis with an emphasis on the role of lipid retention in the endothelium. Excellent illustrations clarify the pathobiology.)
Newbold, PCH. “The skin in genetically-controlled metabolic disorders”. J Med Gen. vol. 10. 1973. pp. 101-11. (An historical reference to the skin manifestations of the hyperlipoproteinemias. Very interesting to see the sophisticated understanding of these conditions in the 1960s and early 1970s.)
Stone, NJ, Blum, CB. “Management of lipids in clinical practice”. 2005. pp. 1-415. (An easily read manual to guide office-based clinical lipid disorder diagnosis and treatment.)
Circulation. vol. 106. 2002. pp. 3143-3421. (This document includes the most recent full report of the National Heart, Lung, and Blood Institute Expert Panel on Lipid Management. An update (ATP IV) is planned for late 2011/early2012.)
Grundy, SM, Cleeman, JL, Merz, CN, Brewer, HB, Clark, LT, Hunninghake, DB. “Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines”. Circulation. vol. 110. 2004. pp. 227-39. (This update of the ATP III guidelines reviews a number of more recent major clinical trials of lipid-lowering therapy and concludes that there is an optional more agressive lipid lowering goal of LDL-C less than 70mg/dL in high-risk patients.)
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