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Hypertriglyceridemia Workup

  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 26, 2016
 

Approach Considerations

Rule out secondary causes of hypertriglyceridemia, including diabetes mellitus (fasting or random glucose levels), hypothyroidism (thyroid-stimulating hormone [TSH] levels), chronic renal failure (urinalysis, creatinine, and microalbumin), alcohol abuse, hormone replacement therapy, and/or oral contraceptives.[37, 38]

Measure plasma lipid and lipoprotein levels while the patient is on a regular diet after an overnight fast. The Endocrine Society also recommends using fasting triglyceride levels over nonfasting triglyceride levels for the diagnosis of hypertriglyceridemia.[38]

Abnormal lipoprotein patterns can often be identified after determining serum cholesterol and triglyceride levels and visual inspection of the plasma sample (stored at 4°C). In some cases, performing electrophoresis and ultracentrifugation of whole plasma specimens may be necessary to help establish a diagnosis.

If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol). A biopsy of cutaneous lesions suspected to be either planar or tuberous xanthomas will reveal cholesterol deposition.

Although some studies have shown that tests such as C-reactive protein (CRP) and total homocysteine levels have some predictive value in screening for vascular disease, and thus are emerging as nontraditional risk factors for coronary heart disease, further investigation is need to determine their value.[37] Nonfasting triglyceride levels may reflect the level of atherogenic remnant lipoproteins and may even be stronger predictors of cardiovascular events than traditional fasting lipids.[39]

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Lipid Analysis

Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.

Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia. Further laboratory workup may not be necessary.

Very low-density lipoproteins (VLDLs) are increased and chylomicrons are absent when triglyceride levels are elevated but below 1000 mg/dL. If triglyceride levels are above 1000 mg/dL, both VLDL and chylomicrons are usually present.

A standard lipid profile using the Friedewald equation to calculate the LDL cholesterol is not useful if the triglyceride level is more than 400-500 mg/dL. The excess cholesterol present in beta-VLDL is included in the LDL cholesterol value. If the triglycerides are elevated but less than 1000 mg/dL and the total cholesterol is elevated, the lipoprotein abnormality may be caused by either: (1) elevations of both low-density lipoprotein (LDL) and VLDL, which is type IIb or mixed hyperlipoproteinemia, or (2) increased remnant VLDL or intermediate-density lipoprotein (IDL), which is type III hyperlipidemia or dysbetahyperlipoproteinemia (total cholesterol levels, about 300-600 mg/dL; triglyceride levels, about 400-800 mg/dL). The 2 disorders may be distinguished by obtaining a direct LDL cholesterol analysis (enzymatic analysis), which is available at most commercial laboratories. If the direct LDL cholesterol is significantly lower than the calculated LDL cholesterol, a diagnosis of type IIIhyperlipoproteinemia is likely. Furthermore, if the cholesterol-to-triglyceride ratio in isolated VLDL is greater than 0.3, dysbetalipoproteinemia is likely (normal ratio, 0.2).

The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL cholesterol and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification (lipoprotein electrophoresis). This expensive analysis involves ultracentrifugation followed by electrophoresis. However, it is not performed by most commercial or hospital laboratories. Studies that can isolate and measure VLDL and IDL include density-gradient ultracentrifugation and nuclear magnetic resonance spectroscopy. These tests are reliable in helping diagnose dysbetalipoproteinemia, but they may be available only at lipid specialty laboratories.

Specialized lipid centers should be contacted if type IIb or III must be confirmed. In most clinical settings, however, distinguishing between these entities is rarely necessary, because the treatment of both conditions is essentially the same. Diet modification, exercise, and appropriate weight loss improve both. Type IIb and III also respond to the same medications—niacin and/or fibric acid derivatives.[40] Therefore, no matter which diagnosis applies to a given patient, the treatment is the same.

The Endocrine Society does not recommend routinely measuring lipoprotein particle heterogeneity in patients with hypertriglyceridemia, suggesting that although apolipoprotein B (apo B) or lipoprotein(a) [Lp(a)] levels may be useful, results of other apolipoproteins are generally not clinically useful.[38] However, apo E genotyping or phenotyping can be used to determine if the patient is homozygous for apo E-2, but this finding is not sufficient for the diagnosis of dysbetalipoproteinemia without clinical or lipid abnormalities consistent with the disorder.

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Chylomicron Determination

If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of an upright tube of plasma or serum. If a creamy supernatant is seen the next day, chylomicrons are present. If the infranatant is cloudy, high levels of very low-density lipoprotein (VLDL) are present (type V hyperlipidemia). If the infranatant is clear, the VLDL content is normal and type I hypercholesterolemia (elevated chylomicrons only) should be suspected.

Type I hyperlipoproteinemia (pure hyperchylomicronemia)

To make a definitive diagnosis of type I hyperlipidemia, a deficiency of either lipoprotein lipase or apo C-II must be confirmed. The presence of lipoprotein lipase activity may be measured in plasma following intravenous heparin administration (50 IU of heparin per kg body weight) or by analysis of muscle or adipose tissue biopsy samples.

Defective or absent apo C-II must be determined at a lipid center that performs 1 of the 3 following assays: (1) gel electrophoresis, (2) radioimmunoassay, or (3) confirmation that lipoprotein lipase added to the patient's plasma is not active.

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Contributor Information and Disclosures
Author

Mary Ellen T Sweeney, MD Associate Professor of Medicine (Endocrinology, Diabetes, and Metabolism), Department of Medicine, Emory University School of Medicine; Physician, Division of Endocrinology, Veterans Administration Medical Center; Physician, Lipid Metabolism Clinic, Emory Healthcare, The Emory Clinic

Mary Ellen T Sweeney, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, National Lipid Association

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Acknowledgements

Steve Charles, MD Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Adjunct Professor of Ophthalmology, Columbia College of Physicians and Surgeons; Clinical Professor Ophthalmology, Chinese University of Hong Kong

Steve Charles, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, Club Jules Gonin, Macula Society, and Retina Society

Disclosure: Alcon Laboratories Consulting fee Consulting; OptiMedica Ownership interest Other; Topcon Medical Lasers Consulting fee Consulting

Karen E Friday, MD, FACP Clinical Core Director of Tulane Xavier National Center of Excellence, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Tulane University School of Medicine

Karen E Friday, MD, FACP is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Heart Association, American Society for Clinical Nutrition, and Endocrine Society

Disclosure: AstraZeneca own AstraZeneca stock None; Merck own Merck stock None; Schering Plough own Schering Plough stock None; Medco Health own Medco Health stock None

Robert A Gabbay, MD, PhD Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Laurence M Demers Career Development Professor, Penn State College of Medicine; Director, Diabetes Program, Penn State Milton S Hershey Medical Center; Executive Director, Penn State Institute for Diabetes and Obesity

Robert A Gabbay, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society

Disclosure: Novo Nordisk Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R. Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America

Disclosure: Nothing to disclose.

Romesh Khardori, MD, PhD Professor and Director, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
Close-up of eruptive xanthomas.
Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.
Lipoprotein lipase (LPL) releases free fatty acids (FFAs) from chylomicrons (chylo) and produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chol = cholesterol; TGs, TGS = triglycerides.
Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing low-density lipoprotein (LDL), or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E. Chol = cholesterol; TGs = triglycerides.
Table 1. Fredrickson Classification of Hyperlipidemia
Type Serum Elevation Lipoprotein Elevation
I Cholesterol and triglycerides Chylomicrons
IIa Cholesterol LDL
IIb Cholesterol and triglycerides LDL, VLDL
III Cholesterol and triglycerides IDL
IV Triglycerides VLDL
V Cholesterol and triglycerides VLDL, chylomicrons
IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein.



Source:  Fredrickson DS, Lees RS. A system for phenotyping hyperlipidaemia. Circulation. Mar 1965;31:321-7.[2]



Table 2. Classification of Triglycerides
Classification TG level, mg/dL
Normal triglyceride level < 150
Borderline-high triglyceride level 150-199
High triglyceride level 200-499
Very high triglyceride level >500
Source:  National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97.[13]
Table 3. Classification of LDL Cholesterol and Non-HDL Cholesterol
Classification LDL Goal,



mg/dL



Non-HDL Goal,



mg/dL



CHD and CHD risk equivalent, diabetes mellitus, and the following: 10-year risk for CHD >20% < 100 < 130
Two or more risk factors and the following: 10-year risk < 20% < 130 < 160
0-1 risk factor < 160 < 190
CHD = coronary heart disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.



Source:  National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97.[13]



Table 4. Fibric Acid Agents, Omega Acid Ethyl Esters, and Niacin Drug Characteristics [73]
Drug Lipid Effects Lipid Effects in Combination with Statin Outcomes Data Comments
Bezafibrate LDL decrease: 9.6-25% (400 mg)



HDL increase: 15-24% (400 mg)



Triglyceride decrease: 25-43% (400 mg)



Further LDL decrease: 1.1% (400 mg)



Further HDL increase: 22% (400 mg)



Further triglyceride decrease: 31.7% (400 mg)



Secondary prevention: Prevents composite endpoint of MI and sudden death in a subgroup with triglycerides of 200 mg/dL or higher. No increase in non-CV death First-line option for triglyceride >10 mmol/L



Option for triglyceride 5-10 mmol/L



Option for low HDL



Reversible increase in serum creatinine



Requires renal dose adjustment



Limited data with statins



Ezetimibe LDL decrease: 18% (10 mg/day)



HDL increase: 1% (10 mg/day)



Triglyceride decrease: 8%



Further LDL decrease: 25%, as add-on



Further HDL increase: 3%, as add-on



Further triglyceride decrease: 14%, as add-on



Prevention of CV events in post-acute coronary syndrome patient when added to statin showed a benefit of reducing the primary endpoint (composite of CV death, MI, unstable angina requiring rehospitalization, coronary revascularization or stroke) by 6.4% vs statin alone



In intermediate outcomes studies, ezetimibe did not reduce regression of carotid intima-media thickness (surrogate marker) when added to a statin



Efficacy studied in combination with atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin



Role as statin add-on to reduce LDL if HDL and triglyceride satisfactory



Fenofibrate LDL decrease: 20.6% (145 mg)



HDL increase: 11% (145 mg)



Triglyceride decrease: 23.5-50.6% (greatest drop in patients with highest triglycerides) (145 mg)



Further LDL decrease: 0-6% (200 mg)



Further HDL increase: 13-17% (200 mg)



Further triglyceride decrease: 20-32% (200 mg)



Prevention of CV events in type 2 diabetes: Did not reduce primary composite outcome (nonfatal MI or CV death). Improved outcomes included nonfatal MI (24% decrease), coronary revascularization (21% decrease), progression to albuminuria, and reduced laser treatments for retinopathy. Nonsignificant increase in risk of CV death.



As statin add-on, did not lower risk of non-fatal MI, nonfatal stroke, or CV death more than statin alone in patients with type 2 diabetes at high risk for CV disease



First-line option for triglyceride >10 mmol/L (about 1000 mg/dL)



Option for triglyceride >500 mg/dL or 5-10 mmol/L



Option for low HDL



Preferred over gemfibrozil for use with statins



Requires renal dose adjustment



Associated with reversible increase in serum creatinine



Gemfibrozil LDL: No effect



HDL increase: 6% (1200 mg/day)



Triglyceride decrease: 33-50% (greatest drop in patients with highest triglycerides) (1200 mg/day)



Further triglyceride decrease: 41%



Further HDL increase: 9%



Primary prevention of coronary heart disease



Secondary prevention of cardiac events in men with low HDL



First-line option for triglyceride >10 mmol/L (about 1000 mg/dL)



Option for triglyceride >500 mg/dL or 5-10 mmol/L



Option for low HDL



Requires renal dose adjustment



Avoid with statin



Icosapent ethyl LDL decrease: 5%



HDL decrease: 4%



Triglyceride decrease: 27%



Further triglyceride decrease: 21.5% (4 g/day), 10.1% (2 g/day)



Further LDL decrease: 6.2% (4 g/day)



A study, REDUCE IT, is underway to look at reduction in CV events with icosapent ethyl Option for triglyceride >500 mg/dL



Safe for use with statins



Use caution with fish or shellfish allergy



Niacin LDL decrease: 14-17% (Niaspan 2 g/day); 12% (niacin immediate-release 1.5 g/day and Niaspan 1.5 g/day)



HDL increase: 22-26% (2 g/day Niaspan); 17% (niacin immediate release 1.5 g/day); 20-22% (Niaspan 1.5 g/day)



Triglyceride decrease: 20-50%



Further LDL decrease: 1-5% (Niaspan 1 g/day); 10% (Niaspan 2 g/day)



Further HDL increase: 24% (Niaspan 2 g/day); 15-17% (Niaspan 1 g/day)



Further triglyceride decrease: 24% (Niaspan 2 g/day); 12-22% (Niaspan 1 g/day)



Secondary MI prevention; in combination with a resin, slows progression or promotes regression of atherosclerosis; reduces mortality



As statin add-on, reduces carotid intima-media thickness (surrogate marker) compared with ezetimibe as statin add-on in patients with lower HDL



No CV event benefit from niacin plus statin versus statin alone in patients with well-controlled LDL, low HDL, and high triglycerides



Option for triglyceride >500 mg/dL (about 5 mmol/L)



Raises HDL more than any other agent



Dose-dependent risk of hyperglycemia (especially in patients with type 2 diabetes) and liver toxicity



May increase risk of statin myopathy



Omega-3 ethyl esters LDL increase: 44.5% (4 g/day)



HDL increase: 9.1% (4 g/day)



Triglyceride decrease: 45% (4 g/day)



LDL increase: 0.7% (4 g/day)



Further HDL increase: 3.4% (4 g/day)



Further triglyceride decrease: 29.5% (4 g/day)



Secondary prevention: Reduces cardiovascular death; sudden death; and combined endpoint of death, nonfatal MI, and nonfatal stroke



Secondary prevention in patients with, or at risk for, type 2 diabetes: did not reduce CV events



Option for triglyceride >500 mg/dL (about 5 mmol/L)



Safe for use with statins



Associated with an increase in risk for recurrence of symptomatic atrial fibrillation or flutter within first 3 months of therapy



Use with caution with fish or shellfish allergy



Table 5. Statin Drug Characteristics [74]
Drug Potency (average LDL decrease) Renal Considerations Liver Function Monitoring
Atorvastatin 10 mg: 35-39%



20 mg: 43%



40 mg: 50%



80 mg: 55-60%



No dose adjustment necessary for reduced renal function Check liver function tests at baseline and when clinically indicated
Fluvastatin 20 mg: 22%



40 mg: 25%



80 mg: 35%



(as XL product)



In severe renal impairment, use daily doses >40 mg with caution Check liver function tests at baseline and when clinically indicated
Lovastatin 10 mg: 21%



20 mg: 24-27%



40 mg: 30-31%



80 mg: 40-42%



(as 40 mg BID)



If CrCl < 30 mL/min, use daily doses over 20 mg with caution Check liver function tests at baseline and when clinically indicated
Pitavastatin 1 mg: 31-32%



2 mg: 36-39%



4 mg: 41-45%



For glomerular filtration rate 15-59 mL/min/1.73 m2, including hemodialysis, initial daily dose is 1 mg, not to exceed 2 mg/day Check liver function tests at baseline and when clinically indicated
Pravastatin 10 mg: 22%



20 mg: 32%



40 mg: 34%



80 mg: 37%



In significant renal impairment, start with 10 mg/day Check liver function tests at baseline and when clinically indicated
Rosuvastatin 5 mg: 45%



10 mg: 46-52%



20 mg: 47-55%



40 mg: 55-63%



If CrCl < 30 mL/min/1.73 m2 (but not on hemodialysis), starting dose is 5 mg/day, not exceed 10 mg/day



Rosuvastatin levels in hemodialysis patients are about 50% higher than levels in normal renal function



Check liver function tests at baseline and when clinically indicated
Simvastatin 5 mg: 26%



10 mg: 30%



20 mg: 38%



40 mg: 29-41%



80 mg: 36-47%



In severe renal impairment, starting dose is 5 mg daily with close monitoring Check liver function tests at baseline and when clinically indicated
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