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Hypertriglyceridemia Clinical Presentation

  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Apr 13, 2015
 

History

The US Preventive Services Task Force (USPSTF) includes the following as risk factors for a 10-year risk of cardiovascular events in patients with dyslipidemias, including hypertriglyceridemia and hyperlipoproteinemia[31] :

  • Diabetes
  • History of coronary heart disease (CHD) or noncoronary atherosclerosis (eg, abdominal aortic aneurysm, peripheral artery disease, carotid artery stenosis)
  • Family history of cardiovascular disease before age 50 years in male relatives or age 60 years in female relatives
  • Tobacco use
  • Hypertension
  • Obesity (body mass index [BMI] >30 kg/m 2)

In addition to the risk factors above, the American Association of Clinical Endocrinologists (AACE) includes the following as major risk factors for dyslipidemia and atherosclerosis[32] :

  • Elevated serum total cholesterol levels
  • Elevated levels of non–high-density lipoprotein (non–HDL) levels
  • Elevated low-density lipoprotein (LDL) levels

Gastrointestinal symptoms

Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL. Patients may report pain, which is commonly mid epigastric but may occur in other regions, including the chest or back.

A history of recurrent episodes of acute pancreatitis is common in patients with severe and uncontrolled hypertriglyceridemia.[33] Triglyceride levels often exceed 5000 mg/dL at the onset of pancreatitis.

Patients with recurrent episodes of abdominal pain that is less severe than acute pancreatitis may experience the chylomicronemia syndrome.[34] Affected patients usually have triglyceride elevations greater than 2000 mg/dL at the onset of symptoms and provide a history of recurrent episodes of abdominal pain, sometimes with nausea, vomiting, or dyspnea. Pancreatitis is not necessarily present. The presentation of hyperchylomicronemia may be confused with conditions such as acute myocardial syndromes or biliary colic.

Dermatologic symptoms

Severe hypertriglyceridemia may cause skin lesions called xanthomas. Patients may report the appearance of any of the following types of xanthomas:

  • Xanthoma striata palmaris: Orange-yellow discolorations of the palmar creases, which in some cases are raised; considered pathognomonic for dysbetalipoproteinemia
  • Tuberoeruptive xanthomas: Nonpainful, raised, erythematous, nodular lesions approximately 0.5 cm in diameter; may be present on the elbows and knees
  • Tuberous xanthomas: Larger, coalesced tuberoeruptive xanthomas; raised, moderately firm, nontender lesions predominantly on the elbows and knees
  • Tendon xanthomas: Occur infrequently; more common in familial hypercholesterolemia
  • Eruptive xanthomas: Small nodular papules commonly seen over the trunk, buttocks, and thighs; associated with chylomicronemia syndrome

Ophthalmologic symptoms

Uncommonly, patients may also note the presence of a corneal arcus, which is a grayish white opacification at the periphery of the cornea and/or xanthelasmas, which are pale yellow, raised lesions around the eyelids.

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Physical Examination

When triglycerides are less than 1000 mg/dL, the physical findings are normal unless the underlying condition is dysbetalipoproteinemia, type III hyperlipoproteinemia. In this condition, palmar xanthomas may be discerned infrequently.

When triglycerides are acutely and massively elevated, physical findings may be absent except on funduscopic examination. Therefore, physical findings in patients with severe hypertriglyceridemia are variable, ranging from normal to one or more of the findings discussed below.

In patients with peripheral vascular disease, the pedal pulses or ankle/brachial index may be decreased.

Gastrointestinal

If pancreatitis or the chylomicronemia syndrome is present, the mid epigastric area or upper right or left quadrants are tender to palpitation. Hepatomegaly and, less commonly, splenomegaly may be appreciated.

Dermatologic

Eruptive xanthomas (see the images below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base that are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.

Eruptive xanthomas on the back of a patient admitt 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. Close-up of eruptive xanthomas.

Patients with dysbetalipoproteinemia (type III) may have palmar xanthomas (yellowish creases of the palms). This type of xanthoma is considered pathognomonic for this disorder. Tuberous or tuberoeruptive xanthomas, which also may occur in other hyperlipidemias, may arise on the elbows, knees, or buttocks.

Ophthalmologic

Corneal arcus, lipemia retinalis, and xanthelasma are the most common ocular abnormalities.[2] Triglyceride levels of 4000 mg/dL or higher may cause lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.

The ocular changes are usually not seen until the triglyceride level reaches at least 2000 mg/dL in the early stages; they are best observed in the peripheral fundus. The vessels initially appear salmon-pink, but when the triglyceride level rises further, they become whitish. These changes, which begin in the periphery, progress toward the posterior pole as the triglyceride level rises. In severe cases, the vessels are creamy white, and differentiating the arteries from the veins is difficult. The findings can fluctuate widely from day to day, depending on the triglyceride level.

Xanthelasma is a deposition of lipid in the eyelid, usually the upper medial lid. The lesions may be excised, but recurrences are common. Current treatments include serial excisions, the use of carbon dioxide and erbium lasers, and trichloroacetic acid peels. With primary excisions, recurrences of up to 40% have been reported, and secondary excision recurrences are even higher.[35] Of the initial failures, 20% are within the first year.[36]

The fundus abnormalities, which improve as the triglyceride levels return to normal, provide a method of following the patient's course and response to therapy.

Neurologic

Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.

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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.[3]



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.[14]
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.[14]



Table 4. Fibric Acid Agents, Omega Acid Ethyl Esters, and Niacin Drug Characteristics [72]
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 [73]
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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