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Home , Hyperlipidemia, Hypertriglyceridemia

J Am Board Fam Med: first published as 10.3122/jabfm.19.3.310 on 3 May 2006. Downloaded from

EVIDENCED-BASED CLINICAL MEDICINE

Rade N. Pejic, MD, and Daniel T. Lee, MD

Hypertriglyceridemia is a commonly encountered abnormality frequently associated with other lipid and metabolic derangements. The National Education Program recommends obtaining a fasting lipid panel in adults over the age of 20. The discovery of hypertriglyceridemia should prompt an investigation for secondary causes such as high , excessive alcohol intake, certain medica- tions, and medical conditions (eg, mellitus, ). In addition, patients should be evaluated for other components of the . These include abdominal , , low high-density (HDL), high , and . Hypertriglyceride- mia is classified as primary hypertriglyceridemia when there are no secondary causes identified. Pri- mary hypertriglyceridemia is the result of various genetic defects leading to disordered triglyceride me- tabolism. It is important to treat hypertriglyceridemia to prevent by reducing triglyceride levels to <500 mg/dL. Furthermore, lowering triglycerides while treating other and com- ponents of the metabolic syndrome will reduce coronary events. However, it is controversial how much isolated hypertriglyceridemia correlates directly with and further studies are needed to clarify whether treatment for this condition leads to meaningful clinical outcomes. Therapeu- tic lifestyle changes (TLC) are the first line of treatment for hypertriglyceridemia. These changes include a low , carbohydrate-controlled diet, combined with alcohol reduction, smoking cessation, and regular aerobic exercise. High doses of omega-3 fatty acids from fish and fish oil supplements will lower triglyceride levels significantly. When patients do not reach their goals by TLC, drug therapy should be started. In cases of isolated hypertriglyceridemia, fibrates are initially considered. When ele- vated low-density lipoprotein levels accompany hypertriglyceridemia, 3-hydroxy-3-methylglutaryl coen- zyme A reductase inhibitors are preferred. In patients with low HDL levels and hypertriglyceridemia, extended release can be considered. A combination of the medicines may be necessary in recalci- trant cases. (J Am Board Fam Med 2006;19:310–6.) http://www.jabfm.org/

Hypertriglyceridemia is defined as an abnormal ide . Secondary causes are acquired concentration of triglyceride in the . Accord- causes, such as, high fat diet, obesity, diabetes, ing to the National Cholesterol Education Pro- hypothyroidism, and certain medications.

gram Adult Treatment Panel (NCEP ATP III) Hypertriglyceridemia is a risk factor for pancre- on 27 September 2021 by guest. Protected copyright. guidelines, a normal triglyceride level is Ͻ150 atitis and it accounts for 1 to 4% of cases of acute mg/dL (Table 1).1 In the United States, the prev- pancreatitis. Although a few patients can develop alence of hypertriglyceridemia defined as a triglyc- pancreatitis with triglyceride levels Ͼ500 mg/dL, eride level Ͼ150 mg/dL is ϳ30%.2,3 Hypertriglyc- the risk for pancreatitis does not become clinically eridemia may be primary or secondary in nature. significant until levels are Ͼ1000 mg/dL.1,4,5 More Primary hypertriglyceridemia is the result of vari- importantly however, hypertriglyceridemia is typi- ous genetic defects leading to disordered triglycer- cally not an isolated abnormality. It is frequently associated with other lipid abnormalities and the metabolic syndrome (, insulin re- Submitted 17 August 2005; revised 24 October 2005; ac- cepted 31 October 2005. sistance, low high-density lipoprotein (HDL), high From Tulane University School of Medicine, New Or- triglyceride, and hypertension), which are linked to leans, LA (RNP); and David Geffen School of Medicine at 3 UCLA, Los Angeles, CA (DTL). coronary artery disease. Conflict of interest: none declared. Considering the current obesity epidemic, there Corresponding author: Rade N. Pejic, MD, 1430 Tulane Avenue, TB-3, New Orleans, LA 70112 (E-mail: will be a significant rise in the incidence of the [email protected]). metabolic syndrome. Thus, primary care physicians

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Table 1. Classification of Triglyceride Levels Fredrickson type IIa (familial hypercholesterol-

Classification Triglyceride Level (mg/dL) emia). In the United States, the 2 most common dyslipidemias are Fredrickson type IIb (familial Normal Ͻ150 combined ) and type IV (familial Borderline high 150 to 199 hypertriglyceridemia). Together, these 2 dyslipi- High 200 to 499 demias account for 85% of familial dyslipidemias. Ͼ Very high 500 In contrast to primary hypertriglyceridemia, there are many secondary causes of hypertriglycer- idemia. These include medical conditions such as will encounter hypertriglyceridemia more fre- diabetes mellitus, hypothyroidism, obesity, and ne- quently and should be familiar with the evaluation phrotic syndrome. In addition, certain medications and management of this common disorder. (Table 3), high carbohydrate diets, and alcohol can cause or exacerbate hypertriglyceridemia. Com- Pathophysiology monly, hypertriglyceridemia results from a combi- Dietary are absorbed by the small in- nation of factors. For example, a patient may be testine, secreted into the lymph system, and enter found to have familial combined , obe- the systemic circulation as via the sity, and high alcohol consumption. thoracic duct. Muscle and adipose tissue remove some of the triglyceride from the and the chylomicron remnant is taken up by the Clinical Presentation and metabolized into a cholesterol rich lipoprotein. The majority of the time, hypertriglyceridemia is Although most of the triglyceride found in blood is discovered after performing a routine lipid profile. absorbed from the small intestine, the liver pro- However, severe hypertriglyceridemia (Ͼ500 mg/ duces and secretes a small amount of triglyceride. dL) may cause pancreatitis, eruptive , or are proteins associated with lipemia retinalis. In some cases, extremely high that assist with their assembly, transport, and me- levels of chylomicrons can cause chylomiconemia tabolism. Defects in any of these structural proteins syndrome, which is characterized by recurrent ab- or the they interact with may result in a dominal pain, nausea, vomiting, and pancreatitis. clinical dyslipidemia. Triglycerides are typically Ͼ2000 mg/dL in this http://www.jabfm.org/ The Fredrickson classification scheme organizes condition. Eruptive xanthomas are 1- to 3-mm yel- these various primary dyslipidemias into a several low papules that can erupt anywhere but are usually categories (Table 2).6 High triglycerides are a com- seen on the back, chest, and proximal extremities. ponent of each of these dyslipidemias except Palmar xanthomas, yellow creases on the palm, may

Table 2. Fredrickson Dyslipidemia Classification on 27 September 2021 by guest. Protected copyright.

Type Elevated Lipoprotein Total Cholesterol Level Triglyceride Level Relative Frequency

I CM* Normal ϩϩ Ͻ1% IIa LDL ϩϩ Normal 10% (FHC) IIb LDL/VLDL ϩϩ ϩ 40% (FCH) III IDL ϩϩϽ1% IV VLDL Normal to ϩϩϩ 45% (FHT) VCM ϩϩϩ5% VLDL

* CM, chylomicron; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; IDL, intermediate density lipoprotein; FHC, familial ; FCH, familial ; FHT, familial hypertriglyceridemia. ϩ, Mild to moderate increase. ϩϩ, Moderate to severe increase. http://www.jabfm.org 311 J Am Board Fam Med: first published as 10.3122/jabfm.19.3.310 on 3 May 2006. Downloaded from

Table 3. Medications That Elevate Triglycerides cholesterol, and triglyceride levels are all elevated.

Atypical anti-psychotics In type IV, the total cholesterol and LDL levels are Beta blockers typically normal but the triglyceride level is ele- binding resins vated usually between 500 and 1000 mg/dL. Pa- (in higher dose oral contraceptives and unopposed tients with type IV disease are very sensitive to oral estrogen) dietary modifications. Glucocorticoids The finding of hypertriglyceridemia should Immunosuppressants prompt an investigation for other components of Isotretinoin the metabolic syndrome [SOR-C].3 In particular, Protease inhibitors patients should be evaluated for fasting hypergly- Tamoxifen cemia, hypertension, abdominal obesity, and low HDL levels. Thyrotropin level, serum urea nitro- gen, creatinine, and urinalysis should be obtained to assess thyroid and renal function (Table 6). Base- be seen in patients with type III hyperlipidemia. line liver function should also be assessed before Lipemia retinalis is the visualization of lipemic starting medication. If there is a clinical suspicion blood in the retinal blood vessels. of pancreatitis, amylase and lipase levels should be measured. A fasting insulin level can be measured Diagnostic Evaluation to look for direct evidence of insulin resistance. A The NCEP recommends obtaining a fasting lipid fasting insulin level above 15 ␮U/mL is abnormal. panel [total cholesterol, low-density lipoprotein However, a fasting glucose to fasting insulin ratio (LDL), HDL, and triglycerides] on patients begin- provides a more sensitive and specific assessment of ning at age 20 and repeated every 5 years [strength insulin resistance.7 A normal glucose-insulin ratio 1 of recommendation (SOR)-C] (Tables 4 and 5). In is Ͼ4.5. Ratios Ͻ4.5 suggest insulin resistance. healthy asymptomatic patients without risk factors, it is acceptable to obtain a nonfasting total choles- terol and HDL cholesterol level every 5 years. Treatment However, for patients with coronary heart disease A major reason to treat hypertriglyceridemia is to (CHD), CHD risk equivalents, familial dyslipide- prevent pancreatitis. The triglyceride level should mia, or risk factors for CHD, a fasting lipid panel be reduced to Ͻ500 mg/dL to prevent this serious http://www.jabfm.org/ should be obtained yearly. If the triglyceride level is disease [SOR-B].1,4,5 The relationship between discovered to be Ͼ150 mg/dL, it should be re- triglycerides and is less clear. checked again after a 12- to 16-hour fast for con- There have been multiple conflicting studies re- firmation. If the triglyceride level is Ͼ1000 mg/dL, garding the role of triglycerides and the develop- beta-quantification by ultra centrifugation and ment of CHD.8–12 Hypertriglyceridemia is clearly electrophoresis can be performed to determine the associated with CHD in univariate analysis. How- on 27 September 2021 by guest. Protected copyright. exact dyslipidemia. ever, many multivariate studies have shown that its The 2 most common dyslipidemias are familial risk is markedly attenuated after adjustment for combined hyperlipidemia (type IIb) and familial other strong CHD risk factors, namely, low HDL hypertriglyceridemia (type IV). In type IIb, the levels and increased small, dense LDL particles. total cholesterol, low-density lipoprotein (LDL) These findings have led some researchers to believe

Table 4. Strength of Recommendations (SORT)

Key Clinical Recommendations Strength of Recommendation References

Obtain fasting lipid panel on patients beginning at 20 years old C 1 Search for other components of metabolic syndrome in C3 patients with high triglycerides Decrease triglycerides to Ͻ500 mg/dL to prevent pancreatitis B 1,4,5 Decrease triglycerides and increase HDL to prevent B 9,10 cardiovascular events

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Table 5. ATP III Adult Lipid Recommendations

Risk Group Begin Screening Frequency Test

CHD* 20 1 to 2 years Fasting lipid panel CHD risk equivalent or 2 or more risk factors† Familial dyslipidemia or family 20 Every 2 years Fasting lipid panel history of premature CHD No risk 20 Every 5 years Fasting lipid panel or non-fasting total cholesterol/HDL

* CHD, coronary heart disease; HDL, high-density lipoprotein. † Risk factors: cigarette smoking, hypertension or taking blood pressure medication, HDL Ͻ40, first degree relative with coronary artery disease (men Ͻ55, women Ͻ65), age (men Ͼ45, women Ͼ55). that hypertriglyceridemia serves more as a proxy ment of the other lipid derangements. In cases for abnormal cholesterol levels and cholesterol sub- where hypertriglyceridemia is found to be the only fractions of which hypertriglyceridemia is fre- lipid abnormality, treatment is still important to quently associated.13 Most interventions aimed at prevent pancreatitis when triglycerides are mark- lowering the triglyceride level also raise the HDL edly elevated. level, which is well known for reducing coronary The treatment of hypertriglyceridemia begins 9,10 events [SOR-B]. A recent review of the litera- with TLC. Specifically, a low fat, carbohydrate- ture concluded that treating isolated hypertriglyc- controlled diet should be adopted. Saturated fat 14 eridemia does not prevent coronary events. How- should not make up more than 7% of total daily ever, a thorough search for other components of calories, carbohydrates should be restricted to 50% the metabolic syndrome is recommended. to 60% of daily calories, and simple sugars like On the other hand, there have been many other sucrose should be avoided.1 Patients may also con- studies that have shown hypertriglyceridemia to be sider increasing intake of oily fish (eg, salmon, an independent risk factor for CHD even after mackerel, herring) to at least 2 servings per week.18 9,15–17 adjustment for HDL and LDL. Further- Alcohol should be greatly reduced or stopped alto- more, the NCEP considers hypertriglyceridemia to gether, along with smoking cessation if indicated. http://www.jabfm.org/ be an independent risk factor for CHD and calls for Discontinuation of any offending medications medical treatment in cases where therapeutic life- should be considered as well. Titration upwards to style changes (TLC) are not adequate to reduce the a goal of at least 30 minutes of aerobic exercise 5 triglycerides to appropriate levels.1 Although the days a week is greatly beneficial. If present, diabetes extent to which hypertriglyceridemia causes CHD and hypothyroidism should be treated accordingly. is controversial at present, the authors feel that These measures often have a dramatic effect on because most cases of hypertriglyceridemia are as- on 27 September 2021 by guest. Protected copyright. triglyceride levels and can lower it hundreds of sociated with abnormal cholesterol sub-fractions points.1 and are frequently found in patients with CHD risk If TLC and control of secondary medical con- factors, treatment of hypertriglyceridemia is often ditions are not adequate to lower the triglyceride warranted in conjunction with the necessary treat- level to Ͻ200 mg/dL, then medical therapy is war- ranted (Figure 1). When triglyceride levels range Table 6. Basic Laboratory Evaluation for Confirmed between 200 mg/dL and 500 mg/dL, treatment Hypertriglyceridemia should be directed primarily toward normalizing 1 Serum urea nitrogen the LDL cholesterol. Once the LDL is at goal, a Creatinine secondary endpoint is the non-HDL cholesterol Fasting glucose (total cholesterol-HDL). Non-HDL goals are 30 Fasting insulin level (if metabolic syndrome is suspected) mg/dL higher than LDL goals. A tertiary treat- Liver function ment goal, particularly in the setting of CHD or Thyrotropin CHD risk equivalents, is to raise the HDL to Ͼ40 Urinalysis mg/dL. The benefit of medically treating triglyc- http://www.jabfm.org 313 J Am Board Fam Med: first published as 10.3122/jabfm.19.3.310 on 3 May 2006. Downloaded from http://www.jabfm.org/ on 27 September 2021 by guest. Protected copyright.

Figure 1. Treatment Algorithm. eride levels between 200 mg/dL and 500 mg/dL ides. Furthermore, fish oil supplementation may be when the other lipid sub-fractions are normal is less added to augment the fibrate treatment, and in clear and medical management in these patients some cases, the patient may elect to try fish oil should be individualized (Table 7).14 supplementation as first line. Fish oils have a dose- In cases of isolated hypertriglyceridemia, fi- dependent effect and many patients will need2gto brates, such as gemfibrozil and fenofibrate, may be 4 g a day of fish oil supplementation to achieve used because they are potent reducers of triglycer- goals. Omega-3 fatty acids (4 g per day) will reduce

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Table 7. Treatment Guidelines for recommended. The best preparation of niacin to be Hypertriglyceridemia. prescribed is extended release (ER) niacin.23 ER

● Initiate therapeutic lifestyle changes (weight loss/exercise) niacin has a lower rate of flushing and no additional first risk of hepatotoxicity as is found with the long- ● Reduce triglyceride level to less than 500 mg/dL to prevent acting preparations. Furthermore, ER niacin can be pancreatitis dosed once daily resulting in better adherence be- ● Primary aim of medical therapy is to reach LDL* goal cause it is typically absorbed over 8 to 12 hours. ER ● Secondary aim of therapy is to reach non-HDL goal niacin has been shown to lower the triglyceride ● In patients with CHD or CHD risk equivalents, tertiary aim of therapy is to reach HDL goal. level by ϳ25% and raise the HDL level by almost 30%.24 To prevent flushing, a low starting dose of * LDL, low-density lipoprotein; HDL, high-density lipopro- niacin should be taken immediately after the tein; CHD, coronary heart. evening meal and increased at monthly intervals. In addition, (325 mg) may be taken 30 to 60 triglyceride levels by 30%.19,20 However, at this minutes before any form of niacin to further reduce dosage, omega-3 will elevate the LDL by 5% to the incidence of flushing. Niacin should be used 10% and will have little effect on the HDL.20 Fish with caution in patients with diabetes (including oil capsules can be taken at any time of the day, glucose intolerance) and gout as it may increase with or without food, together or in divided doses. blood sugar and uric acid levels, respectively. Nia- However, as the capsules dissolve in the stomach cin is contraindicated in patients with active peptic and release the oil, many people experience a “fishy ulcer disease. burp.” Taking the capsule at bedtime, freezing Finally, it is important to note that patients with them, taking enteric-coated capsules, or taking severe hypertriglyceridemia (over 1000 mg/dL) of- them with food may minimize or eliminate this ten need a combination of medicines to achieve problem.21 their goal (Figure 1). In addition, they will benefit In many circumstances, the LDL is elevated in from strict adherence to TLC including a very low addition to the triglycerides. In these cases, the fat diet and complete abstinence from alcohol. If 3-hydroxy-3-methylglutaryl coenzyme A (HMG- patients do not reach their goals with the above CoA) reductase inhibitors () should be used treatment regimens, a referral to a lipid specialist to lower the LDL to the patient’s goal based on and medical dietician may be warranted. In addi- NCEP ATP III guidelines.1 Niacin or fibrates may tion, keep in mind that some physicians may be http://www.jabfm.org/ be added if the LDL and/or the triglycerides re- tempted to add bile acid binding resins to help treat main too high. However, physicians should add elevated total cholesterol and LDL. However, fibrates with great caution as combining them with these medications can worsen triglyceride levels the HMG-CoA reductase inhibitors increases the and should not typically be used in patients with risks of severe myopathy and hepatoxicity. This significantly elevated triglycerides.25,26

combination particularly should be avoided in the on 27 September 2021 by guest. Protected copyright. elderly, in patients with acute or serious chronic Follow Up illnesses (especially chronic renal disease), in those If medical treatment is started, patients may have undergoing surgery, and in patients receiving mul- their lipids tested as soon as 1 to 2 months after tiple medications.22 initiating treatment because the full effect of the For other mixed dyslipidemias involving high medicines are seen within this time interval. Fur- triglycerides and low HDL, niacin may be consid- thermore, this allows for titration of the medicines ered. There are 3 available preparations of niacin: to appropriate levels in an expedient manner.26 immediate acting, long acting, and extended re- This testing interval may continue until the thera- lease. Immediate acting niacin must be taken 3 peutic goal is reached. Once stable, the interval times daily and is associated with flushing, hyper- between testing can be extended to every 6 months. glycemia, and gastrointestinal side effects. The It is reasonable to monitor liver enzymes concur- long-acting preparation can be taken once daily and rently with every lipid draw while on lipid medica- has less flushing. However, with its absorption time tions. Patients taking niacin should also have their lasting generally greater than 12 hours, it carries a blood sugar and uric acid levels checked routinely higher risk of hepatotoxicity and therefore is not as indicated. http://www.jabfm.org 315 J Am Board Fam Med: first published as 10.3122/jabfm.19.3.310 on 3 May 2006. Downloaded from

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