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Hypertriglyceridemia: a Strategic Approach Zahra Raza, MD; Ashwini Kamath Mulki, MD; Linda Contillo Garufi, MD, MEd; Hypertriglyceridemia: Grant M. Greenberg, MD, MHSA, MA Department of Family A strategic approach Medicine, Lehigh Valley Health Network, Allentown, PA This review, and the at-a-glance tables that follow, detail Ashwini.KamathMulki@ indications and strategies for the treatment of adults with lvhn.org hypertriglyceridemia. The authors reported no potential conflict of interest relevant to this article. CASE 1 u PRACTICE Tyler M, age 40, otherwise healthy, and with a body mass index RECOMMENDATIONS (BMI) of 30, presents to your office for his annual physical ex- ❯ Evaluate patients for amination. He does not have a history of alcohol or tobacco use. hypertriglyceridemia when Mr. M’s obesity raises concern about metabolic syndrome, they have a comorbid condition (eg, type 2 diabetes, which warrants evaluation for hypertriglyceridemia (HTG). You obesity, hypothyroidism, offer him lipid testing to estimate his risk of atherosclerotic car- metabolic syndrome, diovascular disease (ASCVD). alcoholism). B The only abnormal value on the lipid panel is a triglyceride ❯ Do not require fasting status (TG) level of 264 mg/dL (normal, < 175 mg/dL). Mr. M’s 10-yr when evaluating triglycerides ASCVD risk is determined to be < 5%. in a lipid panel. B What, if any, intervention would be triggered by the find- ing of moderate HTG? ❯ Make therapeutic lifestyle changes first-line treatment u for hypertriglyceridemia. C CASE 2 Alicia F, age 30, with a BMI of 28 and ASCVD risk < 7.5%, comes ❯ Prescribe fibrates for severe to the clinic for evaluation of anxiety and insomnia. She reports hypertriglyceridemia to eating a high-carbohydrate diet and drinking 3 to 5 alcoholic reduce the risk and recurrence beverages nightly to help her sleep. of pancreatitis. A Ms. F’s daily alcohol use prompts evaluation for HTG. Re- ❯ Prescribe a statin and an sults show a TG level of 1300 mg/dL and a high-density lipopro- omega-3 fatty acid (fish oil) tein (HDL) level of 25 mg/dL (healthy HDL levels: adult females, to lower the triglyceride level ≥ 50 mg/dL; adult males, ≥ 40 mg/dL). Other test results are nor- and thus reduce resulting atherogenicity when the risk of mal, except for elevated transaminase levels (just under twice atherosclerotic cardiovascular normal). disease is > 7.5%. B What, if any, action would be prompted by the patient’s severe HTG and below-normal HDL level? Strength of recommendation (SOR) A Good-quality patient-oriented evidence B Inconsistent or limited-quality How HTG is defined: patient-oriented evidence Causes, cutoffs, signs C Consensus, usual practice, opinion, disease-oriented HTG is most commonly caused by obesity and a sedentary life- evidence, case series style; certain associated comorbid medical conditions can also be a precipitant (TABLE 11,2). Because the condition is a result of polygenic phenotypic expression, even a genetically low-risk 180 THE JOURNAL OF FAMILY PRACTICE | MAY 2020 | VOL 69, NO 4 Even a genetically low- risk patient can present with hypertriglyceridemia when exposed to certain medical conditions and environmental causes. patient can present with HTG when exposed lipid profile is ordered to evaluate the risk of to certain medical conditions and environ- ASCVD. (Of note, for people older than 20 mental causes. years, the US Preventive Services Task Force Primary HTG (genetic or familial) is rare. no longer addresses the question, “Which Genetic testing may be considered for patients population should be screened for dyslipid- with TG > 1000 mg/dL (severely elevated emia?” Instead, current recommendations TG = 500 to 1999 mg/dL, measured in fast- answer the question, “For which population ing state*) or a family history of early ASCVD should statin therapy be prescribed?”5) (TABLE 11,2).2,3 ❚ Effect on ASCVD risk assessment. TG Typically, HTG is asymptomatic. Xan- levels are known to vary, depending on fast- thelasmas, xanthomas, and lipemia retinalis ing or nonfasting status, with lower levels re- are found in hereditary disorders of elevated ported when fasting. An elevated TG level can TGs. Occasionally, HTG manifests as chylo- lead to inaccurate calculation of LDL when micronemia syndrome, characterized by re- using the Friedewald formula6: current abdominal pain, nausea, vomiting, and, in severe HTG, pancreatitis.3 LDL = total cholesterol – (triglycerides/5) – HDL Fine points of TG measurement The purpose of testing lipids in a fasting state Triglycerides are a component of a complete (> 9 hours) is to minimize the effects of an IMAGE: ©ALICIA BUELOW lipid profile, which also includes total cho- elevated TG level on the calculated LDL. In lesterol, calculated low-density lipoprotein severe HTG, beta-quantitation by ultracen- (LDL-C), and HDL.4 As in both case vignettes, trifugation and electrophoresis can be per- detection of HTG is often incidental, when a formed to determine the LDL level directly. ❚ Advantage of nonfasting measure- *In comparison, a normal level of triglycerides is < 175 ment. When LDL-C is not a concern, there is, mg/dL; a moderately elevated level, measured in a fasting or nonfasting state, 175-499 mg/dL; and a very in fact, value in measuring TGs in the nonfast- severely elevated level, ≥ 2000 mg/dL.2 ing state. Why? Because a nonfasting TG level MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 4 | MAY 2020 | THE JOURNAL OF FAMILY PRACTICE 181 TABLE 1 Causes of hypertriglyceridemia1,2 Primary Secondary • Familial chylomicronemia (and related • Chronic kidney disease and nephrotic disorders) syndrome • Familial combined hyperlipidemia • Chronic liver disease • Familial dysbetalipoproteinemia • Drug-inducedb • Familial hypertriglyceridemiaa • Excessive alcohol consumption • Familial hypoalphalipoproteinemia • Hypothyroidism • Primary genetic susceptibility • Metabolic syndromec • Obesity • Poorly controlled type 2 diabetes mellitus • Other disorders - Glycogen storage disease - Multiple myeloma - Systemic lupus erythematosus aCommon (5% to 10% of cases); likely polygenic; often not expressed until adulthood because of environmental Studies have factors, obesity, or stress. found a higher bIncluding antipsychotics, beta-blockers, corticosteroids, estrogens, immunosuppressants, protease inhibitors, ASCVD risk in tamoxifen, and thiazides. cAbdominal obesity, increased level of triglycerides, decreased level of high-density lipoprotein, hypertension, and the setting of elevated fasting level of glucose (ie, insulin resistance). an elevated postprandial triglyceride level is a better indicator of a patient’s average TG reduce both the risk and recurrence of pan- accompanied by status: Studies have found a higher ASCVD creatitis12,13; given that the postprandial TG a low HDL level. risk in the setting of an elevated postprandial level can change rapidly from severe to very TG level accompanied by a low HDL level.7 severe (> 2000 mg/dL), multiple guidelines The Copenhagen City Heart Study identi- recommend pharmacotherapy to a TG goal fied postprandial HTG as an independent risk of < 500-1000 mg/dL.1,9,13,14 factor for atherogenicity, even in the setting of ❚ An ASCVD risk–HTG connection? a normal fasting TG level.8 American Associa- In the population already at higher risk of tion of Clinical Endocrinologists and American ASCVD (> 7.5%), HTG is recognized as a College of Endocrinology guidelines endorse risk-enhancing factor because of its athero- testing the nonfasting TG level when the fast- genic potential (TABLE 22); however, there is ing TG level is elevated in a lipid profile; if insufficient evidence that TGs have a role the nonfasting TG level is > 500 mg/dL, evalu- as an independent risk factor for ASCVD. In ation for secondary causes is warranted9,10 a population-based study of 58,000 people, (TABLE 11,2). 40 to 65 years of age, conducted at Copen- In a practical sense, therefore, offering hagen [Denmark] University Hospital, inves- patients nonfasting lipid testing allows more tigators found that those who did not meet people to obtain access to timely care. criteria for statin treatment and who had a ❚ Pancreatitis. Acute pancreatitis com- TG level > 264 mg/dL had a 10-year risk of a monly prompts an evaluation for HTG. The major adverse cardiovascular event similar risk of acute pancreatitis in the general popu- to that of people who did meet criteria for lation is 0.04%, but that risk increases to 8% statin therapy.15 to 31% for a person with HTG.11 Incidence The FIELD (Fenofibrate Intervention and when the TG level is > 500 mg/dL is thought Event Lowering in Diabetes) and AIM-HIGH to be increased because chylomicrons, acting (Atherothrombosis Intervention in Metabolic as a TG carrier in the bloodstream, are re- Syndrome with Low HDL/High Triglycerides sponsible for pancreatitis.3 Treating HTG can and Impact on Global Health Outcomes) 182 THE JOURNAL OF FAMILY PRACTICE | MAY 2020 | VOL 69, NO 4 HYPERTRIGLYCERIDEMIA TABLE 2 Risk factors and risk-enhancing factors for atherosclerotic cardiovascular disease2 Risk factors Risk-enhancing factors • Age • Parental history of cardiovascular disease - Men > 45 y • Family history of stroke - Women > 55 y • Metabolic syndrome, with or without diabetes • Male gender • Chronic kidney disease • Race (eg, African American) • Inflammatory disorder • Diabetes • Hypertriglyceridemia • Hypertension • Ankle–brachial index < 0.9 • Prior cardiovascular event • Elevated level of C-reactive protein (on high-sensitivity • Smoking testing) • Elevated level of low-density lipoprotein •
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