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Hypertriglyceridemia
S. Lindsey Clarke, MD, FAAFP
image BASICS
DESCRIPTION
  • Hypertriglyceridemia is a common form of dyslipidemia characterized by an excess fasting plasma concentration of triglycerides (TG).
    • TG are fatty molecules made of glycerols that are esterified by fatty acids at all three hydroxyl groups.
    • They occur naturally in vegetable oils and animal fats.
    • In humans, TG are major sources of dietary energy; they are packaged into chylomicrons and very-low-density lipoproteins.
    • Hypertriglyceridemia is independently associated with cardiovascular disease risk, but the degree to which excess TG cause atherosclerosis is uncertain and debatable.
  • Hypertriglyceridemia is a biomarker of risk for premature coronary artery disease in both men and women at levels ≥200 mg/dL and for pancreatitis at levels ≥1,000 mg/dL.
  • Classifications of TG levels in adults after a 12-hour fast:
    • Normal: <150 mg/dL (1.7 mmol/L)
    • Borderline to high: 150 to 199 mg/dL
    • High: 200 to 499 mg/dL
    • Very high: ≥500 mg/dL
    • Divide by 88.5 to convert to millimoles per liter.
  • TGs are considered high in children when TG exceed the 95th percentiles for age and sex.
    • 143 mg/dL for adolescent boys, 126 mg/dL for adolescent girls
    • 111 mg/dL for preadolescent boys, 120 mg/dL for preadolescent girls
EPIDEMIOLOGY
  • Predominant gender: male > female
  • Predominant race: Hispanic, white > black
Prevalence
  • 33% of U.S. population has TG levels ≥150 mg/dL.
  • 1.7% has TG levels ≥500 mg/dL.
  • Highest prevalence at age 50 to 70 years
  • The most common genetic syndromes with hypertriglyceridemia are familial combined hyperlipidemia and familial hypertriglyceridemia (≤1% of general population each).
ETIOLOGY AND PATHOPHYSIOLOGY
  • Primary
    • Familial
    • Acquired (sporadic)
  • Secondary
    • Obesity and overweight
    • Physical inactivity
    • Cigarette smoking
    • Excess alcohol intake
    • Very high carbohydrate diets (>60% of total caloric intake)
    • Certain medications
      • Interferon-&agr;
      • Atypical antipsychotics
      • &bgr;-Blockers other than carvedilol
      • Bile acid sequestrants
      • Corticosteroids
      • Oral estrogens
      • Protease inhibitors
      • Raloxifene
      • Retinoic acid
      • Tamoxifen
      • Thiazides
    • Medical conditions
      • Type 2 diabetes mellitus
      • Hypothyroidism
      • Chronic renal failure, nephrotic syndrome
      • Autoimmune disorders (e.g., systemic lupus erythematosus)
      • Paraproteinemias (e.g., macroglobulinemia, myeloma, lymphoma, lymphocytic leukemia)
      • Pregnancy (usually physiologic and transient)
Genetics
  • Familial hypertriglyceridemia: autosomal dominant
  • Familial dysbetalipoproteinemia: autosomal recessive
  • Familial combined hyperlipidemia: unknown
RISK FACTORS
  • Genetic susceptibility
  • Obesity, overweight
  • Lack of exercise
  • Diabetes
  • Alcoholism
  • Certain medications (see “Etiology and Pathophysiology”)
  • Medical conditions (see “Etiology and Pathophysiology”)
GENERAL PREVENTION
  • Weight reduction
  • Moderation of dietary fat and carbohydrates
  • Regular aerobic exercise
COMMONLY ASSOCIATED CONDITIONS
  • Coronary artery disease
  • Diabetes mellitus type 2 and insulin resistance
  • Dyslipidemias
    • Decreased high-density lipoprotein (HDL) cholesterol
    • Increased low-density lipoprotein (LDL), non-HDL, and total cholesterol
    • Small, dense LDL particles
  • Metabolic syndrome (three of the following):
    • Abdominal obesity (waist circumference >40 inches in men, >35 inches in women)
    • TG ≥150 mg/dL
    • Low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women)
    • BP ≥130/85 mm Hg
    • Fasting glucose ≥100 mg/dL
  • Nonalcoholic steatohepatitis (NASH)
  • Pancreatitis
  • Polycystic ovary syndrome
image DIAGNOSIS
PHYSICAL EXAM
  • Obesity, overweight (body mass index ≥25 kg/m2)
  • Eruptive cutaneous, tuberous, and striate palmar xanthomas
  • Lipemia retinalis
  • Epigastric tenderness in pancreatitis
  • Hepatomegaly in NASH and chylomicronemia
DIFFERENTIAL DIAGNOSIS
Primary and secondary hypertriglyceridemia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Serum: turbid with milky supernatant
  • Fasting lipid profile (12-hour fast)
    • Routine screening every 5 years beginning at age 35 years for men and age 45 years for women
    • Begin screening earlier in those at higher risk for coronary heart disease.
    • For interpretation, see “Description.”
  • Secondary causes
    • Glycosylated hemoglobin, fasting or postprandial glucose for type 2 diabetes mellitus
    • Creatinine, urinary protein measurement for nephrotic syndrome, renal failure
    • Thyroid-stimulating hormone for hypothyroidism
    • Human chorionic gonadotropin for pregnancy
  • Atherosclerosis: cardiac stress imaging, coronary angiography, CT arteriography
  • Pancreatitis: CT scan, US of pancreas
Follow-Up Tests & Special Considerations
  • Repeat lipid panel after 2 months of therapy.
  • High levels of apolipoprotein (APO) B (≥90 mg/dL) are a strong predictor of coronary death in patients whose LDL cannot be calculated because of very high TGs. However, evidence for routine clinical use is lacking.
Test Interpretation
  • Chylomicronemia syndrome: lipid-laden macrophage (foam cell) infiltration of visceral organs, bone marrow, and skin
  • Atherosclerosis
  • Pancreatitis
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image TREATMENT
GENERAL MEASURES
  • Therapeutic lifestyle changes, first-line interventions for all patients, can reduce TG by as much as 50% (1)[C]:
    • Dietary modifications can reduce TG by 20-50% (see “Diet”).
    • Moderate-intensity physical activity can reduce TG by 20-30%.
    • Weight loss of 5-10% can reduce TG by 20%.
    • Persons with very high TG should abstain from alcohol.
  • Search for correctable secondary causes, treat underlying illness, or remove offending drug.
  • Improve glycemic control if diabetic.
  • Control other cardiac risk factors such as hypertension, diabetes mellitus, and smoking.
  • Primary hypertriglyceridemia: Screen other family members.
  • Cardiovascular risk reduction through LDL lowering should be prioritized over TG lowering unless patient is at risk for pancreatitis because of very high TG (≥500 mg/dL) (1)[C]. Usually outpatient; see “Admission Criteria/Initial Stabilization.”
MEDICATION
First Line
  • Statins: the most effective agents for reducing cardiovascular risk; primarily affect LDL but also have modest TG-lowering effect; dosing depends on intensity of statin desired based on 10-year cardiovascular risk; 2013 ACC/AHA guidelines recommend initiating therapy for 7.5% 10-year risk and other clinical factors (2)[C]:
    • Atorvastatin (Lipitor): 10 to 80 mg/day
    • Pravastatin (Pravachol): 10 to 80 mg/day
    • Rosuvastatin (Crestor): 5 to 40 mg/day
    • Simvastatin (Zocor): 5 to 40 mg nightly
    • Adverse reactions: myalgias, myopathy, rhabdomyolysis (especially if combined with fibrates); contraindicated in pregnancy and lactation
  • Fibrates: the most effective agents for reducing TG; used primarily to reduce risk of pancreatitis when TGs very high (≥500 mg/dL); have been shown to decrease nonfatal myocardial infarction but not all-cause mortality (1)[C],(3)[A]:
    • Fenofibrate (Tricor, others): 35 to 200 mg daily
    • Gemfibrozil (Lopid): 600 mg BID
    • Adverse reactions: GI upset, hepatotoxicity, cholelithiasis, myalgias, rhabdomyolysis (when combined with a statin), gemfibrozil-warfarin interaction (enhanced anticoagulation)
    • Gemfibrozil should be avoided in combination with statins due to high risk of muscle injury. If combination therapy is needed, use fenofibrate.
Second Line
  • Omega-3 fatty acids
    • Lovaza: 4 g daily or 2 g BID
    • Epanova: 2 to 4 g daily (4)[C]
    • Vascepa: 2 g BID with food (5)[C]
    • Safe, well-tolerated but limited outcomes data
  • Niacin (6)[A]. Clinical use of niacin should be very limited, as it fails to show outcome benefit in statin users:
    • 1,000 to 3,000 mg IR daily divided BID-TID; 500 to 2,000 mg ER nightly
    • Adverse reactions: flushing, pruritus, peptic ulcer disease, hepatotoxicity, fulminant hepatic necrosis (with ER forms), hyperuricemia and gout, hyperglycemia, and toxic amblyopia
    • Pretreatment with aspirin reduces flushing.
ISSUES FOR REFERRAL
  • Hypertriglyceridemia refractory to treatment
  • Familial hypertriglyceridemia syndromes
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Acute pancreatitis
  • Acute coronary syndrome
  • In medical emergencies such as acute hypertriglyceridemic pancreatitis with TG levels >1,000 mg/dL, TG can be lowered rapidly and safely by apheresis or insulin infusion.
Discharge Criteria
Stabilization of acute complicating illness
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
2 months after initiation or modification of therapy (repeat fasting lipid profile)
Patient Monitoring
  • Fasting lipid profile q6-12mo
  • Maintain TG <1,000 mg/dL to reduce risk of acute pancreatitis (possibly effective, unproven).
  • Hepatic transaminases
  • Creatine phosphokinase if patient has myalgias
DIET
  • Restrict dietary fat to 30% of total caloric intake; restrict further to 15% of caloric intake if TG ≥1,000 mg/dL (1)[C].
  • Limit carbohydrates (especially simple carbohydrates and sugars) to 60% of total caloric intake.
  • Mediterranean-style diet reduces TG 10-15% more than a low-fat diet.
  • Increase marine-derived omega-3 polyunsaturated fatty acids (4 g/day reduces TG by 25-30%, dose-response relationship).
  • Eliminate trans fatty acids.
  • Increase dietary fiber.
  • Avoid concentrated sugars such as fructose.
  • Moderate alcohol intake (<1 oz/day or complete abstinence if TGs are very high)
PATIENT EDUCATION
Smoking cessation
PROGNOSIS
  • Good with correction of TG levels
  • Patients with primary hypertriglyceridemia usually require lifelong treatment.
REFERENCES
1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25)(Suppl 2):S1-S45.
3. Wi J, Kim JY, Park S, et al. Optimal pharmacologic approach to patients with hypertriglyceridemia and low high-density lipoprotein-cholesterol: randomized comparison of fenofibrate 160 mg and niacin 1500 mg. Atherosclerosis. 2010;213(1):235-240.
4. Kastelein JJ, Maki KC, Susekov A, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014;8(1):94-106.
5. Maki KC, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther. 2013;35(9):1400-1411.e1-e3.
6. Abourbih S, Filion KB, Joseph L, et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med. 2009;122(10):962.e1-962.e8.
Additional Reading
&NA;
  • Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-2989.
  • Pharmacist's Letter. PL Detail-Document. Strategies for lowering triglycerides. Pharmacist's Letter/Prescriber's Letter. June 2011.
See Also
&NA;
  • Hypercholesterolemia; Pancreatitis, Acute
  • Algorithm: Hypertriglyceridemia
Codes
&NA;
ICD10
E78.1 Pure hyperglyceridemia
Clinical Pearls
&NA;
  • Hypertriglyceridemia is a risk factor for coronary artery disease at levels ≥200 mg/dL and for pancreatitis at levels ≥1,000 mg/dL.
  • Diet and exercise are first-line interventions for all patients who have hypertriglyceridemia.
  • In patients with TG levels <500 mg/dL, the primary treatment for cardiovascular risk management is statins.
  • For patients with TG levels ≥500 mg/dL, the greatest amount of TG lowering is achieved with fibrates, although magnitude of clinical benefit is uncertain.