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-α
- Atypical antipsychotics
- β-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
DIAGNOSIS
HISTORY
- Usually asymptomatic
- Patients with chylomicronemia syndrome can have memory loss, headache, vertigo, dyspnea, and paresthesias.
- Pancreatitis: epigastric pain, nausea, and vomiting
- Assess for other cardiac risk factors.
- Family history of coronary artery disease
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
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 �
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.
COMPLICATIONS
- Atherosclerosis
- Chylomicronemia syndrome
- Pancreatitis
REFERENCES
11 Miller �M, Stone �NJ, Ballantyne �C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333.22 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-S45.33 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):235-240.44 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):94-106.55 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-e3.66 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
- 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
- Hypercholesterolemia; Pancreatitis, Acute
- Algorithm: Hypertriglyceridemia
CODES
ICD10
E78.1 Pure hyperglyceridemia �
ICD9
272.1 Pure hyperglyceridemia �
SNOMED
- 302870006 Hypertriglyceridemia (disorder)
- 238083002 Primary hypertriglyceridemia (disorder)
- 238087001 secondary hypertriglyceridemia (disorder)
- 267433009 Pure hyperglyceridemia (disorder)
- 34528009 Familial hypertriglyceridemia (disorder)
CLINICAL PEARLS
- 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.