Hypertriglyceridemia

BASICS

DESCRIPTION

- 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)

- 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

- 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

- 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

- 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.

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/dLHigh: 200 to 499 mg/dLVery high: ≥500 mg/dLDivide 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 girls111 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 (в‰¤1% of general population each).

ETIOLOGY AND PATHOPHYSIOLOGY

PrimaryFamilialAcquired (sporadic)
SecondaryObesity and overweightPhysical inactivityCigarette smokingExcess alcohol intakeVery high carbohydrate diets (>60% of total caloric intake)Certain medicationsInterferon-О±Atypical antipsychoticsβ-Blockers other than carvedilolBile acid sequestrantsCorticosteroidsOral estrogensProtease inhibitorsRaloxifeneRetinoic acidTamoxifenThiazidesMedical conditionsType 2 diabetes mellitusHypothyroidismChronic renal failure, nephrotic syndromeAutoimmune 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"пїЅ)
Medical conditions (see "Etiology and Pathophysiology"пїЅ)

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
DyslipidemiasDecreased high-density lipoprotein (HDL) cholesterolIncreased low-density lipoprotein (LDL), non-HDL, and total cholesterolSmall, dense LDL particles
Metabolic syndrome (three of the following):Abdominal obesity (waist circumference >40 inches in men, >35 inches in women)TG ≥150 mg/dLLow HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women)BP ≥130/85 mm HgFasting 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 пїЅ

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 womenBegin screening earlier in those at higher risk for coronary heart disease.For interpretation, see "Description."пїЅ
Secondary causesGlycosylated hemoglobin, fasting or postprandial glucose for type 2 diabetes mellitusCreatinine, urinary protein measurement for nephrotic syndrome, renal failureThyroid-stimulating hormone for hypothyroidismHuman 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"пїЅ).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."пїЅ

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/dayPravastatin (Pravachol): 10 to 80 mg/dayRosuvastatin (Crestor): 5 to 40 mg/daySimvastatin (Zocor): 5 to 40 mg nightlyAdverse 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 dailyGemfibrozil (Lopid): 600 mg BIDAdverse 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 acidsLovaza: 4 g daily or 2 g BIDEpanova: 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 nightlyAdverse reactions: flushing, pruritus, peptic ulcer disease, hepatotoxicity, fulminant hepatic necrosis (with ER forms), hyperuricemia and gout, hyperglycemia, and toxic amblyopiaPretreatment 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 пїЅ

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

2 months after initiation or modification of therapy (repeat fasting lipid profile) пїЅ

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 пїЅ

PROGNOSIS

Good with correction of TG levels
Patients with primary hypertriglyceridemia usually require lifelong treatment.

COMPLICATIONS

Atherosclerosis
Chylomicronemia syndrome
Pancreatitis

REFERENCES

11 Miller пїЅM, Stone пїЅNJ, Ballantyne пїЅC, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333.22 Stone пїЅNJ, Robinson пїЅJG, Lichtenstein пїЅAH, 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 пїЅJ, Kim пїЅJY, Park пїЅS, 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 пїЅJJ, Maki пїЅKC, Susekov пїЅA, 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 пїЅKC, Orloff пїЅDG, Nicholls пїЅSJ, 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 пїЅS, Filion пїЅKB, Joseph пїЅL, 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 пїЅL, Brunzell пїЅJD, Goldberg пїЅAC, 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.

CODES

ICD10

E78.1 Pure hyperglyceridemia пїЅ

ICD9

272.1 Pure hyperglyceridemia пїЅ

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.