Hypertriglyceridemia

DefinitionTop

Fasting serum triglyceride (TG) levels >1.7 mmol/L (150 mg/dL) are considered elevated, as they are associated with an increased risk of atherosclerotic cardiovascular disease (CVD). Levels >1.7 mmol/L up to 2.3 mmol/L are considered borderline high; those > 2.3 mmol/L to 5.6 mmol/L, as high; and those >5.6 mmol/L, as very high. Severe hypertriglyceridemia is defined as TG levels >9.9 mmol/L (885 mg/dL) or 11.3 mmol/L (1000 mg/dL).

Etiology and PathogenesisTop

TG elevation results from a combination of genetic, nutritional, and demographic factors. Contributing individual factors include obesity, diabetes mellitus, untreated hypothyroidism, HIV infection, lipodystrophy, anorexia, Cushing syndrome, sarcoidosis, systemic lupus erythematosus, alcohol consumption, and certain drugs (oral estrogen, glucocorticoids, protease inhibitors, hydrochlorothiazide, nonselective beta-blockers, retinoic acid, tamoxifen, raloxifene, cyclosporine [INN ciclosporin], sirolimus).

The classification and etiology of severe hypertriglyceridemia (ie, fasting TG concentrations >10.0 mmol/L) include:

1) Polygenic hypertriglyceridemia (type V hyperlipoproteinemia according to the Fredrickson classification): A combination of genetic, demographic, and clinical factors.

2) Familial chylomicronemia syndrome: Genetic (type I hyperlipoproteinemia according to the Fredrickson classification).

Severe hypertriglyceridemia, in addition to elevated very low–density lipoprotein (VLDL) level predominating in its milder forms, is associated with fasting chylomicronemia. Familial chylomicronemia syndrome tends to be more severe and resistant to treatment. Hypertriglyceridemia has been linked to an increased risk of CVD and, when severe, to acute pancreatitis.

Clinical Features and DiagnosisTop

Milder forms of hypertriglyceridemia have no specific clinical features, and the diagnosis is based on laboratory tests results. Severe hypertriglyceridemia with the presence of chylomicrons may present as abdominal pain or acute pancreatitis.

Low-density lipoprotein cholesterol (LDL-C) levels are generally low in more severe forms of hypertriglyceridemia, whereas total cholesterol may be high, depending on the cholesterol content of chylomicrons.

Fasting chylomicronemia is usually accompanied by fasting TG levels >10.0 mmol/L and is never considered normal. Its recognition is usually prompted either by the occurrence of acute pancreatitis or by finding turbid plasma in a fasting patient or high serum TG levels in routine laboratory tests. Genetic testing is usually necessary to distinguish polygenic hypertriglyceridemia from familial chylomicronemia syndrome.

TreatmentTop

At the lower levels of TG elevation, dietary changes play an important role: decreased intake of simple carbohydrates, increased intake of dietary fibrates (eg, oat bran, beans, barley, prunes, citrus fruits, apples, Brussels sprouts, broccoli, apricots), and decreasing caloric content of fat <30% to 35%. Control of diabetes and/or obesity, as well as reduction of alcohol intake and following recommendations for hypercholesterolemia are advisable. Pharmacotherapy, influenced by the extent of individual cardiovascular risk factors, may include statins (to normalize elevated LDL-C levels, if present), omega-3 fatty acids, and/or fibrates (see below). Of note, TG elevation is associated with an increased risk of CVD, but the effects of TG lowering is less clear

In severe hypertriglyceridemia the main goal of treatment is prevention of acute pancreatitis.

1. A very low-fat diet (<10% of daily caloric requirements covered by fats), including both saturated and unsaturated fats. Additionally, reduce the intake of carbohydrates, particularly simple carbohydrates.

2. Abstinence from alcohol.

3. Control of diabetes and weight management.

4. Considering the possibility of drug-induced TG elevation: Hormonal medications (estrogen, including birth control pills, tamoxifen, testosterone, glucocorticoids); nonselective beta-blockers (propranolol); thiazide diuretics; immunosuppressants (cyclosporine, tacrolimus); antipsychotics (olanzapine and clozapine); some HIV medications (protease inhibitors such as ritonavir and lopinavir); antidepressants (some selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants); antiepileptics (valproic acid and carbamazepine).

5. Fibrates (eg, fenofibrate, gemfibrozil) should be used in patients with very high TG levels (Table 1 in Lipid Disorders: General Considerations). We suggest the threshold for treatment of ~5 mmol/L. In patients with fasting TG concentration ≥10.0 mmol/L (885 mg/dL), starting a fibrate is highly recommended for prevention of pancreatitis.

Contraindications and major adverse effects: see Lipid Disorders: General Considerations.

6. Omega-3 fatty acid derivate icosapent ethyl (IPE): In a population with established CVD or diabetes and other< risk factors (eg, hypertension, smoking, decreased high-density cholesterol [HDL] levels) in whom elevated TG level (1.7-5.3 mmol/L) persisted despite treatment with statins, a purified, costly form of omega-3 fatty acid, IPE, dosed 2 g bid, reduced the risk for developing cardiovascular events and mortality but increased the risk for atrial fibrillation and bleeding, and is recommended in that specific population in the last Canadian dyslipidemia practice guidelines.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10. PMID: 30415628. Yokoyama M, Origasa H, Matsuzaki M, et al; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S0140-6736(07)60527-3. Erratum in: Lancet. 2007 Jul 21;370(9583):220. PMID: 17398308. There is no proven cardiovascular benefit from regular use of over-the-counter omega-3 fatty acids, although they can be effective at decreasing TG levels at a dose of 1 g tid.

6. Statins are mildly effective at treating hypertriglyceridemia, although patients with hypertriglyceridemia often have coexisting hypercholesterolemia: see Table 1 in Lipid Disorders: General Considerations.

7. Nicotinic acid at a dose of up to 3 g/d can have a limited effect on lowering plasma TG levels, increasing HDL-C, and minimally lowering LDL-C concentrations, but its effect is limited by its adverse effect profile, and it is therefore generally not recommended and rarely used. Adverse effects include flushing, pruritus, paresthesias, and nausea.

Contraindications: Gout, active liver disease, acute myocardial infarction, peptic ulcer disease, pregnancy, breastfeeding, diabetes mellitus (only for crystalline nicotinic acid).

COMPLICATIONSTop

Pancreatitis secondary to hypertriglyceridemia (usually associated with fasting TG level >10 mmol/L) is significantly more severe than pancreatitis due to other etiologies. It is associated with higher risk for developing pancreatic necrosis, pseudocyst, and other complications, as well as with higher mortality.

While patients who develop pancreatitis due to other causes are now encouraged to maintain enteral nutrition, patients with acute pancreatitis secondary to hypertriglyceridemia should fast or restrict fact intake to a minimum (<5% of caloric intake) until TG levels decline significantly (usually within a few days) (see Acute Pancreatitis).

Apheresis can rapidly lower excessively elevated TG levels, but fasting is the most effective aspect of management of acute pancreatitis secondary to hypertriglyceridemia: the decrease of TG level with fasting or major reduction of fat intake (to <10%) may exceed 25% per day. Insulin should also be considered in patients with diabetes and poorly controlled glycemia, but insulin/glucose infusion (independent of the presence of hyperglycemia or even diabetes) may be used in severe cases.

After the acute episode resolves, patients should be advised to maintain a very low–fat diet, abstain from alcohol, and start treatment with a fibrate. The risk of repeat pancreatitis is considered minimal when fasting TG levels are maintained at <10.0 mmol/L.