A severe elevation of triglycerides (TG) increases a person's risk for pancreatitis and requires lowering by lifestyle change and pharmacotherapy. Also, etiology needs to be addressed. Although statin therapy has improved atherosclerotic cardiovascular disease (ASCVD) outcomes, residual risk remains. In this setting of residual atherosclerotic cardiovascular disease risk, mild to moderate hypertriglyceridemia (HTG) has been shown in many studies to be an independent risk factor for cardiovascular disease (CVD), but data does not show definite evidence that cardiovascular disease risk diminishes with the treatment of hypertriglyceridemia.
Hypertriglyceridemia in many cases is multifactorial, resulting from the combination of genetic factors and other causes of increased production and or impaired clearance of triglyceride-rich lipoproteins (TRLP).
Familial hypertriglyceridemia: secretion of large VLDL particles, typically with low LDL and HDL. Autosomal dominant inheritance. Usually asymptomatic but in the setting of secondary contributors to hypertriglyceridemia, can present with chylomicronemia syndrome and pancreatitis. Not associated with premature cardiovascular disease
Familial dysbetalipoproteinemia (type III hyperlipoproteinemia): elevated remnant VLDL and chylomicron. Elevation in both cholesterol and triglycerides which are roughly equal. Associated with premature cardiovascular disease and peripheral vascular disease
Serum triglycerides are higher in men than in women. They increase with age in both genders. In youth and adolescents, with increasing obesity rates, the prevalence of hypertriglyceridemia is increasing as well. In the National Health and Nutrition Examination Survey (NHANES), 1999 through 2004, about a third of participants had serum triglycerides above 150 mg/dL. In subjects aged 60 years or older, prevalence was 42%. Two percent of subjects with hypertriglyceridemia had triglycerides of more than 500 mg/dL. Severe hypertriglyceridemia is the third leading cause of pancreatitis in the United States. The incidence of hypertriglyceridemia also varies by race, with a higher incidence in Hispanic-Americans and Asian-Indians, and lower incidence in African-Americans who generally have lower triglyceride levels. Although current guidelines agree that a triglyceride level of less than 150 mg/dL is desirable, the number varies in definitions of hypertriglyceridemia and recommendations concerning management.
The serum triglyceride level reflects the concentration of the triglyceride-rich lipoproteins (VLDL and chylomicrons). VLDL and chylomicrons become relatively cholesterol-enriched once the triglyceride core is hydrolyzed at peripheral tissues. It appears that remnant triglyceride-rich lipoproteins, as opposed to very large triglyceride-rich lipoproteins, may be atherogenic. Although triglyceride itself is not found in atherosclerotic plaques, it is thought that the cholesterol content of triglyceride-rich lipoproteins may contribute to plaque development. Also, the lipolysis of triglyceride-rich lipoproteins produces free fatty acids, lysolecithin, and other reactive lipids that may have pro-inflammatory and pro-coagulant effects.
The mechanisms leading to pancreatitis are not clear. It is suspected to be related to release of excess free fatty acids and lysolecithin from chylomicrons exceeding the binding capacity of albumin in pancreatic capillaries. The unbound free fatty acids are thought to form micellar structures with detergent properties, causing injury and ischemia leading to pancreatitis. Risk of pancreatitis markedly increases with triglycerides levels above 200 mg/dL and in most cases can be prevented by keeping triglycerides levels below 250 mg/dL to 500 mg/dL.
Practitioners should evaluate for secondary causes of hypertriglyceridemia including alcohol use, metabolic syndrome, endocrine disorders, and medications. Patients with primary hypertriglyceridemia should be assessed for other cardiovascular risk factors, such as obesity, diabetes, hypertension, and tobacco use. The family history of dyslipidemia and cardiovascular disease should be sought. In patients with familial dysbetalipoproteinemia, pathognomonic palmar xanthomas (orange, yellow deposits along the palmar creases), and tuberoeruptive xanthomas at pressure sites on the elbows, buttocks, and knees are seen. Chylomicronemia syndrome can present with epigastric abdominal pain, cutaneous eruptive xanthomas on the buttocks and the extensor surfaces of the upper limb, hepatosplenomegaly, acute pancreatitis, transient memory loss, lipemia retinalis, and rarely, focal neurologic deficits.
The diagnosis of hypertriglyceridemia should be made based on a fasting lipid panel with recommended length of the fast of 12 hours. An important point in the setting of triglycerides higher than 400 mg/dL, the Friedewald equation which is commonly used to calculate LDL-C levels, underestimates LDL-C levels. In this setting, it is best to rely on calculation of non-HDL-C levels (total cholesterol minus HDL cholesterol) or obtain direct LDL-C levels when available.
Regarding utility of advanced lipoprotein testing, measurement of LDL size or density is not recommended for prevention of cardiovascular events. Apo B and Lp(a) may have utility for assessment of cardiovascular risk in the setting of hypertriglyceridemia. Although effective therapies exist for Apo B lowering, there is no evidence-based therapy for Lp(a) lowering in the prevention of atherosclerotic cardiovascular disease events, although niacin and estrogen have been shown to lower levels of Lp(a). Lp(a) has strong familial inheritance and association with premature cardiovascular disease, thus aggressive LDL lowering is recommended when Lp(a) is high.
Hepatic steatosis, commonly associated with insulin resistance states and hypertriglyceridemia, can be associated with elevation of aminotransferases on hepatic function panel (commonly alanine aminotransferase (ALT) elevation) and should be evaluated radiologically with ultrasound as an initial step.
First-line therapy for acute hypertriglyceridemia pancreatitis includes intravenous (IV) fluids and fasting. Pancreatitis can be a life-threatening condition and may require admission to an intensive care unit. Identifying and treating the underlying cause is important. Also, low-dose IV insulin infusion (as low as 1 unit/hour) is effective through suppression of lipolysis and decreased hepatic triglyceride assembly. With IV insulin infusion, concomitant glucose infusion may be needed in the absence of hyperglycemia to prevent hypoglycemia. Heparin causes a release of LpL from the capillary endothelial surface and may reduce triglyceride levels rapidly, but is short-acting and so not commonly used. Plasmapheresis is an option, when available, for extremely high triglyceride levels but the cost is limiting, the risk of infection is a concern, and the effect is also short-lived. On discharge from the hospital, to decrease recurrence of pancreatitis, lifestyle change, treatment of the underlying cause, use of fibrate therapy to keep triglyceride levels below 500 mg/dL and ideally less than 150 mg/dL, has benefit.
Fibrates are first-line medications for triglyceride lowering with a decrease of 30% to 50% with concomitant increase in HDL-C. Fibrates decrease VLDL production, increase catabolism of TGRL through increased fatty acid oxidation, increased LpL synthesis, and reduced apoC-III. The effect on LDL-C can be variable in that with high triglyceride levels, LDL-C can increase but can decrease with mildly elevated hypertriglyceridemia. Dose adjustment is required with renal insufficiency, and pre-existing liver and gallbladder disease are contraindications. In the setting of concomitant statin use, fenofibrate is the preferred fibrate as gemfibrozil is associated with a higher risk of myositis. Due to protein binding, fenofibrate has an interaction with warfarin and requires close monitoring. Treatment triglyceride goal of less than 500 mg/dL is recommended to decrease the risk of recurrent pancreatitis. Concerning cardiovascular disease reduction, secondary analysis and meta-analysis of cardiovascular disease trials have shown the consistent reduction in cardiovascular disease in subgroups with baseline triglycerides below 200 and low HDL. Other potential benefits include the reduction in retinopathy and albuminuria in patients with diabetes.
Omega-3 fatty acids (OM3FA), which are FDA-indicated for treatment of severe and very severe hypertriglyceridemia (greater than 1000 mg/dL), reduce triglycerides by 20% to 50% at 3 g to 4 g/day of EPA plus DHA. Higher baseline triglycerides are associated with greater triglyceride lowering. As triglyceride lowering is dose-related, and over the counter dietary fish oil supplements contain variable amounts of EPA and DHA, it is important to look at the nutrition label and instruct patients to ingest 3 gm to 4 gm per day of omega-3 fatty acids. Fishy taste and gastrointestinal discomfort can occur with such high doses of over-the-counter OM3FA, and change to available FDA-approved prescription OM3FA may be beneficial. Increased conversion of VLDL to LDL can lead to a rise in levels of low-density lipoprotein cholesterol (LDL-C) but has not been shown with the EPA-only prescription product. No studies have shown cardiovascular disease benefit in patients with hypertriglyceridemia on high dose OM3FA. Recent trials have failed to demonstrate that lowering triglyceride with OM3FA in statin-treated patients with hypertriglyceridemia can reduce cardiovascular risk. A diet rich in omega-3 fatty acids is associated with cardiovascular health benefits.
Niacin reduces triglyceride by about 15% to 40%, decreasing triglyceride synthesis through inhibition of liver DGAT 2, and decreasing lipolysis by inhibiting hormone-sensitive lipase. With recent clinical trials not showing any cardiovascular disease benefit when used with statins, the use of niacin has declined. Flushing is a common side effect that can be reduced by concomitant aspirin use and starting with a low dose at bedtime and slow-dose titration. Complications include hepatotoxicity, impaired glucose tolerance, and hyperuricemia. Niacin is contraindicated in patients with active peptic ulcer disease.
Statins lower triglyceride by about 10% to 30% in a dose-dependent manner and can be used as monotherapy in triglyceride levels of more than 500 m/dL when indicated to decrease cardiovascular risk.
In April 2016, the FDA withdrew approval for the triple therapy of extended-release niacin plus fenofibric acid plus a statin, citing the lack of evidence for the reduction in cardiovascular risk in statin-treated patients.
The management of hypertriglyceridemia is by a multidisciplinary team that includes an endocrinologist, gastroenterologist, internist, primary care provider, nurse practitioner and a cardiologist. Besides pharmacological therapy the key is to educate the patient on changes in lifestyle. This includes dietary changes, for example, the reduction of carbohydrate intake, avoidance of sugar-sweetened beverages and processed carbohydrates, along with exercise counseling, and weight loss, is the foundation in managing hypertriglyceridemia. Weight loss of 5% to 10% can reduce triglycerides by about 20%, and regular aerobic exercise can reduce triglycerides by 10% to 20%. Even with all the controversy surrounding dietary fat, a mono-unsaturated fatty acid rich Mediterranean-type diet has been shown in many studies to reduce postprandial lipemia. In the setting of triglyceride levels above 500 mg/dL, dietary fat restriction becomes important to avoid post prandial rise in chylomicrons to levels that increase risk of pancreatitis. Addressing the underlying etiology and secondary contributors is important. Quitting alcohol, and improving glycemic control in patients with diabetes, is effective in improving secondary components of hypertriglyceridemia. In patients with triglycerides of more than 500 mg/dL, the primary goal is to reduce triglycerides levels to triglycerides the risk of pancreatitis. In patients with mild to moderate elevations in triglycerides (200 mg/dL to 500 mg/dL), the focus should be on preventing cardiovascular disease. For cardiovascular risk reduction, the goal should be to reduce non-HDL cholesterol level down to 30 mg/dL above LDL goal. Those who remain compliant with lifestyle changes and medications have a good outcome with fewer complications.  (Level V)
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