CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: January 28, 2024
Expiration: January 29, 2025
Hypertriglyceridemia in the United States
Hypertriglyceridemia remains an important issue in the United States. A significant proportion of adults 20 years of age and older have elevated triglyceride levels; we define “elevated” as ≥150 mg/dL. In total, 25% to 30% of people in the United States have elevated triglycerides—a significant proportion of the population—and this causes significant burden to the US healthcare system.1
Elevated Triglycerides Convey Cardiovascular Risk
It is important to recognize that the higher the triglycerides, the greater the likelihood of an individual having a cardiovascular event over time.2 Comparing people in the lowest quartile (triglycerides <82 mg/dL) with people in the top quartile (triglycerides ≥153.5 mg/dL), you see that the likelihood of having an event increases with increasing triglyceride levels. Ten years from baseline, the risk of a cardiovascular event is 3 times greater for people in the highest quartile vs the lowest quartile.
Elevated triglycerides are now considered an ASCVD risk‑enhancing factor in the most recent expert consensus decision pathway on the management and treatment of hypertriglyceridemia.3 When we evaluate triglyceride cut points for determining cardiovascular risk, having an elevated nonfasting triglyceride of ≥175 mg/dL or a fasting triglyceride of ≥150 mg/dL is considered a risk‑enhancing factor. The more ASCVD risk factors an individual has, the more proactive their treatment may need to be to reduce cardiovascular risk and prevent a cardiac event.
Defining Hypertriglyceridemia and Cut Points
How do we define hypertriglyceridemia, and how does it differ from simply having elevated triglycerides? Patients with hypertriglyceridemia have consistently elevated triglycerides at levels of ≥150 mg/dL that persist even after upwards of 3 months of lifestyle interventions and maximally tolerated statin therapy, when indicated.3,4 For hypertriglyceridemia to be persistent, there must be an evaluation of any secondary causes that may be contributing to the elevation. As triglycerides rise, we denote severe hypertriglyceridemia as triglyceride levels of ≥500 mg/dL.
Through the years, there have been significant changes in triglyceride cut points, going all the way back to the original National Institutes of Health consensus conference in the 1980s that defined a desirable level as <250 mg/dL and very high as >1000 mg/dL.5 It became appreciated that lower cut points more accurately reflected risk.6 Nowadays, a desirable level would be considered a fasting level <150 mg/dL, whereas an optimal fasting level is <100 mg/dL.7-9 When we reach levels that are considered high, cardiovascular disease risk begins to increase. At very high levels—especially at levels exceeding 1000 mg/dL—we also see an elevated risk of pancreatitis, which has a host of associated complications that we will discuss.
Fasting vs Nonfasting Lipid Panels
Why do we need to consider fasting lipid vs nonfasting lipid panels? Triglycerides are the most important lipid with respect to being highly variable, depending on what is consumed prior to measurement. We know there is a very high correlation between fasting triglyceride level and postprandial response.3,9 In individuals who have an optimal triglyceride level (<100 mg/dL), we do not expect to see an appreciable postprandial rise. However, if an individual has a higher fasting baseline triglyceride level, they are more likely to experience a greater postprandial rise, especially if they have eaten a high-fat meal. One could screen an individual with a nonfasting lipid panel as long as that nonfasting triglyceride level is <200 mg/dL. However, if the nonfasting triglyceride level is 200 mg/dL or higher, I would recommend a repeat fasting lipid profile to get a better assessment of the patient’s fasting triglyceride levels and LDL-C. The important thing to remember is that if triglyceride levels are normal, LDL-C is accurately reflected. However, as triglycerides start to increase—especially >200 mg/dL—then the accuracy of the LDL-C measurement decreases, so a direct LDL-C measurement should be obtained in those instances.
Fasting Lipid Panels: Preferred for Assessing Specific Populations
Fasting lipid panels also are preferred for specific populations.3 For example, in metabolic syndrome, many patients will have one of the criteria to define this syndrome, triglycerides of ≥150 mg/dL. According to the National Cholesterol Education Program Adult Treatment Panel III definition, metabolic syndrome is present if 3 or more of the following 5 criteria are met:
So, a fasting lipid panel is helpful in establishing a diagnosis of metabolic syndrome. A fasting lipid panel also may identify other lipid disorders in patients without clinical ASCVD who have a family history, can be used to assess adherence in individuals being treated for ASCVD risk reduction, and can identify individuals at risk of triglyceride‑induced pancreatitis.
Primary and Secondary Cases of Hypertriglyceridemia
Many primary and secondary factors can contribute to hypertriglyceridemia. Some key primary causes are genetic; several different genes may cause marked elevation in triglycerides, but lipoprotein lipase and allelic abnormalities are the most common. With regard to secondary causes, hypertriglyceridemia can occur because of poorly controlled diabetes or other medical conditions, such as severe kidney disease and inflammatory diseases, as well as lifestyle behaviors that promote hypertriglyceridemia; these include alcohol ingestion, consuming fatty foods, or use of certain medications, such as hormones (namely estrogen), protease inhibitors, steroids, β-blockers, and some of the atypical antipsychotics.9-11
Consider Chylomicronemia Syndrome if Triglycerides >880 mg/dL
We have established that normal fasting triglyceride levels are <100-150 mg/dL, whereas levels of ≥200 mg/dL are considered high. This bell‑shaped curve shows that most of the population is within the 80-120 mg/dL range, and smaller numbers of patients are at the lower and higher extremes. At the very high extreme, people with fasting triglycerides >880 mg/dL may have chylomicronemia syndrome, including FCS, a disorder in which the body is not able to break down lipids correctly because of impairment of lipoprotein lipase. These patients make up approximately 0.2% of the population but can have a large burden of care.12,13
Chylomicrons May Cause Injury, Leading to Acute Pancreatitis
In chylomicronemia syndrome, the body’s inability to break down lipids results in buildup of fat particles, or chylomicrons, in the blood.14 Chylomicrons are composed of a lipid core, consisting primarily of triglycerides, encased in a phospholipid shell. Although chylomicrons carry out important biological functions, an excess of them may cause injury. The precise mechanism of how chylomicronemia causes pancreatitis is unclear, but it is thought that excessive chylomicrons can promote inflammation in the pancreas when broken down by pancreatic lipases because of the release of free fatty acids. Increased inflammation in the pancreas leads to necrosis of the pancreatic acinar cells and rupture of the small capillaries in the pancreas, thereby enhancing ischemia and acidosis. Chylomicronemia also can cause impairment in blood flow, further contributing to this process. All of this leads to the development and physical manifestations of pancreatitis.
As part of that proinflammatory milieu from release of free fatty acids, trypsin activation occurs, leading to the release of local mediators of inflammation, such as IL-1, IL-8, and TNF-α.15,16 The tissue levels of these cytokines correlate with the severity of disease. Local tissue inflammation can enhance systemic tissue inflammation, again inducing release of inflammatory cytokines and triggering other organ involvement, during which cytokines are activated via Kupffer cells in the liver and produced in other organs. Ultimately, this cascade contributes to multiorgan failure, with death as the final result.
Pancreatitis Caused by Severe Hypertriglyceridemia: Greater Morbidity and Mortality
Pancreatitis caused by severe hypertriglyceridemia is associated with increased risk of death, as well as chronic hospitalization and other adverse outcomes.17 Up to 80% of patients with FCS will experience ≥1 episode of acute pancreatitis, with most patients experiencing many more. This slide also shows that individuals with severe hypertriglyceridemia are at greater risk of pancreatic necrosis, persistent organ failure, need for intensive care, and mortality, and experience a much higher median hospital stay.18
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