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Severe Hypertriglyceridemia

CE / CME

Current Challenges and Emerging Treatments for the Management of Severe Hypertriglyceridemia

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

CME/CE Information

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FCS: Fasting Chylomicronemia (Triglycerides >880 mg/dL)

Up until this point, we have discussed chylomicronemia syndrome and MCM but have not made the distinction between chylomicronemia and FCS. So, what is FCS, and how does it differ from MCM? Like MCM, FCS is defined as triglyceride levels of ≥10 mmol/L, which is the equivalent of 880 mg/dL, and results in an elevation of chylomicrons in the blood.28-30

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Impaired Function of Lipoprotein Lipase Enzyme

Also similar to MCM, FCS results from impaired function of lipoprotein lipase, the critical enzyme that hydrolyzes triglycerides out of the chylomicrons and releases them as free fatty acids.10,28,31 The key difference between MCM and FCS is that MCM is a polygenic disorder that is characterized by the presence of secondary, exacerbating factors and can occur without loss of function mutations in lipoprotein lipase, whereas FCS is defined as a genetic disease of chylomicron metabolism.29 In FCS, impaired triglyceride hydrolysis by lipoprotein lipase results in chylomicron remnant particles that are high in cholesterol ending up in the circulation, leading to many complications.

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FCS: Clinical Signs and Symptoms

There are numerous signs and symptoms of FCS, including turbid serum and abdominal pain.28 Additional symptoms can include rashes such as eruptive xanthomas, which occur on the torso with a red surface and yellow dotted areas.32 Lipemia retinalis, or chylomicronemia in the retina, also may occur, although these symptoms are unlikely until triglyceride levels are in the multi‑thousands of mg/dL. Lastly, hepatosplenomegaly or cognitive impairment may occur, as chylomicrons can affect some of these more distal processes. Some individuals also can appear depressed or socially isolated because of the general malaise this syndrome causes.

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FCS: Lack of Lipoprotein Lipase Activity Increases Risk of Pancreatitis

Let us now consider the risk and burden of FCS. The likelihood of pancreatitis in people with high triglycerides is already higher than in people with normal levels, but the lack of lipoprotein lipase activity in people with FCS raises their risk of pancreatitis by a staggering 360 times.33

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FCS Leads to Recurrent Abdominal Pain and Acute Pancreatitis

FCS also can result in recurrent abdominal pain that can lead to nausea, vomiting, and hospitalization with recurrent acute pancreatitis in approximately 50% of episodes.34 Even 1 episode of pancreatitis can cause inflammation and damage.35-38 Patients with recurrent pancreatitis can have dilatation of the pancreatic duct, pseudocysts, and other kinds of abnormalities as shown on CT scans and MRI.

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Women May Face Additional Risks: Pregnancy

There is further evidence that women with FCS may be at even higher risk. During pregnancy, cholesterol and triglyceride levels increase, even in women who have no prior evidence of triglyceride abnormalities.39,40 Between conception and delivery, women can experience an approximately 2- to 3-fold increase in triglycerides.

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FCS Manifestations Affect Daily Living: Cognitive, Emotional, and Physical Impairments

In addition to the aforementioned health risks, FCS symptoms are a daily burden and can greatly affect an individual’s quality of life. Many patients complain of brain fog, difficulty concentrating, and emotional symptoms, as shown here.41 Mental, emotional, and physical symptoms are all part and parcel of this syndrome.

The daily burden of FCS also affects employment. Constant mental, physical, and emotional symptoms can make it difficult to maintain full-time employment.42 Many patients with FCS have to resort to part‑time employment, and even most part‑time employee respondents felt that FCS affected their careers to some degree. Patients have reported an average of 30 sick days taken per year, and up to 65% of those who reported being unemployed stated that their unemployment was due to their FCS. This demonstrates that there is an impact beyond physical health for these patients.

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Diagnosis Is Critical to Care for Patients With FCS

Unfortunately, FCS can be difficult to diagnose.41,43 Many patients are misdiagnosed initially or have to see multiple healthcare professionals before obtaining a diagnosis. Swift and accurate diagnosis is key to enable care coordination.

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FCS Can Be Clinically Recognized or Diagnosed

Clinical recognition of FCS is dependent on the presence of these characteristics: severe refractory hypertriglyceridemia of >880 mg/dL, with minimal or no response to standard therapies; a clinical history of pancreatitis and abdominal pain; and the absence of known secondary causes.28,44-47 This is key to diagnosis of FCS because standard medical therapies for hypertriglyceridemia work by upregulating lipoprotein lipase activity. However, patients with FCS have impaired lipoprotein lipase activity and therefore will not see much benefit from therapies that target this pathway.

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Tailored and Stringent Diets for Patients With FCS Are Critical

For initial management of FCS, it is critical to initiate a tailored and stringent low-fat diet, including no more than 20 g of fat per day.48,49 Patients must restrict simple refined carbs and avoid alcohol. It also is recommended that patients with FCS use prescription‑grade medium-chain triglyceride oil, as medium-chain triglycerides are not made into chylomicrons but are diverted directly into the portal circulation, making them much less likely to promote pancreatitis. Frequent follow-up with a registered dietitian and nutritionist is advised.

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Clinical Considerations: FCS or Not?

To illustrate the difference between patients with and without FCS, we will consider 2 cases. First is a 35-year-old woman with normal body weight, BMI, and A1C but significantly high fasting triglycerides. By contrast, the second patient is a 45-year-old man with a high BMI and A1C.

The first patient does not have diabetes and has a healthy body weight but has marked hypertriglyceridemia. She has been treated with medications and has had multiple hospitalizations for pancreatitis. In all, this patient is much more likely to have FCS as a diagnosis vs the patient on the right, who has numerous secondary causes, including high BMI, diabetes, and alcohol use.

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