Managing sHTG: How to Identify Chylomicronemia Syndrome and Reduce Pancreatitis Risk
Key Highlights
- Severe hypertriglyceridemia (sHTG) above 880 to 1000 mg/dL suggests chylomicron presence and increased pancreatitis risk.
- Chylomicronemia syndrome involves signs and symptoms such as abdominal pain, eruptive xanthomas, lipemia retinalis, hepatomegaly, splenomegaly, or brain fog.
- Distinguishing multifactorial chylomicronemia syndrome from familial chylomicronemia syndrome can guide management, including the role of secondary factors, clinical scoring, and genetic testing.
- Management may include dietary fat restriction, alcohol avoidance, treatment of secondary factors, dietitian support, and newer ApoC-III–targeting therapies for familial chylomicronemia syndrome.
In this expert Q&A, Robert Hegele, MD, discusses how clinicians can recognize sHTG-related chylomicronemia syndrome, assess pancreatitis risk, distinguish familial from multifactorial disease, and apply dietary, diagnostic, and emerging treatment strategies.
Consultant360: What are the key clinical signs that should prompt clinicians to suspect chylomicronemia syndrome rather than more routine hypertriglyceridemia?
Robert Hegele, MD: Chylomicrons are the particles that carry triglyceride that is of dietary origin. There is a range, and the lab captures that as a triglyceride level. In milligrams per deciliter, on the American scale, an average triglyceride level would be around 100. In millimoles per liter, it would be about 1 mmol/L. Then you go through a spectrum: mild, moderate, and severe.
What we are talking about today is severe hypertriglyceridemia. That is typically regarded as levels over around 1,000 mg/dL. Technically, it is around 880 mg/dL, but that is severe hypertriglyceridemia. In millimoles, that is about 10 mmol/L. Levels that high start to tell you that chylomicrons are present. At levels lower than that, it is mainly VLDL, or very-low-density lipoprotein, but the higher levels are from chylomicrons.
The reason that is important is that chylomicrons are really the main pathogenic agent for acute pancreatitis. Under a level of 800 or 1,000 mg/dL, there is no chylomicron presence, so the risk of pancreatitis is actually quite low or minimal, or it would be related to causes other than triglycerides. Once you are above 1,000 mg/dL, and certainly once you are above 2,000 mg/dL, chylomicrons are there, and they are present in abundance. There is not a specific lab test that tells you chylomicrons are there, but we know from experience in physiology that they are present, and then the risk of pancreatitis is high.
Hypertriglyceridemia just refers to the level without any symptoms, which is often or usually the case: 1,000 mg/dL or higher with no symptoms. Chylomicronemia syndrome means it is the same level, but there are symptoms; there is a syndrome. That includes abdominal pain and some physical findings, such as eruptive xanthomas or lipemia retinalis when you look into the eyes. There can also be hepatomegaly, splenomegaly, or brain fog.
When these symptoms or signs are present, that makes it a syndrome. Pretty much when you know that the triglycerides are over, say, 880 or 1,000 mg/dL, you know that the chylomicrons must be there, even though the lab is not reporting them as such.
Consultant360: Why is it so important to distinguish familial chylomicronemia syndrome from multifactorial chylomicronemia syndrome in adult patients, and which history or lab findings are most helpful early in the workup?
Hegele: Let’s say a patient comes in with severe hypertriglyceridemia, typically with acute abdominal pain or in the emergency room, and the triglycerides are very high, say 1,000 or 2,000 mg/dL. You are trying to figure out the underlying diagnosis, or they have just been incidentally found to have high levels without symptoms.
Levels that high are seen in about 1 in 500 people. Most of the time, it is a complex disorder, the so-called multifactorial chylomicronemia syndrome. That is due to a little bit of genetic predisposition, deficiency of an enzyme called lipoprotein lipase, but not full deficiency, just partial deficiency. Then, on top of that, you add obesity, alcohol, diabetes, and all kinds of secondary factors, and that pushes the triglycerides into a very high range. That is multifactorial. That is the garden-variety form, and that is by far the majority of cases.
Familial chylomicronemia syndrome, FCS, is a special case. It is a genetic disorder that is present from birth, where the child is born with a deficiency of the key enzyme that cleans these chylomicrons out of the blood. Normally, chylomicrons should be gone 2 to 3 hours after eating. Because of the genetic deficiency, inheriting 2 copies—1 copy from each parent—of this deficient enzyme or its cofactors. Then, from youth or from infancy, the child is unable to clear chylomicrons. They rise to these very high levels without obesity, alcohol use, diabetes, or whatever. It is a metabolic disorder, and that form is very rare. It is maybe 1 in 100,000 or 1 in 300,000, but it is very hard to treat.
With the former form, you can lose weight, give them fibrates, cut out alcohol, and treat the diabetes. Now we have GLP-1s, and they are actually quite useful in helping get the triglycerides down for the multifactorial form. The multifactorial form is more treatable.
The true FCS, the genetic form, is an enzymatic deficiency that is genetically determined and essentially a pediatric disorder. There is very little that we can do other than this extreme fat restriction. We cannot increase the activity of the enzyme because it is not there, so we cut down the amount of fat. That is very hard for any human being to adhere to, especially a child or an adolescent. That is the concern.
What distinguishes it? First, for the multifactorial kind, the garden-variety kind, it is the presentation in adulthood and the presence of these secondary factors. There is also a clinical scoring system. You can go online and Google the NAFCS score, the North American Familial Chylomicronemia Syndrome score. You can enter the points, and it includes things such as the ratio of cholesterol to triglycerides and a blood test called ApoB. You can put these all in, and that gives you a score. If the patient has a very high score, it is much more likely to be the genetic form.
Most of the time, when you enter those factors, the patient will have a low score, so they are more likely to have the multifactorial form. That is good because it is potentially treatable, whereas familial chylomicronemia syndrome, until recently, did not have treatments. It was a lifelong disorder that was extremely draconian for the child and their family to live with, and then to live into adulthood with this extreme fat restriction. The usual lipid drugs—statins, fibrates, and omega-3 fatty acids—do not work for treating the triglycerides in that genetic form.
Consultant360: Because acute pancreatitis is a major risk in these patients, what triglyceride thresholds or clinical features should trigger more aggressive intervention?
Hegele: We know that above a level of, say, and I am going to go back and forth roughly between millimoles and milligrams, above a level of 1,000 mg/dL is where you start increasing the risk of pancreatitis due to triglycerides, due to chylomicrons. Above a level of 2,000 mg/dL, or 22 mmol/L, that risk exponentially shoots up. That is a huge risk.
In that range, we know that if you just let it rip and do not do anything about the triglyceride levels, there is a very high annual rate of pancreatitis, to the point that over 10 years, there is about a 50% chance of having at least 1 attack of pancreatitis. That can be fatal. There can be hospital admission, sometimes ICU care, a lot of fluids, and it is complicated.
The threshold starts at around 1,000 mg/dL, or 10 mmol/L, and it really rises at 2,000 mg/dL, or 20 mmol/L. We know from administrative databases that getting it down to, say, 500 mg/dL, or 5 mmol/L, is associated with virtually no pancreatitis. We do not need to get it down to a perfectly normal level. We do not need to get it down to 100 mg/dL or 1 mmol/L. Even just getting it down to 500 mg/dL, or getting it below 1,000 mg/dL, eliminates the risk of pancreatitis due to triglycerides. There still may be pancreatitis for other reasons—gallstones, alcohol, whatever—but not from triglycerides. That is really the goal. What should trigger your concern would be these very high levels.
Consultant360: Dietary fat restriction and alcohol avoidance are central to management. What practical challenges do patients face with these recommendations, and how can clinicians better support adherence?
Hegele: For the multifactorial chylomicronemia, the 1 in 500 people with triglycerides over 1,000 mg/dL who have secondary factors, fat restriction is still important, and weight loss goes a long way. If they have diabetes, controlling diabetes helps. You can actually get the majority of those patients, the vast majority, over 90%, down below 500 or 300 mg/dL with just these interventions.
You do not need a crazy fat restriction. You just need to reduce portion size, cut out trans fats, and reduce the percentage of fat from the typical North American 45% or 50% fat down to 30% or 35% fat. But for the rare disorder, familial chylomicronemia syndrome, it is much more draconian than that. First of all, those patients are thin. They do not have secondary factors. They are children, and they are probably already on a low-fat diet. To get them down, you need to get them to about 10% fat intake.
If you go over with a professional dietitian what is involved with a 10% fat intake, it is virtually something no average adult could sustain. You might be able to tolerate it for one meal, but then that will be enough of that. Literally for their whole lives, that is what these young people and their families have to deal with. Even a slice of pizza could put them at risk of pancreatitis.
Fortunately, as I said, it is important to make the distinction. For multifactorial chylomicronemia syndrome, it is a moderate fat restriction. For the true genetic familial chylomicronemia syndrome, it is this draconian fat restriction, and you need to engage a professional dietitian to advise families on what foods are allowed and what is possible.
Consultant360: Looking ahead, what developments in diagnosis or treatment do you think could have the greatest impact on outcomes for patients with chylomicronemia?
Hegele: Right now, there are a couple of things. First, now we have genetic testing and genetic lipid panels. Familial chylomicronemia syndrome is a genetic disorder, so it can now be diagnosed with very high specificity with these lipid genetic panels. What you are looking for is a pathogenic DNA variant on two alleles, one from each parent. The parents are heterozygotes, and heterozygotes may not even have a triglyceride problem, but the homozygote, the affected child or young person, has 2 copies. They are completely deficient, and you can now pick that up with a very commonly performed DNA test. It is a one-time test, and that is the definitive diagnosis.
Diagnostically, I also mentioned that there are clinical scoring systems. If you do not have access to DNA testing, you can look up the NAFCS score, the North American Familial Chylomicronemia Syndrome score, enter the points, and that will tell you.
The third thing is that now we have new treatments that have become available in about the last year or 2. These are biologic agents, and there are 2 of them. One is olezarsen, and the other is plozasiran. These are injectable drugs. They both work on the RNA. I will not go into the mechanism, but it is a well-worked-out mechanism where they target a protein called ApoC-III, which is important in triglyceride metabolism.
Both of these drugs reduce ApoC-III. They work in the liver, and that helps the patient. Even in patients with this genetic deficiency, especially FCS patients, it helps them start clearing this big backlog of chylomicrons, and it helps reduce triglyceride levels. Both of these drugs reduce the risk of pancreatitis by about 90%.
This is a big step forward. Before, we had to totally rely on diet. These patients still have to watch their diet, but at least they are not totally afraid every time they have a potato chip that they are going to suffer pancreatitis. These drugs are game changers for FCS patients.
I think the future is that they are probably going to have broader indications for the more garden-variety severe hypertriglyceridemia as well. For patients who do not have the genetic deficiency, but you try treating them and their triglycerides do not quite normalize and they are still at risk for pancreatitis, we now have at least these other drugs potentially in the future. These new drugs would have an application there.
I think it is actually a really good time to be practicing in this area because we do have new diagnostic options and new treatment options.
This transcript was edited for clarity.