Editor's Note:
The following is an edited, translated transcript of a conversation between Boris Hansel, MD, endocrinologist-nutritionist, and Philippe Giral, MD, PhD, a lipid management specialist, in Paris, France, taped in December 2015.Triglyceride levels have been converted from g/L to mg/dL for the US audience.
Although hypertriglyceridemia is a common condition (overall, it affects 31% of adults in the United States[1]), the severe form is rare and its clinical signs are difficult to interpret. How is it diagnosed? What treatments should be considered? What about pregnant women? Dr Philippe Giral, a lipid management specialist at Hôpital de la Pitié-Salpêtrière in Paris, answers questions from Dr Boris Hansel, an endocrinologist at Hôpital Bichat, also in Paris.
Dr Hansel: Hypertriglyceridemia is a common condition, given that it affects nearly 10% of the adult population in France and 31% of adults in the United States.[1] In most cases, the triglyceride level is moderately elevated and is easy to lower with simple lifestyle and dietary measures. But in some cases, it can rise to 20 g/L (2000 mg/dL) and in some rare cases to as high as 100 g/L (10,000 mg/dL). Such situations are rare but not exceptional. Nonetheless, health professionals are often baffled because they do not understand why triglyceride levels increase so much and because they have difficulty bringing them down.
How to Diagnose Major Hypertriglyceridemia
Dr Hansel: Dr Giral, as a lipid management specialist you see quite a few patients with triglyceride levels of up to 10,000 mg/dL. Is this the highest level you have seen?
Dr Giral: The highest triglyceride level I have seen is 25,000 mg/dL.
Dr Hansel: Let's explain this. Triglyceride excess begins at 150 mg/dL, which is extremely common. But at what triglyceride level does it become major hypertriglyceridemia?
Dr Giral: Major hypertriglyceridemia is when the triglyceride level is greater than 500 mg/dL. The American nomenclature uses the term "severe" when the triglyceride level is above 2000 mg/dL. But as soon as it's above 500 mg/dL, the risk for pancreatitis doubles. For people with a triglyceride level above 2000 mg/dL, we do not know exactly because such levels are found in less than 1 in 1000 population.
Dr Hansel: So, it is quite rare, and thus it is difficult to determine the exact prevalence of this condition.
Dr Giral: That is correct.
Dr Hansel: In the case of severe familial hypercholesterolemia, we know that there are clinical signs. You can see tendinous xanthomas and xanthelasma deposits in the eyelids. Are there any clinical signs for detecting major hypertriglyceridemia?
Dr Giral: In general, when the level is very high we look for clinical signs, including an exanthematous rash. This consists of small, yellowish spots, which are usually seen on the sides of the chest. They are very transient; they go away as soon as the triglyceride level decreases.
Dr Hansel: Because they are transient, you generally do not see them, so there is little point to looking for them to determine whether a patient has a very high triglyceride level.
Dr Giral: The easiest thing is to look at the patient's blood. Generally, when the triglyceride level is greater than 2000 mg/dL, the blood looks like a slightly pinkish mousse, and the diagnosis is made immediately. Normally, in the laboratory, as soon as they take a blood sample, they can make a diagnosis just by looking at the specimen in the tube.
What Risks Are Associated With Severe Hypertriglyceridemia?
Dr Hansel: Let's talk about the risks associated with major hypertriglyceridemia. Unlike familial hypercholesterolemia, hypertriglyceridemia does not increase the risk of developing early cardiovascular disease. So, in the end, why is it dangerous to have a very high triglyceride level?
Dr Giral: The danger is pancreatitis. Pancreatitis is an uncommon but serious illness that can have disastrous consequences. Once you have had it, you will remember it for the rest of your life. Hypertriglyceridemia is the third leading cause of pancreatitis. The leading cause is gallstones, followed by excess alcohol consumption.
Dr Hansel: At what triglyceride level does a person start running the risk of developing pancreatitis? Are people really at risk as soon their triglyceride level reaches 500 mg/dL?
Dr Giral: The problem is that the triglyceride level is highly variable. For someone who has a triglyceride level of 500 mg/dL, the level can rise to 2000 mg/dL after a large meal with lots of wine. This is why one should know when the level was measured in relation to food and alcohol intake. But the risk is considered very real when the triglyceride level reaches 2000-3000 mg/dL.
Risk Factors for Hypertriglyceridemia
Dr Hansel: We know the dietary risk factors that promote hypertriglyceridemia. They are usually excess carbohydrates, excessive alcohol consumption, and abdominal obesity. Just the same, not all alcoholics, and not even the most severe alcoholics, develop major hypertriglyceridemia. Similarly, not everyone who eats a lot of sugary foods develops major hypertriglyceridemia. So, this is not enough to explain it. Why do some people develop very severe hypertriglyceridemia while others with the same diet do not?
Dr Giral: That is a very good question. We do not know the answer. However, there is fat-induced hypertriglyceridemia and there is sugar-induced hypertriglyceridemia. Most cases of hypertriglyceridemia are sugar induced. We do not know exactly which genes are involved. The fact remains that hypertriglyceridemia is linked to insulin resistance, which promotes an increase in triglycerides.
Dr Hansel: Patients with type 2 diabetes are therefore at particularly high risk for a very elevated triglyceride level.
Dr Giral: Exactly. And there can be a significant increase in the triglyceride level, especially when the diabetes is uncontrolled. Incidentally, insulin lowers the triglyceride level.
Dr Hansel: Also, some drugs cause an increase in triglycerides. Antiretrovirals have often been mentioned, although now they seem to be implicated less.
Dr Giral: HIV specialists have a good understanding of this. They have cut down on the use of antiprotease drugs, which caused an increase in triglyceride levels. Now, they actually avoid them in patients with hypertriglyceridemia.
Treatments
Dr Hansel: Let's talk about therapies. Fibrates are among the drugs that lower triglyceride levels, but there are no longer many indications for fibrates in the management of dyslipidemia. Do they work when it comes to treating major hypertriglyceridemia?
Dr Giral: Triglyceride levels can be lowered with fibrates, but so far it has never been demonstrated that they reduce the risk for pancreatitis. And it can even be said that they do the opposite. The FIELD[2] study, which involved about 10,000 diabetic patients in Australia and New Zealand, found even more cases of pancreatitis in the fenofibrate-treated group than in the placebo group. This is why, in my opinion, there is no real indication for administering fibrates to patients with severe hypertriglyceridemia in order to reduce the risk for pancreatitis.
Dr Hansel: Fibrate-induced pancreatitis could be related to another mechanism. Gallstones, perhaps?
Dr Giral: Perhaps. Fenofibrates have not been shown to promote gallstones (this has been shown for clofibrate, an old fibrate that was withdrawn from the market). It is, perhaps, conceivable that they do. In any event, we are not sure.
Dr Hansel: So, do you give fibrates to patients with triglyceride levels of 1000, 1500, or 2000 mg/dL?
Dr Giral: No, I do not. I put them in bed, have them fast, and watch what happens to their triglyceride levels. In general, if a patient truly remains fasting, the triglyceride level will decrease by about one fourth to one third every day. This is very pedagogical. Patients realize that when their triglyceride level is very high and they stop eating, the level will come down.
Dr Hansel: If fibrates have not been effective in lowering the risk for pancreatitis, what about omega-3 fatty acids, which are known to lower triglyceride levels?
Dr Giral: Omega-3's lower triglyceride levels when they are slightly high. Now, suppose you swallow 2 or 3 g of fish oil, which is what is in omega-3 capsules. This is no match for elevated triglyceride levels. Once again, this is of no value for severe hypertriglyceridemia.
Dietary Measures
Dr Hansel: If I understand correctly, dietary measures are the only thing that works. What dietary measures are the most effective in lowering very high triglyceride levels?
Dr Giral: You must not eat, and you have to remain in the fasting state and have your triglyceride level checked. I know this might sound a bit surprising, but it is perfectly logical.
Dr Hansel: But you have to eat to live.
Dr Giral: Yes, but be careful. Hypertriglyceridemia always occurs in surges. Not everyone has a triglyceride level of 2000 or 3000 mg/dL at all times. When someone's triglyceride level is 2000-3000 mg/dL, the thing to do is to stop eating for 48 hours and check as it comes down. Obviously, when the level drops back down to below 1000 mg/dL—that is, below the risk threshold—the patient can start eating again.
Dr Hansel: And what can they eat to prevent a repeat?
Dr Giral: Nine out of 10 cases are carbohydrate- and alcohol-induced; thus, no carbohydrates and no alcohol. Fast-absorption carbohydrates should be the first to go.
Dr Hansel: The patient should eat foods with a low glycemic index, such as lentils and other dried legumes, anything that is high in fiber, and try to avoid refined carbohydrates, including rice. I have often seen patients of Asian origin with very high levels. When we have them cut down on their rice significantly, things improve a lot. I do not know if you have had the same experience.
Dr Giral: Yes, absolutely. And everyone eats sushi. It should be noted that the rice used in sushi is cooked in vinegar with sugar, so this is a very fast-absorption carbohydrate. People think that when they eat sushi, there's a slice of salmon and some rice, but it actually increases their triglyceride level. There are also cases of hypertriglyceridemia induced by bread. Fresh bread is another fast-absorption carbohydrate that can very well cause an increase in triglyceride levels.
What is important is that patients have their triglyceride levels measured often and that they ask themselves the following: What is my triglyceride level today? It is simple: They have the test and they do not have to be fasting. It is annoying when some laboratories refuse to measure nonfasting triglyceride levels. Pancreatitis does not occur in the morning when the person is in the fasting state. It occurs in the evening or at night after a large meal with wine.
Sugar- and Fat-Induced Hypertriglyceridemia?
Dr Hansel: You said that hypertriglyceridemia is induced by sugars and alcohol in 90% of cases. What causes the other 10% of cases?
Dr Giral: Fats. This is due to the genetic abnormalities in the form of lipoprotein lipase mutations. Lipoprotein lipase is the enzyme that hydrolyzes triglycerides and mediates the release of fatty acids into the tissues. Some mutations cause lipoprotein lipase to be ineffective. This hereditary abnormality results in triglyceride levels that are sometimes very high and that cause pancreatitis.
Dr Hansel: How do we know if a patient's hypertriglyceridemia is sugar- or fat induced?
Dr Giral: Lipase activity can be measured. We can measure what's called a PHLA, which stands for post-heparin lipase activity. Heparin releases lipase, which is attached to endothelial cells in the blood vessels, and its activity can be measured. When there is a lipase mutation, the lipase does not work and its activity is close to zero in relation to controls.
The Case of Pregnant Women
Dr Hansel: In some cases, experience has shown us that we are unsuccessful in lowering triglyceride levels, perhaps, because the patients were not able to follow the dietary recommendations, which are, after all, fairly strict. So what do we do when we want to prevent triglyceride surges? I am thinking of a particular case, of a pregnant woman in whom, at the end of her pregnancy, there may be an exacerbation of her hypertriglyceridemia with a significant risk for pancreatitis.
Dr Giral: In this case, we can perform apheresis. If a woman is pregnant, has a triglyceride level greater than 4000 mg/dL, for example, and is at substantial risk for pancreatitis, we can remove triglycerides from her blood. In general, one apheresis session will reduce the triglyceride level by half. This can be repeated every week, with close monitoring of her triglyceride level.
We can also do this in patients with a history of hypertriglyceridemia who are unable to control their triglyceride levels. However, we would not do this straightaway in a patient with a very elevated triglyceride level who does not have any complaints. Instead, we put them in bed and watch what happens by measuring the triglyceride level every day and monitoring the changes.
Therapeutic Outlook
Dr Hansel: Do we have any therapeutic prospects? In the case of cholesterol, we know that many treatments are emerging that can reduce cholesterol levels in severe hypercholesterolemia. Are there any prospects for the severe forms of hypertriglyceridemia as well?
Dr Giral: Yes. A protein called Apo-C3 inhibits lipase. The Apo-C3 level can be modified by RNA, which makes it possible to prolong the action of lipase and, in the end, achieve better triglyceride elimination. There are presently a few ongoing studies, and I hope they show positive results, but I do not think this will be for another 3 or 4 years.
Conclusion
Dr Hansel: For now, we have no effective treatment for major hypertriglyceridemia. However, dietary measures, when properly prescribed, can bring down triglyceride levels but they have to be prescribed properly. The physician must therefore determine the type of dyslipidemia—sugar-induced or fat-induced. In addition, we should tell our colleagues to feel free to get advice from specialists, lipid management specialists, who can help provide accurate dietary advice and monitor triglyceride excess. Thank you.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Severe Hypertriglyceridemia: How Should It Be Managed? - Medscape - Mar 01, 2016.
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