ACMI Caldas Chapter Annual Symposium
Updates 2022 – June 10 -11, 2022
Severe hypertriglyceridemia of difficult management.
Conferencia Prof. Dorá Inés Molina
See take-home messages at the end of this post.
This subject that we are going to see is a topical issue that should call us to make a diagnostic disquisition in our patients. First of all, the subject is aimed at severe hypertriglyceridemias, those, as Dr. Cristian said, that are difficult to approach therapeutically.
En ese contexto, quiero aclarar que esta es una actividad patrocinada con el apoyo de PTC Therapeutics, que las ideas presentadas expresan la opinión del autor y que la presentación está dirigida exclusivamente a profesionales de la salud.
Let’s then go in to see the agenda:
- Lipoprotein composition, epidemiology and classification.
- Let’s get into a little bit of lipid metabolism.
- What are the causes of primary and secondary hypertriglyceridemia.
- What is the risk of hypertriglyceridemia in relation to atherosclerosis and pancreatitis.
- Diagnosis and difference with hyperchylomicronemia.
- Which are the genes that we will find involved and clinical manifestations.
- And we will finish with take home messages.
First of all:
Hypertriglyceridemia is one of the most common abnormalities in the type of dyslipidemias that we encounter every day in our clinical practice.
Many, many monogenic disorders have been identified that cause severe hyperglyceridemia but in most patients this elevation has not only genetic factors, but also environmental factors that are causing or contributing to the elevation of triglycerides.
Among the secondary causes of hypertriglyceridemia we can talk then about how obesity, uncontrolled diabetes, alcohol abuse and various drugs that we are going to see, can increase triglycerides in the blood.
To make a recorderis of the composition of lipoproteins, the chylomicron has a very high component between 80-95% of triglycerides, let’s look at the issue of cholesterol in the chylomicron is more or less 2% to 7% and remember that the life of formation of these is intestinal after dietary intake.
By the hepatic route we have the formation of LVDL where the triglyceride composition is 55% to 65% and we have cholesterol more or less from 10% to 15%. LDL has less amount of triglycerides but has a percentage of more or less 10% and the highest cholesterol is more or less 45%. The HDL we are going to find that its triglyceride content is very low 5%, cholesterol 20%.
So we can see that really when we are talking about hypertriglyceridemia we are thinking of two molecules or two entities which are chylomicrons and VLDL whose origins are different, chylomicrons have their origin or are formed from the intake of saturated fatty acids, carbohydrates and VLDL is from hepatic formation.
In this context I would like to draw a lot of attention to the fact that this is what we normally see and we would like to have our patients with triglyceride levels below 150 mg/dl and if you look at this triangle this is what we generally find in our population.
We are looking at a small group of the triangle like the iceberg where we are talking about severe hypertriglyceridemia and there in these severe hypertriglyceridemia and we can find two types of these, the monogenic type which is the familial chylomicronemia syndrome and the polygenic type or genetic pattern where we will also find secondary factors in the environment that can cause triglycerides to rise in these patients.
In the context of epidemiology we are then facing an orphan disease, a disease whose prevalence is not very high but which we have to start looking for and that picture where we find triglycerides above 885 mg/dl whose prevalence is in the order of 0.10% to 0.20% and some patients can be found with triglycerides above 1770 mg/dl whose prevalence as you can see is much lower.
In this context, from the clinical perspective we have to take into account that patients with hypertriglyceridemia have a higher risk of developing atherosclerosis and its late complications, but also those patients with much higher triglycerides have a much higher risk of developing acute pancreatitis and recurrent pancreatitis.
This is how the different scientific societies show us for them what is the limit of triglycerides to talk about severe hypertriglyceridemia, we can be like the American society of cardiology of the college says that for them it is greater than 500 mg/dl. The endocrine society talks about figures between 1000 and 1199 mg/dl and the European society of atherosclerosis and the European society of cardiology is talking about severe hypertriglyceridemia for them it is figures greater than 880 mg/dl.
We have to identify when we see our patients whether it is primary or secondary hypertriglyceridemia, if we talk about hypertriglyceridemia we have to look at whether they are mild, moderate or severe, when we find figures in our laboratory at levels between 177 mg/dl and 885 mg/dl we can say that we are dealing with mild to moderate hypertriglyceridemia.
Here we have to think about these pathologies where the multifactorial polygenic context is playing a preponderant role associated in many opportunities also to environmental factors. But if we talk about severe hypertriglyceridemia here we have to look at when these patients constantly have triglyceride levels above 885 mg/dl.
Here we can think about monogenic chylomicronemia or familial chylomicronemia syndrome, remember Freidzon’s chart that we analyzed, which is monogenic hyperlipidemia type 1, or multifactorial chylomicronemia, which according to Freidzon’s chart is type 5.
Here we can look at what are the causes of secondary hypertriglyceridemia, lifestyle factors very important that we find out in our patients the association with frequent alcohol consumption, in terms of diet we have to ask about diet consumption in saturated fatty acids, refined sugars, excessive caloric intake and therefore reduced physical activity.
Cigarette smoking can cause secondary hypertriglyceridemia and there are some medical conditions that are associated with hypertriglyceridemia, diabetic patients, patients with obesity, hypothyroidism that in hypothyroidism we can find elevation of triglycerides but also the elevation of cholesterol can be more prominent in them, nephrotic syndrome, cushing, all patients with HIV associated with their therapy and pregnancy,
As for medications we have to take into account thiazide-type diuretics, non-selective beta-blockers, atypical antipsychotics, steroids, there are some medications such as oral estrogens, tamoxifen, raloxifene, cyclosporine, protease inhibitors that can also produce an increase in triglycerides in our patients.
The 2019 guidelines of lipid management make important emphasis on the relationship between elevated triglycerides and atherosclerotic disease, it is important that we keep in mind that the particles that are rich in triglycerides as I showed you in the composition of lipoproteins many of them also have presence of cholesterol and presence of apoprotein B100, which makes many of these patients with hypertriglyceridemia their increase in apob100 with small and dense LDL can lead us to the presentation of atherosclerotic disease in our patients.
Triglycerides have a linear association with risk of developing pancreatitis, it has been found that the risk of pancreatitis is 3% when we have triglycerides above 885 mg/dl to ranges of 1770 mg/dl but look how you can get to 15% the presentation of pancreatitis if we have triglycerides above 1770 mg/dl .
The risk of pancreatitis is always higher in those patients with monogenic chylomicronemia so it is important that we have a clinical eye and that patient with recurrent pancreatitis we always look at the triglycerides and see if they can really be framed in this familial chylomicronemia syndrome.
This is a very interesting article that you can download from the journal of the Colombian Society of Cardiology where we made a review of what is severe hypertriglyceridemia and chylomicronemia syndrome, everything we found in the recent review of the literature and what we have at the moment as a possible therapeutic approach in these patients.
Here we can see then two important aspects, the first when we ask for the lipid profile, at least we have to have our patients fasting for at least 12 hours, this fasting will then allow us to see if the patient has triglycerides above 150 and to see if we then frame it as a mild to moderate hypertriglyceridemia.
Let us remember that at this level there is a greater relationship with the development of cardiovascular disease and that here there may be polygenic genetic factors because there is interaction of mutations of several genes that are associated with changes in lifestyle pathologies in our patient and can lead to the risk of cardiovascular disease.
We will also find patients specifically with severe hypertriglyceridemia or familial chylomicronemia syndrome which is monogenic in nature where there are mutations of great effect where there is loss of function in genes that regulate triglyceride metabolism.
The 90% of the loss is of the function of the lipase protein, many of these patients having a monogenic alteration increases not only the number of triglycerides but also the number of chylomicrons.
Regarding the lipid profile, it is important to keep in mind that triglycerides must always be part of the minimum lipid profile analysis, we ask for total cholesterol, HDL and triglycerides, LDL is generally not calculated by the formula in our laboratories, but when triglycerides are high it is very important that we ask for direct measurement of that LDL in order to be able to accompany us in the diagnosis.
This then has a class I and level of evidence C and as the ideal according to your risks and your comorbidities is that the therapeutic targets for triglycerides should be below 150 mg/dl.
Here we can see then what the clinical manifestations may be that guide us to look for patients with severe hypertriglyceridemia and to think of familial chylomicronemia syndrome. The first thing is that the diagnosis can start from the laboratory when we have a patient with a 12-hour fasting period and generally the sample is taken in the laboratory, it is centrifuged and the sample is left refrigerated for 12 hours and we can see this difference in the sample where the milky serum is indicating that this patient has chylomicronemia, which is the supernatant cream from the tube.
Our bacteriologist can report to us that there is a serum with a milky supernatant that may be indicating that those triglycerides that we are seeing elevated are more from chylomicrons.
These patients may also have eruptive xanthomas, they may have lipemia retinalis, which is generally diagnosed by the ophthalmologist because the patients do not have vision loss, but there are alterations in the fundus of the eye in these patients, the other thing is to look at how they may also be associated with abdominal pain, pancreatitis, recurrent pancreatitis, hepatosplenomegaly.
Miramos aquí algo interesante ustedes pueden ver entonces el fondo del ojo normal y aquí están viendo la lipemia retinalis entonces si un oftalmólogo nos reporta esta lipemia retinalis tenemos que estar avizorados a la búsqueda del síndrome quilomicronemia familiar.
Eruptive xanthomas are seen here, they are much more frequent in the abdomen, anterior parts of the limbs and I would like to remind you of something that seems very important to me, recurrently in the emergency services we may have patients with this picture of abdominal pain, nausea, distension, fever, diarrhea, weight loss, vomiting, yellowish stools and these are patients who are repeatedly returned from the emergency services.
These patients should have a minimal lipid profile because they may be suffering from a familial chylomicronemia syndrome and have indications for management different from what is usually done to these patients.
What is the dysfunction or alteration of lipoprotein lipase in patients with familial chylomicronemia syndrome?
Generally the fat ingested through the diet is absorbed at intestinal level and generates the formation of chylomicrons, these pass into the blood and if there is alteration of lipoprotein lipase we will then have remnants of chylomicrons and hyperchylomicronemia that makes that lipoprotein lipase does not generate the release of free fatty acids that is so important for energy and that will accumulate these chylomicrons both in blood and in remnants at other organs aggravating the patient’s situation.
How then can we differentiate familial chylomicronemia syndrome from polygenic or multifactorial chylomicronemia syndrome?
It is important that we take into account several aspects, first the familial chylomicronemia syndrome or type 1 hyperlipidemia is less frequent, it is in younger people, there are no secondary factors except pregnancy.
If they have a high risk of developing pancreatitis, generally as they begin to have abdominal pain when ingesting fats and carbohydrates they lose weight and do not have a good response to fibrates and you will see that despite good lipid-lowering management with fibrates there is no good response and the genetic load in these patients will be very high.
Multifactorial chylomicronemia syndrome or type 5 hyperlipidemia is more frequent in older people, it has associated secondary factors so we can often look at whether they are diabetics or alcohol abusers.
These patients may be at risk of pancreatitis, overweight, metabolic syndrome and the response to fibrates is more or less adequate but it is not a 100% response because the genetic load of these patients is lower than the genetic load that we are going to find in patients with familial chylomicronemia syndrome so in the context of clinical manifestations we are talking about the monogenic cause familial chylomicronemia syndrome type I.
I have already talked about abdominal complications; in hematologic we can find thrombocytopenia, thrombocytosis and hyperviscosity, in neurologic I found it very interesting that many of these patients may start to consult for symptoms of cognitive impairment, memory loss, mild dementia, confusion and fatigue.
We already know that there can be hepatosplenomegaly, fatty liver and there is a very high emotional burden in these patients that makes them present with anxiety, depression, guilt, social isolation.
Most of these patients have very severe restrictive diets with 10 to 20 grams of total fat per day when the normal Western diet is 120 grams, a Western diet is 120 grams of fat per day and we are giving them between 10 and 20 grams, so there is a total restriction and the economic burden they generate because they are patients who have days of absence from work, permanent visits to emergency services, prolonged hospitalization and they begin to have permanent disability.
So we have to look from the context of our clinical practice as internists at how we are going to approach these patients, the first thing to think about is those patients who have frequently come with fasting triglycerides with a fasting time of 12 hours at figures higher than 880 mg/dl and the patient tells us that despite all the management with lipid-lowering fibrates he has not had a good response, he has not reduced his triglycerides.
In the clinical history we have to find out about a history of pancreatitis, recurrent abdominal pain that has had no other explainable cause, that abdominal pain and that has an absence of secondary causes then we have to rule out that the patient has not been a consumer of alcohol, uncontrolled diabetes or the medications that we have already seen that have a direct relationship with elevated triglycerides.
In 2017 a group of experts in Amsterdam met facing the need to make an algorithm that would allow us to make a diagnosis and a proximity to these patients with familial chylomicronemia syndrome and they came out with this score which is important that we take it into account, it will not help how we are going to select patients who in second instance we are going to send those to genetic assessment we have to look at what are the clinical conditions that make us think that the patient may have more than 10 points and that it is really very likely that he has a familial chylomicronemia syndrome.
If the patient has fasting triglycerides greater than 880 mg/dl in 3 consecutive blood measurements, one reviews the history and there is a history that has always been between 800-1,000 mg/dl, then with this we already have a score of 5, if the patient has had triglycerides in any fasting measurement greater than 1760 mg/dl even once in his life and we have seen them sometimes in the emergency room with 3000 mg of triglycerides.
We also have to be alert, that gives us one more point, that takes away minus 5 points any previous triglyceride measurement lower than 175 because it is already telling us that it is not that familial chylomicronemia syndrome that can be another secondary cause and if the patient had at some point in his life a good control, if the patient has a secondary factor except pregnancy.
For example, if the patient is taking the medications I have already mentioned, it gives 2 points, a history of pancreatitis gives us one point, unexplained recurrent abdominal pain gives us one point, no history of combined familial hyperemia gives us one point, lack of response to lipid-lowering therapy gives us one point, and age is very important.
The age of symptom onset if the patient starts less than 40 years of age one point, less than 20 gives 2 points and less than 10 gives three points because it is talking about a genetic pattern and the younger the age, the higher the score.
If you add these points and you get more than 10 it is very probable that the patient has a familial chylomicronemia syndrome, less than 9 is not very probable and less than 8 is very unlikely, after we have done this analysis and we have applied these parameters to the patient, we have to think if this patient with high triglycerides and we have made this Moulin score of 10 points and it is indicating to us that the diagnosis of familial chylomicronemia syndrome is very probable.
We enter the genetic diagnosis that is to say that the patient is a candidate for genetic analysis, these are the panels that are generally measured lpl, apoc2, apoas, lmf1, do not be anxious about that because the only thing you should put is genetic panel for familial chylomicronemia syndrome, but what we do have to do as internists is the clinical and laboratory analysis that allows us to direct appropriately.
There are some important factors for example we said that there are patterns that define the orientation towards the patient has familial chylomicronemia syndrome and they are the following Generally they are patients who have body mass index less than 26, the ldl was with them and the diagnosis of diabetes is subsequent to the diagnosis of dyslipidemia.
So it is important to remember that we very often find diabetes associated with dyslipidemia in about 50%, but if in this case we see that the diagnosis of diabetes was subsequent to the diagnosis of dyslipidemia, we are much more oriented to the diagnosis of familial chylomicronemia syndrome.
It is important to scan this code because I think that contact is important. This is a completely free program and if you scan it you will have all the data. This is a diagnostic support program that is available in Colombia at a national level in alliance with PTC Therapeutics, the important part is that they will guide you on how to take the sample and how to do the analysis of the genetic panel which does not have any cost for the patient, so we can help you to make a proper diagnosis.
Finally we are going to look at how we approach this patient with dyslipidemia, we already know that the dyslipidemia goal should be less than 150 mg/dl if it is higher we are thinking that it is altered and if it was not in fasting we have to tell the patient to fast for 12 hours, we repeat and we get higher than 150 and 499 mg/dl, then we always look for secondary causes, we look for alcohol consumption, diabetes, medications, hypothyroidism, renal disease, liver disease.
Based on this we initiate therapeutic lifestyle changes, abstinence from alcohol, weight loss, exercise, all the advice to lower sugar, fructose, saturated fat, increase fiber and decrease all types of mono and polyunsaturated fats; if the patient gives more than 500 then we will also have the same management, which is important, between 150 and 499 mg/dl we will have the same management, what changes is the follow-up time, then after this you will repeat the lipid profile in 8 to 12 weeks.
If the triglycerides are less than 200 we will continue with therapeutic lifestyle changes and there is no need for pharmacological therapy but if the patient is between 200 and 499 let us remember the high relationship with cardiovascular disease if the patient does not improve then we have to think about management with statins with fibrates or EPA.
If the patient is tested at 4 weeks and triglycerides are less than 500 we continue on this side but if they are over 500 we have to start a fibrates, omega-3 fatty acids we repeat in six to eight weeks if it is over 500 fibrates, omega-3 fatty acids, niacin is no longer our means but if we have to reevaluate diet and always our patients always look for secondary causes that is very important.
If that patient then with elevated triglycerides we do not manage to bring them to the LDL cholesterol goals, let us remember that for hypertriglyceridemia we have to do the no hdl formula which is: subtract HDL from total cholesterol and then look at what the no hdl and hdl goal should be, exclude secondary causes.
If it is below 885 mg/dl the fundamental thing is to have an impact on cardiovascular risk and in these patients try to bring them to the ldl hdl goal and here the management should be with fibrates and Omega 3, above 885 the primary objective should be to prevent the presentation of acute pancreatitis, intensify lifestyle, fibrates, Omega 3, consider medium chain fatty acids, refer to an expert in lipids and consider because these patients, remember, respond very little to fibrates, so it is time to consider new therapies for them.
To remind them of the goals let us remember that the ideal if we have a patient at extreme high risk LDL less than 55 and that he has no HDL, simply add 30 mg to the goal we have for LDL and therefore it will be a non-HDL in this patient of 85 and if we can measure apoprotein B100.
It would be important because it is a fundamental target in relation to cardiovascular disease risk and there are some treatments here that are important, many are ongoing. Volanosorsen is an apoc3 inhibitor, that is to say, approved in Europe, at this moment in Colombia we have patients managed with this drug through PTC, it helps those who have had an adequate diagnosis, in Brazil it is approved, the effect is to lower triglycerides, increase HDL and specifically the indication in familial chylomicronemia syndrome.
Here we have other drugs that are currently under study, evinacumab, which is an anti ANGPTL3 antibody, which are like cofactors that act by inhibiting LP lipoprotein lipase and which are currently undergoing phase 2 and phase 3 studies because with volanosorsen only thrombocytopenia has been found as a side effect and therefore the FDA has NOT tested it.
This is a new generation drug in which the evaluation that is being done is producing this collateral effect of thrombocytopenia.
We also have gene therapy that was done but due to costs it has been taken off the market, so most of the ones you can see are in phase 2 and phase 3 in the world where these patients have been diagnosed and they are being managed with the restrictive diet plus volanosorsen.
Take home messages
Familial chylomicronemia syndrome, today as you can see in the context of prevalence, can be considered a rare disease, but the diagnosis should be made by the physician as early as possible, given the very high risk that these patients have of developing acute pancreatitis that can develop into potentially fatal recurrent pancreatitis especially in young people.
The only treatment available so far is a very restrictive diet as we saw in relation to fat intake 20 grams per day of lipids difficult to maintain for our patients in the long term.
A new therapeutic tool is volanosorsen, which is an antisense oligonucleotide that acts by specifically inhibiting the therapeutic target of apoprotein C3. It is available and is indicated in adult patients with familial chylomicronemia syndrome who have undergone the entire diagnostic process, including the genetic panel, patients who are at high risk of pancreatitis and those in whom the responses to diet and treatment fail to bring triglyceride levels to the indicated goals.
The approach to this clinical entity is done with multidisciplinary teams, you will see that we have to have nutritionists, geneticists in order to provide the patient with support from diagnosis and therapeutic management and an adequate follow-up of his disease.
Today, when you see patients with severe hypertriglyceridemia with figures above 885 mg/dl and who have had more than 3 episodes and you see that it is constant, you have to think of two pathologies: familial hyperchylomicronemia or multifactorial hyperchylomicronemia.
In familial hyperchylomicronemia, which is where you ask for the genetic panel, we must first have clinical elements to support this request. Generally we are going to find patients with BMI below 26 kg m2 , low density lipoprotein LDL values are going to be low in these patients.
It is an important parameter for the diagnosis and the onset of diabetes will be after the diagnosis of dyslipidemia there with all the follow-up, with all the genetic panel we can then reach the diagnosis of familial hyperchylomicronemia.
The genetic load is in charge of loading the gun but the lifestyle is in charge of firing the gun or damaging the whole process.
So it seems to me that it is important that we keep in mind that many of our patients may have a genetic burden, but it is the lifestyle that ultimately pulls the trigger.
So, fundamentally, our lifestyle has to be associated with the management of all these pathologies and take into account that we have to try to diagnose these patients as early as possible because their quality of life deteriorates a lot.
You mentioned looking for other causes look for other metabolic diseases, medications, it would be good to look at what other entities to look at for clinical practice?
Let us remember that 50% of diabetic patients have dyslipidemia because we are going to find in many diabetics elevated triglycerides, the fundamental thing as this is a secondary hypertriglyceridemia is to manage the diabetes, control it and see what remains.