Familial Chylomicronemia Syndrome Overview 

The Correlation Between Acute Pancreatitis and FCS 

 Dr Gelrud, what does the clinical presentation of FCS [familial chylomicronemia syndrome] encompass?

 We see pancreatitis often in the GI [gastrointestinal] world. Pancreatitis can be the combination of severe pain for the patient resulting in visits to the emergency department and subsequent lab tests to confirm that their amylase and lipase levels are above 3 times the upper limit of normal. Imaging from tests often show that patients may have inflammation in the pancreas, indicating GI manifestation. But other presentations of this condition have a multitude of different manifestations.

For example, when you physically examine a patient in a clinic, even with a diagnosis of pancreatitis, you can see what is called an eruptive xanthoma, an accumulation of fat in the skin. If you do an eye exam, you can see a lipemia retinalis, which are deposits of fat in the eyes. The interesting thing is that they tend to regress as patients are treated. During a physical exam you might see hepatomegaly, an enlarged liver. Frequently patients also have splenomegaly. It’s because they develop these fatty livers that make the liver really big.

Patients also have many GI complaints. Frequently, we see chronic abdominal pain that is unrelated to pancreatitis. We don’t have any explanation of why this happened, and it can be challenging to treat. Of course, having excessive lipids in the blood can give the blood hyperviscosity.

When these patients get admitted [to a health care facility], they may have blood drawn, and it is very lipemic. That means that in the tube of blood you see a lot of milky-type of blood instead of the standard red color as the blood starts to sediment and differentiate.

Frequently, these patients have thrombocytopenia. This is [the result of] a whole milieu of signs and symptoms that we must think about. They may also have memory and neurological presentations for whatever reason. We think it’s related to hyperperfusion. Patients may also have some cognitive disorders. These patients can have brain fogginess, so they’re not thinking clearly. I have heard from my patients’ family members that they know an attack is about to happen because [the person] starts to think and act strangely.

As patients start treatment and their triglyceride levels go down, they start to clear up again. These are the most frequent clinical manifestations we find in a physical exam.

 It’s important to emphasize that acute recurrent pancreatitis and abdominal pain are the primary clinical manifestations of FCS. Large studies of FCS patients—which are never that large because this is still a rare condition—have shown that up to 50% of patients will have acute pancreatitis at some point in their lifetime. Another 59% or 60% of patients will have abdominal pain for which they don’t seek medical attention. The burden of pain and pancreatitis is quite high in the FCS population.

The Clinical Presentation of FCS

Dr Singh, what would make you think that a patient you’re treating in your pancreas clinic with recurrent acute pancreatitis and elevated triglycerides may have this rare condition? What would prompt you to think that this patient may have FCS [familial chylomicronemia syndrome] and is not a poorly controlled diabetic? We know there are medications that may trigger elevation in the triglycerides. A person may also be drinking too much, and that’s why their triglycerides are high. What would prompt you to think that this patient may have FCS? What test do you do [to determine that]?

 It’s important to remember that you don’t need to conduct lipid genetic testing to diagnose someone with FCS. It is being done increasingly at several centers, particularly in lipid disorder clinics. Patients are undergoing genetic testing to determine whether they have a mutation in 1 of the genes that regulate LPL [lipoprotein lipase] activity.

There are generally 4 things to look for to diagnose somebody with FCS on a clinical basis. First, you want to see high fasting triglyceride levels, typically greater than 880 mg/dL. Most practicing clinicians are looking for something that is closer to 1000 mg/dL or greater.

The second feature is that FCS patients do not respond to standard hyper triglyceride anemic treatments. So fish oil capsules, statins, fibrates tend not to work as well for lowering triglyceride levels, partly because all those standard treatments require functional LPL. If you have LPL that’s not working or you don’t have enough of it, then the standard treatments are not going to be effective. That’s usually the first clue. If I put someone on a very high dose of statins as well as fish oil capsules and fibrates, and I’m not seeing their triglyceride level come down, that is often 1 big clinical clue that this patient might have FCS.

The third thing I look for is a clinical history that would be compatible with FCS. Because the clinical manifestations that are most common are recurrent and acute pancreatitis and abdominal pain, we know that something to look for.

Finally, there’s the exclusion or the absence of all the secondary things that cause the triglycerides to become elevated, some of which we’ve already mentioned. We want to make sure that the patient doesn’t have uncontrolled diabetes, that they’re not excessively consuming alcohol, that they’re not on birth control pills, that they’re not on a high-fat diet or a fad-type diet. All these things need to be excluded to be firm and convinced that your patient has FCS.

Those 4 things can go a long way in assisting the clinician with a diagnosis of FCS.

 I’m glad you brought up women in pregnancy because that is often not looked at. Most people assume triglycerides go up during pregnancy, especially in the third trimester. I am glad you touched on that, because it seems to be a sticking point for many women with FCS. A lot of them don’t even realize they have FCS until then.

 We diagnosed a patient like that, and it was very difficult for everyone involved.

 I can speak from personal experience. I knew I had FCS, but the doctors didn’t realize how it would affect pregnancy, so I had a very hard time. I got very sick and I was in ICU [intensive care unit] for weeks. That is a sore spot for me—to make sure that is known—because many people do not realize that pregnancy and hormones for women with FCS can make their triglycerides skyrocket and cause problems.

 Darlene, that’s a very good point. Physiologically, for any woman who is pregnant in the third trimester, triglyceride levels tend to go up. That’s completely normal and acceptable. So, patients with this condition run the risk of what unfortunately happened to you.

 It is not something I want to repeat or wish on anyone behind me.

 It’s also important to highlight that with acute pancreatitis in pregnancy, up to half of those cases are because of hypertriglyceridemia; the other half are gallstones. That’s often overlooked: Half the patient population is because of hypertriglyceridemia. There is a misconception on the part of GI [gastrointestinal] physicians that everybody who is pregnant is coming in with a gallstone, because that’s commonly how we’re instinctively taught. We need to be aware that half of those pregnant women who are coming in with acute pancreatitis have hypertriglyceridemia.

FCS Diagnostic Process

 How does FCS [familial chylomicronemia syndrome] impact a patient’s quality of life? What risk factors make a person more vulnerable to the complications that result from FCS? Perhaps the first part of that question is something that Darlene can answer for us? As someone who has lived with the condition her whole life, Darlene has a unique insight that certainly Andres and I can’t provide for our audience.

 I have lived with FCS all my life, so I can say it can be challenging at times, especially as there are no real medications or any kind of help to support this disease. I am following a very low-fat diet with no alcohol. As a result, the diet for FCS patients can be isolating at times, especially for a child. However, nowadays it is more acceptable due to allergies and similar issues where children may be excluded as far as not being able to eat or drink what everyone else does.

It can be challenging and isolating when you can’t participate or partake in all the activities that others can. It may sound silly, but not being able to eat and drink what everyone else can affects you and decreases your quality of life, especially when attending big events, such as weddings and parties, where people don’t realize what a very low-fat diet is for someone with FCS. Due to the restrictions, there is typically not much that you can eat at an event like that.

I think that knowing that up front and being positive about it and taking steps to mitigate the challenges can be helpful, such as eating before a social gathering, so you don’t feel left out. With the restrictions, it is possible to have 1 or 2 little things, so people may not recognize that you’re not eating what everyone else is. When you have something like that, you just don’t want to call attention to yourself. You don’t want it to be a big deal.

As mentioned earlier, it can be quite difficult to deal with the pain management. There are many patients with FCS who deal with chronic pain or have bouts of acute pancreatitis that can set us back, or even brain fog on occasion that may affect us, particularly during work. While it can be difficult, if you truly follow a low-fat diet, you can manage your triglycerides and keep them at an attainable level below 1000 [mg/dL]. Additionally, exercising and drinking lots of water helps as well. All those routines and behaviors can improve the quality of life for patients with FCS.

 Actually, I think that the tricks you just mentioned are invaluable because it is very effective coming from you versus us, but those are usually the accommodations we try to make. Darlene, is there anything else that patients with this condition should try? Your suggestions so far are great, like eating before the parties, staying hydrated, exercising, and keeping one’s diet very low in fat.

: Track what you eat. You’d be surprised how much fat is in different food items that you once thought were healthy. There are healthy fats, but even healthy fats are bad for someone with FCS. Work to understand labels, nutrition values, and total fat grams while limiting your intake to between 20 and 30 g of fat a day, which is the best way to maintain a healthy lifestyle. Also, keep your triglyceride levels managed so you don’t end up with chronic pain or chronic pancreatitis.

 Darlene, who helped you or who taught you how to read labels? Did you do that alone? Did you have a dietitian? Did you go to a nutritionist?

 I’ve been to many doctors. I was diagnosed with FCS as an infant, so I don’t really know any other way. I was raised to look at labels my whole life. It is something that anyone with a new FCS diagnosis needs to be aware of, and there are great nutritionists and dietitianswho can help explain what that means and what we need to look out for with managing FCS. I strongly recommend anyone with FCS or who may think they have FCS to have those discussions with their dietitians.

The Impact of FCS on Quality of Life

: Darlene, why is it so important to create awareness around FCS [familial chylomicronemia syndrome]? Secondly, how can people get involved? I believe many people who have FCS wish they could do more to create awareness and to help other people who may be struggling. What do you recommend? What are your words of wisdom?

 The importance of creating awareness is promoting the fact that we’re so rare. People simply don’t know what FCS is. They don’t understand the condition, so making more people aware of FCS may connect the dots to help others achieve a diagnosis. Many people don’t have lipid specialists, or they live in an area where physicians are not as familiar with this disease. Therefore, if people can become their own advocate and understand what their symptoms are while being aware of FCS, it may trigger the desire to investigate further. Acquiring a diagnosis is significant because an individual could be going down the wrong path to manage symptoms without the FCS diagnosis.

As a result, the more people who can share stories and experiences can combat that fact that there is not a lot of information when you may potentially have FCS. For the individual who is going through a medical issue that no one understands how to treat, having that awareness and connection to others who have this illness is invaluable. I never met someone with FCS until I was 40 years old, and now I can help others with the disease who are younger than me, who have similar circumstances. Now, I can share my experiences and teach others about what has helped me over the years. Truly, having an active community to look out for each other and help one another is priceless.

We have a website called livingwithfcs.org. We also have a Facebook community called Living With FCS. People can reach out on the website or they can reach out on Facebook to join us. Our Facebook group is very active. Again, we have people who just received a diagnosis and they don’t know what the first steps are. What is the diet? The community often responds with recipes and similar resources while we rally around them and help them get used to dealing with FCS.

 Darlene, you’re making a very good point because I think people don’t know in general what resources are available out there for patients and family members. It is nice to hear that there is so much activity and resources available.

 Yes, it has increased greatly over the last few years with the creation of the FCS Foundation and the FCS Facebook group, which has 60 members. Notably, many members are caregivers, or patients themselves, or grandparents of children who’ve just been diagnosed, and are looking for advice or people who understand what it’s like and can provide support. The online community is a great thing to have and a great tool to use if you’re newly diagnosed, or even if you’ve had FCS your whole life.

The Importance of Creating Awareness for FCS 

 What are some of the unmet needs in the management of FCS [familial chylomicronemia syndrome]? Shifting back to our providers and how they need to think through their care of patients with this disorder, what do you think are some of the unmet needs, and how do you address some of these comorbidities and comanifestations of FCS?

 The primary unmet need is that we don’t have an effective treatment. Unfortunately, when patients make a small mistake, such as putting an extra tablespoon of fat in whatever they’re eating, that error may be enough to make the patient have a bad episode of pain, which can lead to the emergency department and hospitalization. It’s such a basic unmet, need not having a treatment for FCS. It’s very difficult for patients with FCS to live with this condition and not derail their lives due to small mistakes.

I was very happy to hear the comments from Darlene, specifically that with social media we are starting to see support for patients with FCS. I believe education is going to be key in bypassing some of these unmet needs. Additionally, not only is education important for the patients who are suffering but for their physicians, too. The sad reality is that these patients’ struggles can become frustrating for physicians.

We may be trying our best, but our best may not be enough. FCS can be very difficult and challenging to treat. Patients may require large portions of our time, yet sometimes physicians are too busy to dedicate the amount of time needed. We have ancillary people who can help, who may be extremely capable and helpful, but the fact that that we don’t have satisfactory treatment to keep the disease under control makes it very challenging. The comorbidities we see because of the elevation in the triglycerides are other things that we need to try to treat. In general, doctors who are working with the patient to help prevent disease progression are doing a good job. However, the real challenge is when a small mistake is made causing a patient pain or pancreatitis, and the lack of an effective and simple treatment can be very difficult.

Unfortunately, we frequently put our patients on IV [intravenous] drips of different treatment to bring the triglycerides down. At times, we will have patients for whom we must do hemofiltration and plasmapheresis to clear out the blood due to high lipid levels. We may have to do that every week, or twice a week, or every other week, depending on how aggressive the condition is to prevent another attack.

It is also sad to see pregnant females have their triglyceride levels rise in the third trimester. These are problems that impact the unborn baby, so it can be very stressful for the patient, their family, and for the physicians. In total, the list of unmet needs is quite significant. FCS is a rare disease, and it is difficult for physicians to provide an effective treatment when there isn’t one available.

Unmet Needs in FCS Management 

 What advice would you have for clinicians, lipidologists, or gastroenterologists, who are the people we see and work with every day, to treat patients with FCS [familial chylomicronemia syndrome]?

 Foremost, you must make the correct diagnosis. If you don’t have the correct diagnosis, then the correct treatment is always going to be elusive. It is probably worth repeating what the diagnostic criteria are for FCS. This a condition that can be diagnosed clinically on the basis of elevated fasting triglycerides, typically greater than 1000 [mg/dL], that are not responsive to standard or conventional hypertriglyceridemic treatments; is typically characterized on a clinical level by either recurrent acute pancreatitis and/or abdominal pain; and an exclusion of a secondary cause of those triglycerides being elevated. Those 4 factors must run in our minds when we think about how to make sure that we’re diagnosing FCS correctly. Unfortunately, most practitioners are not going to have access to genetic testing or have access to test for LPL [lipoprotein lipase] activity. There are some lipid laboratory tests that do that, but most practitioners are just not going to have access to that. Therefore, it’s important to keep in mind that this condition can be diagnosed clinically.

Once you have a diagnosis, the most important thing we can do is to counsel our patients on the dietary modifications that are so important to keeping triglyceride levels down. Specifically, that entails sticking to a low-fat diet that can be very restrictive, as Darlene mentioned earlier. Patients should not go above the 20 to 30 g of fat a day, which is a very important and tangible thing that patients with FCS can do to make sure that their triglyceride level stays low. Additionally, avoiding simple carbohydrates is important because simple carbohydrates can turn into fat in the body. It is critical to watch your intake of carbs. Finally, patients should stick to either no alcohol, so if you don’t drink then please do not start, or for those who do drink occasionally, drinking on special occasions may be permissible. In total, those are likely 3 tactics that are going to be the most important in combatting FCS.

It is important to note that there is significant research and progress inching slightly closer to developing treatments that are going to be helpful for patients with FCS. We do know that there are some drugs in development that target APO3C [apolipoprotein C3], and we know that they can be effective in reducing triglycerides, even in the short term. I think that the future is bright for some of these treatments being approved by the FDA in the next year or so. Possibly, we may start to see the treatment landscape evolve as a result of these therapies being available for patients with FCS.

: It is important to know that there’s a lot of work being done, and hopefully in the near future we’re going to have a treatment that we’re going to be able to provide to patients like Darlene, which will have a significant impact on quality of life. Many of the restrictions that you have right now, Darlene, hopefully one day you will be able to eat more and enjoy more of the things that you have done throughout your life.

From your personal experience, what advice would you give to the caregivers of patients who have this condition? We just heard that the primary treatment is a restrictive diet. What recommendations do you have for people taking care of children?

I talk about this often because I was never raised as if it was an issue, it was treated as something I had to deal with. It was never a problem. My parents were great at doing things that now seem kind of silly, but they always would make it so that I would get something extra since I didn’t get what everyone else received, which is a little backward, but it worked for me. I was a happy kid, and I never realized that I couldn’t be like everyone else until I became a teenager and you’re off on your own.

As a young child during Easter, my brother and sister, who do not have FCS, would get big chocolate rabbits in their baskets, which I could not have. I couldn’t have any chocolate. To compensate, my dad would get a pineapple because, perhaps it was big? He would make a big deal on Easter morning about cutting up the pineapple, and I got to share it with everyone. In retrospect, it was a pineapple, but as a kid it made Easter an event where I got something extra, so I felt like I wasn’t missing out on what everyone else had. It changes your perspective if you concentrate on the positive and make that child feel a little special, and it changes their outlook and makes it a little easier for them to follow the restrictive diet.

FCS Treatment Advice for Clinicians and Caregivers 

 Darlene, how can a patient or a caregiver get involved with lobbying for improved testing for FCS [familial chylomicronemia syndrome]? What have you done, and what have you seen people do that has been effective?

 On the FCS Facebook site we provide information regarding lobbying for specific bills. Our foundation will send out template forms with letters for some of the FCS community to fill out to send to their states’ representatives when bills go for passing in Congress. The FCS Foundation has also joined the Haystack Project and other leaders in the rare disease community, and they just came up with a new bill called the Heart Act; the name is an acronym for Helping Experts Accelerate Rare Treatments. The purpose of the Heart Act is to ensure that experts who truly understand a rare disease are involved with the FDA review process.

In our world, there’s a lot of information that experts and physicians need regarding clinical trials and test data. In the case of an ultra-rare disease, that’s not always feasible. You may not be able to get all the data that the FDA requires to approve a drug. However, for these rare diseases we’re asking the FDA to look at things a little differently and to look to experts and doctors who have seen these diseases and can attest that the benefits outweigh the risk because there are no treatments for people with FCS.

There may be risks associated with taking that drug or treatment, but if the benefit is that your triglycerides drop by 70% or 80% and you may no longer have acute pancreatitis, it’s worth it for the patient to make that decision themselves while being monitored by their doctor. We’re making great progress for changes as far as FDA approvals, and hopefully the Heart Act will go to Congress in the next 6 months and get approval.

 Excellent. That’s a great example of how working together can make a huge impact.

Darlene, Vikesh, thank you so much for this insightful discussion. Thank you to our audience for watching this 

 discussion to be useful and informative. Hopefully, you’ll be able to apply what you learned with your patients soon. Thanks so much for joining us.

Understanding and Managing Familial Chylomicronemia Syndrome

EP 1: Familial Chylomicronemia Syndrome Overview

EP 2: The Correlation Between Acute Pancreatitis and FCS

EP 3: The Clinical Presentation of FCS

EP 4: FCS Diagnostic Process

EP 5: The Impact of FCS on Quality of Life

EP 6: The Importance of Creating Awareness for FCS

EP 7: Unmet Needs in FCS Management

EP 8: FCS Treatment Advice for Clinicians and Caregivers

EP 9: Lobbying for Improved FCS Testing