FCS Expert Explains Difficulty in Making a Diagnosis

In a recent interview with Dr Steven Freedman, a gastroenterologist affiliated with Beth Israel Deaconess Medical Center, Rare Disease Report asked for the specifics on familial chlyomicronemia syndrome (FCS).

FCS, an often misdiagnosed genetic disorder, causes a build-up of chlyomicrons in the blood that can lead to abdominal pain and fatal bouts of pancreatitis.

RDR: Can you provide some background of familial chlyomicronemia syndrome? Have there been any exciting pieces of news recently?

Freedman: FCS is an ultra-rare disorder. As you know, normally, this has been in the lipidologists arena—whether it’s endocrinologists or cardiologists—that are usually running lipid clinics that find these patients. Obviously, this is a pretty rare condition.

The diagnosis can be tough to make. In fact, lipidologists have been trying to develop a scoring system that will help with the diagnosis, but it’s not that you can do a simple genetic test. It’s not necessarily that it can just be a measurement of lipase protein levels, and so that’s made this more problematic. You know, I think one question is how under-recognized is this disorder?

I chaired an advisory board for Akcea in Pheonix a few months ago, and we brought together gastroenterologists who are pancreatic specialists. We brought them together because pancreatitis is one of the driving diseases that’s the expression of hypertriglyceridemiain these patients. We also had lipidologists who are experts in the field, as well. There was a survey done through the National Pancreas Foundation, asking gastroenterologists: “Do you see patients with FCS?”

Of course, the response was no, or that it was incredibly rare. But then they presented the case of a patient that would be typical of someone with FCS. Then, we had to respond and say, “Oh yeah, I see at least 1 or 2 patients a year,” some said—perhaps one patient a month that exactly matches that description. I think one of the questions is: Are there patients out there that are being missed as a result of the difficulty in trying to diagnose these patients? The answer is almost certainly yes. A number of these patients probably haven’t been brought to our attention but need to be.

RDR: Would you mind going into a little but about the age, gender, and other features of a person who might start to present with FCS?

Freedman: I have 1 patient I follow. As far as their disease, there haven’t been great studies. But, there’s a study here that was published—it’s mostly a single page article—I think it was in the Journal of Clinical Lipidology. It really is one of the few articles that asks the question: So how do these patients present? At what age? What’s the mortality/death rare in these patients?

This was the study that was in Journal of Clinical Lipidology in 2016. It’s kind of a who’s who in lipidologists around the world, and basically, 21 lipidologists from 9 countries completed a survey. They had a total of 251 patients with FCS. And they looked at symptoms. Seven percent had neurological symptoms. One of the things that seems to be coming up in surveys with patients with FCS, including the ones from Akcea, is patients complaining of this sort of brain fog, which is perhaps much more common than people think.

If you look at recurrent abdominal pain that does require hospitalization, that was seen in 57% of patients with FCS. If you look at hospitalizations for confirmed acute pancreatitis, that was 67% of patients. So, 2/3 of the patient population with FCS has acute pancreatitis. Half the patients have recurrent episodes, ranging from 2 hospitalizations to as many as 96 hospitalizations, and that’s why gastroenterologists and pancreatic specialists are now getting involved. Lipidoligists were doing a great job of helping care for these patients, but there wasn’t a lot focus on bringing together pancreatic specialists specializing in pancreatitis with these lipidologists here

One-third of these patients who came in with acute pancreatitis had to be in the ICU. The youngest admitted to the ICU was 5 months of age. 12 subjects, so 5%, died from their acute pancreatitis, and that included as young as 2 years of age to 18 years of age. One patient died during pregnancy. This disease can have a significant morbidity, meaning pancreatitis symptoms, including abdominal pain neurocognitive issues all the way through having pancreatitis. One third are in the ICU and have pretty significant mortality and death rate.

RDR: When people get admitted into the ICU, is it because of pancreatitis? Could it be a seizure from the pain?

Dr Freedman: That’s a good question. With these patients, it’s clear that it’s pancreatitis. These patients come in with the characteristic upper abdominal pain, liphase, and as part of the survey, there’s the revised Atlanta Criteria; these are published criteria for diagnosis of the acute pancreatitis, and these patients meet that criteria.

We know that patients with very high triglyceride, so even unrelated to FCS, who present with pancreatitis due to extremely high triglycerides those patients tend to come in with a much more severe course compared to other causes of their pancreatitis. So, at least, it all comes with hypertriglyceridemia. this pancreatitis, several complications on, puts half these patients in the ICU. Death rate is at least 8% but as high as 30%, so it’s almost as if having very high triglycerides is kind of pouring gasoline on the fire in your pancreas, so to speak.

RDR: How do these patients typically present? Is it just severe pain in the abdomen? Are there other symptoms that may lead someone to believe it is pancreatitis or something more severe?

Dr Freedman: Usually it’s pancreatitis. These patients will present with abdominal pain, and acute pancreatitis is usually not something you can ride out at home. This is acute onset, very severe pain, they will have nausea as well as potentially vomiting with this. They have fevers as high as 102. When these patients come to the hospital, diagnosis of the acute pancreatitis is usually clearly made by just checking the liphase level in the emergency room. Usually that will be very elevated.

These patients, what puts them in the ICU is that they’re having death of parts of their pancreas. As a result of that, they present they have some other severe inflammatory conditions. They may come in, they’ll end up in shock, and that’s why they end up in the ICU. They also end up weeping fluid into their lungs as a result of this massive inflammatory response going on that just kind of goes on throughout the body and becomes systemic. We call it ARDS. They end up in the ICU on a ventilator, and then they have kidney failure. That also goes along. So, pancreatitis is no just terrible inflammation of the pancreas, but it can be associated with multi-organ failure. This multi-organ failure is what makes people very sick, puts them in the ICU, and it’s also frequently the cause of death if they die. So, playing with the pancreas is not a good thing.

RDR: Obviously there aren’t any approved therapies specifically for FCS. Would you mind just talking about the current standard of care? Some things that might be in development that patents might be able to expect in the coming months and years?

Dr Freedman: So, right now there are no FDA approved efficacious therapeutic drugs to normalize the triglycerides and prevent all these related issues to them. In severe triglyceride hypertriglyceridemiathat’s not FCS, we will put people on a very low-fat diet, but there are some therapies, like fish oil, and things like that, that may be a benefit to patients. In FCS, these therapies, they work through the protein liphase—what’s defective in patients with FCS.

By definition, patients with FCS are refractory to our medical therapies. We put them on an extremely low-fat diet, and that’s it. That’s state of the art so far. Up till now, there’s really been nothing for these patients except being on super low-fat diets. We’re talking much less than 20 grams of fat per day, which is a very difficult diet. There’s been gene therapy studies—I’m not that familiar with them, but I know that currently there’s none that are approved. I think there’s one, if I remember correctly, that was approved in Europe, but it’s not approved anymore. So, there’s no therapies out there. I think the Akcea pharmaceutical looks very promising with the data so far using anti-sense RNA approach to inhibit the effective production of these chylomicrons so they can be cleared and basically keep the triglycerides in a much lower realm.

RDR: Were there any final points you wanted to touch on?

Dr Freedman: I think probably the last point I’d like to make is that this is a disease where patients enter the medical system through many different ways—through the emergency room, or maybe as an outpatient for some reason, picked up by their primary care doc. I think there’s an advantage by single physicians, so lipidologists, or maybe a primary care doc, or maybe a gastroenterologist. However, there hasn’t been a lot pf emphasis on the multi-disciplinary approach that’s needed. And I think this approach—I’m the one trying to spearhead this—where we develop a multi-disciplinary approach to these patients is key.

So, we have a gastroenterologist and a pancreatitis specialist working with the lipidologist here. At our center here in Bethel Israel, I work closely with our lipids clinic, so anyone with severe triglyceride hypertriglyceridemia, whoever they’re seen by, they’re seeing a lipid clinic. That’s where their initial referral is, then I see them relatively promptly in my pancreas center or vice versa.

If I see someone who’s admitted to the ICU, get them through it, and they clearly they have triglyceride hypertriglyceridemia, whether it’s FCS or not, our lipid clinic sees them within about 2 or 3 weeks, and we co-manage the patient. So that’s my last point I’d like to make. I think this really needs a multi-disciplinary approach between a lipidologist, gastroenterologist. We also clearly we need a dietician involved with this extremely low fat diet, and obviously anything that makes the patient more informed and a partner in their care as we go along this process. I think we’ll see whether or not there’s neurologic issues, and then maybe a neurologist needs to become a part of that multi-disciplinary team. The important next step, besides any therapies that are about to come along, is the multi-disciplinary nature that’s required to taking the best care of these patients.

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While Dr Freedman reiterated the known absence of treatments for FCS, he also highlighted the necessity for different approaches to the disease. Specifically, he emphasized multi-disciplinary approaches. Since there is no cure for FCS, perhaps the best treatment for those living with FCS is through multiple physicians.

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