FCS Community Highlights Disease Clinical Presentation and Lifestyle

APRIL 30, 2018
Krista Rossi
At the National Lipid Association (NLA) Scientific Sessions in Las Vegas last weekend, Akcea Therapeutics hosted an Expert Theatre panel discussion entitled, “Hypertriglyceridemia-Induced Pancreatitis: How Lipidologists Can Partner to Optimize Complex Care.”

Its primary aim was to educate physicians and practitioners on familial chylomicronemia syndrome (FCS) and hypertriglyceridemia-induced pancreatitis.

The disease awareness program was moderated by James Trippi, MD, interventional cardiologist at St Vincent Medical Group in Indianapolis, IN, and headed by Vikesh Singh, MD, MSc, director of the Pancreatitis Center and associate professor of medicine at Johns Hopkins University, and David J. Davidson, MD, a clinical lipidologist at NorthShore Medical Group in Bannockburn, IL. Additionally, FCS patient Aaron Bowman spoke as a guest.

The didactic presentations included an overview of the causes of severe hypertriglyceridemia that lead to pancreatitis and its secondary and primary genetic causes with the common being polygenic-combined hypertriglyceridemia, familial hypertriglyceridemia and dysbetalipoproteinemia, and FCS. Risks and disease burdens were also assessed.

Davidson explained the characterization of FCS, which is having chylomicrons in the blood. “FCS is generally when the triglycerides are over 880 milligrams per deciliter; you get a milky serum [in the blood]. Chylomicrons are the lipoproteins that are rich in triglycerides. About 90% of the chylomicron content is triglyceride.”

He went on to present a distribution of the triglyceride concentrations across the population, which showed people with chylomicronemia to have extremely high levels of triglycerides (10 to 20 times above normal), making approximately up 0.1% of the population with FCS including only a portion of that 0.1%. However, founder populations, such as French Canadians, Netherlands, Moroccans, South Africana, Mumbai Indians, and those from China and Japan, have a higher prevalence for FCS.

The dysfunction of lipoprotein lipase (an enzyme involved in the hydrolysis of triglycerides) was described as the main driver regarding FCS, specifically, a mutation of lipoprotein lipase. As a result of the lipoprotein lipase mutation, chylomicron clearance delays, consequently causing an accumulation of chylomicrons due to the inability of hydrolysis to drive them into the remnants.

A series of genes can affect lipoprotein lipase activity, primarily the LPL gene but also the APOC2, GPIHBP1, APO5, and LNF1 genes. However, according to Davidson, in order to differentiate the exogenous and endogenous conditions, it is important to distinguish some of the different genetic disorders in order to classify between polygenics versus monogenics. Specifically, measuring the apoB or apoB100 levels can help track the sources of where triglycerides are coming from, and consequently, the dysfunctions.

Clinical signs and symptoms of FCS include having severe hypertriglyceridemia, poor/no responses to lipid-lowering therapies, and classic exam findings that include lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, cognitive impairment, and emotional symptoms. Patients also often exhibit wide ranges of abdominal pain and acute pancreatitis.

Singh then highlighted risks of pancreatitis in patients with lipoprotein lipase deficiency (LPLD), about 360 times higher than average population. While the potential mechanism for acute, unpredictable pancreatitis is still unclear for patients with FCS, it is believed in some cases to be due to the generation of free fatty acids by pancreatic lipase or the obstruction of capillary blood flow by chylomicrons. Whichever the cause of acute pancreatitis, it results in the inflammation and ischemia.

“It’s important to note that hypertriglyceridemia-induced pancreatitis patients have more severe presentations and worse outcomes than other ideologies of pancreatitis,” he said.

Referencing a study conducted by the University of Pittsburgh, he explained how a greater proportion of patients who had high triglycerides defined as greater than 1,000 milligrams per deciliter required the intensive care unit, developed pancreatic necrosis, developed persistent organ failure (the primary determiner of mortality in acute pancreatitis), and higher overall mortality rates (8% compared to 3%). In addition, patients with acute hypertriglyceridemic pancreatitis spend more days in the hospital as a median in comparison to patents with lower triglyceride levels.

Patients with hypertriglyceridemic acute pancreatitis also don’t always present with it at the hospital. Abdominal pain that sometimes brings them to the hospital is common, and as a result, they often stay at home and try to treat it independently, which is a recurrent process. In another study mentioned that was surveyed to specialists at lipid centers and 251 patients with FCS, the majority of patients reported recurrent abdominal pain, and half had recurrent acute pancreatitis, which is the primary and strongest risk factor for developing chronic pancreatitis. After several or just one episode of acute pancreatitis, chronic pancreatitis can develop, which is much more difficult to treat.

In addition, chronic pancreatitis can cause functional deficiencies that can include Type 3c diabetes (pancreatogenic diabetes) and exocrine pancreatic insufficiency and other conditions that require interventional procedures, such as waldo necrosis and pancreatic pseudocyst.

Furthermore, women with FCS face significant risks since estrogen levels rise with oral contraceptive use and pregnancy, which cause triglycerides to rise 2-fold to 3-folds above the upper limit of normal. Among women who develop acute pancreatitis, about 50% are due to hypertriglyceridemic. As a result, miscarriages and maternal fatality pose serious risks for pregnant women with FCS.

In terms of a diagnosing FCS, Davidson clarified that genetic testing is not necessary; FCS can be diagnosed clinically. However, awareness is necessary, and physicians have to be looking for it. “We’re going to throw out a sort of clinical scoring system similar to Simon Broome, Dutch Lipid Clinic to apply to FCS or familial hypertriglyceridemia. The criteria we would put into the scoring system would be having this severe refractory hypertriglyceridemia with the fasting triglycerides be over 880, and refractory means minimally or not responsive to standard therapy. Once you have that. You can start factoring in the clinical history where acute pancreatitis or recurrent abdominal pain without other causes is part of it, and very importantly, there needs to be absence of a secondary cause.”

Davidson went on to describe secondary causes as alcohol, uncontrolled diabetes, and certain medical conditions, including chronic renal failure, Cushing syndrome, hyperthyroidism, HIV, nonalcoholic fatty liver disease (NASH), pregnancy, and lupus. Several medications can also cause hypertriglyceridemia, such as atypical antipsychotics, beta blockers, bile acid resins, steroids, estrogen, and tamoxifen to name a few. If answers are still unclear, genetic testing can still be a viable option.

Unfortunately, Davidson added that misdiagnosis is not uncommon with FCS, but diagnosis is necessary to initiate patient care. Sixty-seven percent of patients with FCS have reported previous misdiagnoses, and many had to see more than 5 doctors before receiving a proper diagnosis. Davidson also highlighted that collaborative care is also necessary for the proper care of FCS patients across all the physicians—cardiology, endocrinology, gastrointestinal, pancreatology.

Towards the close of the session, Aaron Bowman, a preschool teacher of children with special needs and FCS patient, shared some of his struggles, joys, and hopes as a person living with FCS. “My disease gave me the grace to understand the challenges of others,” said Bowman, “and oftentimes, my own wellbeing took a backseat. Being diagnosed with FCS and working through the grief related with this condition showed me the importance of putting myself first and becoming my own advocate and advocating for others with this condition.”

He further described the social and emotional toll the disease took on him. He often had to miss activities, school, and work, and hospital visits were no strangers to him. By the time he reached his 30s, he had given up on trying to find a diagnosis due to the same answers he constantly heard and the constant questioning he received surrounding his honesty in his lifestyle.

When he finally did receive the proper diagnosis from a specialist, Bowman described the instance as “a two-edged sword.” While there is relief and hope in having a diagnosis, there is also a grieving process. “The way I lived my life and the way I wanted to live my life was going to have to change. Eating what I wanted when I wanted was no longer an option; I grieved for hamburgers, pizza, and for God’s gift to the world, chimichangas.”

After realizing he was going through the five stages of grief with his diagnosis and overcoming them, Bowman settled on accepting his condition but also accepting the depression, anxiety, and struggles that come with it. “I came to the conclusion that this genetic disorder was not going to stop me,” said Bowman. “I think going through the five stages of grief was the best thing I’ve ever done.”

In addition, Bowman has adopted the military philosophy of “embracing the suck” with his wife in order to help him face and accept his condition. “To me, it means I can’t hide from my disorder,” said Bowman. “I have to run with it with all I have and conquer it.”

Bowman concluded by highlighting the value of his family and relationships (which keep him going), while also echoing his determined vigor to live his best life with FCS. “Having FCS is terrible, but life isn’t,” he said. “FCS is just a part of my life; it’s not my whole life.”

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