Alan S. Brown, MD MHA FACC FAHA MNLA

FCS in Pregnancy and Optimizing Specialist Referral for High-Risk Patients

Pregnancy in a patient with FCS represents one of the highest-acuity scenarios in lipid medicine, with estrogen-driven triglyceride rises compounding an already unmanageable baseline and creating meaningful risk for both mother and fetus.

Alan Brown, MD, MHA, describes managing a patient who had experienced 30 episodes of pancreatitis since age 3, first encountered at age 28 and newly pregnant. With the published literature limited to scattered case reports, and the patient already highly adherent to her diet yet still experiencing recurrent pancreatitis, observation alone was not viable.

Brown describes 2 evidence-supported options beyond strict dietary management: serial plasma exchanges timed to keep triglycerides in check between sessions, and total parenteral nutrition with complete fat restriction for the full duration of pregnancy, requiring prolonged inpatient admission. His patient declined the latter. Plasma exchanges were initiated on a weekly schedule, with triglycerides measured before each exchange to guide the interval. She had no pancreatitis during the pregnancy and delivered a healthy infant.

The case continued after delivery. Enrolled in an early APOC3 inhibitor study, she arrived for her first on-study visit with a positive pregnancy test, this time carrying twins. The plasma exchange strategy was repeated throughout. She delivered 2 healthy babies and has remained pancreatitis-free for more than 5 years on an APOC3 inhibitor. Brown notes that data from centers managing multiple FCS pregnancies show meaningful maternal and fetal mortality, and describes monitoring triglycerides every 2 weeks with a low threshold for intervention as the appropriate approach. No safety data currently exist for newer FCS therapies in pregnancy.

Stephan P. Babirak, MD, PhD, addresses the clinical signals that should prompt any non-specialist to refer. Both experts describe a consistent set of flags: persistent severe hypertriglyceridemia unresponsive to therapy, recurrent pancreatitis, absence of the usual secondary causes, a lean body habitus particularly in younger patients, and a history of unexplained abdominal pain. Babirak notes that dermatologists flagging eruptive xanthomas and ophthalmologists identifying lipemia retinalis have been among his most diagnostically productive referral sources. Brown highlights the role of dietitians as a frontline touchpoint in FCS diagnosis.

Both close by noting that APOC3 inhibitors have changed the management landscape for eligible patients, with Brown emphasizing that getting patients to a specialist who can evaluate them for these agents is the priority.

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Alan Brown, MD, MHA, is a professor of cardiovascular medicine at Wake Forest University and a past president of the National Lipid Association.

Stephan P. Babirak, MD, PhD, is the founder and medical director of Metabolic Leader, a metabolic and endocrine care center in Scarborough, Maine, where he specializes in lipoprotein disorders.

Disclosures for Brown include New Amsterdam, Merck, Novartis, Arrowhead, Amgen, Regeneron, and Ionis. Babirak has no relevant disclosures to report.

1. Javed F, et al. Familial chylomicronemia syndrome: an expert clinical review from the National Lipid Association. J Clin Lipidol. 2025;19(3):382-403. doi:10.1016/j.jacl.2025.03.013

2. US Food and Drug Administration. FDA approves drug to reduce triglycerides in adults with familial chylomicronemia syndrome. FDA. November 18, 2025. Accessed June 12, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-triglycerides-adults-familial-chylomicronemia-syndrome

3. US Food and Drug Administration. FDA approves drug to reduce triglycerides in adult patients with familial chylomicronemia syndrome. FDA. December 19, 2024. Accessed June 12, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-triglycerides-adult-patients-familial-chylomicronemia-syndrome

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Explore plasma exchange as a management strategy for FCS in pregnancy and the clinical red flags that should prompt referral to a lipid specialist.

Managing FCS: LPL-Targeted Therapy, Drug Rationalization, and Atherosclerosis Risk

Patients with FCS frequently arrive at a lipid specialist's office already on phenofibrate, omega-3 fatty acids, a statin, and sometimes a PCSK9 inhibitor, a regimen assembled over years of unsuccessful management. Deciding which agents to continue requires a precise understanding of how each drug acts in the context of LPL deficiency.

Stephan P. Babirak, MD, PhD, approaches the question through a framework built over decades of work focused on lipoprotein lipase as the central therapeutic target. LPL is modifiable in patients with partial deficiency, an insight he demonstrated in 1974 showing that 45 to 60 minutes of exercise every other day measurably increases skeletal muscle LPL activity. Phenofibrate, from his own 1989 research, increases LPL expression by roughly 20 to 30%, making it worth maintaining for patients with residual enzyme activity. In patients with complete LPL knockout mutations, fibrates have no meaningful effect. Omega-3 fatty acids are largely unhelpful in this population: their primary mechanism, reducing hepatic VLDL synthesis, is largely irrelevant in patients who already have markedly suppressed VLDL production because they cannot absorb chylomicron remnants, the substrate for VLDL assembly. When he does prescribe omega-3 therapy, he specifies icosapentaenoic acid rather than over-the-counter formulations.

Alan Brown, MD, MHA, reinforces the pharmacologic logic: roughly 75% of VLDL building blocks derive from dietary chylomicron remnants, and without LPL to clear those remnants, VLDL and LDL production are inherently suppressed in true FCS. He is comfortable stopping omega-3 fatty acids in these patients, and tends to leave phenofibrate in place given the possibility of some residual lipase activity.

The segment closes on the question of cardiovascular risk. Babirak references FATS trial findings showing that LPL-deficient heterozygotes can develop atherosclerosis. Brown adds that data from centers with large clinical FCS registries suggest approximately 15% of patients with chylomicronemia phenotypes have detectable subclinical disease, and that secondary diabetes arising from recurrent pancreatitis adds further risk. He describes coronary calcium scoring as his tool of choice for assessing cardiovascular risk before deciding whether to initiate or continue LDL-lowering therapy.

Understand the evidence base for LPL-targeted treatment strategies in FCS, when to discontinue ineffective agents, and how to assess atherosclerosis risk in this population.

Diagnosing FCS Without Genetic Confirmation: Scoring Tools and Referral Gaps

Confirming an FCS diagnosis without genetic testing has historically been one of the field's central practical challenges, and the development of the North American FCS score was a direct attempt to address it.

Alan Brown, MD, MHA, describes the debates that shaped the scoring tool. It was built around data available in a standard clinical encounter: lipid panel values, physical findings, clinical history, and a single additional test, the apolipoprotein B level. Because patients with true FCS characteristically have low apo B, a consequence of impaired chylomicron remnant absorption reducing the substrate for VLDL assembly, that value carries particular diagnostic weight. Everything else in the score requires no specialized testing.

Stephan P. Babirak, MD, PhD, frames the tool's practical value by analogy to the Dutch Lipid Clinic Network score for familial hypercholesterolemia: just as the Dutch score supported PCSK9 inhibitor access for patients with a compelling clinical phenotype and a negative genetic test, the North American FCS score provides documentation to support treatment authorization while awaiting or unable to obtain genetic results. Brown adds that the cost and logistics of genetic testing have changed substantially, with several laboratories now supplying collection kits at no charge and out-of-pocket costs having fallen to approximately $250.

The conversation turns to a consequential gap in the referral ecosystem: gastroenterology. Brown notes that triglyceride levels are frequently not measured in the emergency department when a patient presents with pancreatitis. Where a lipid panel is run, a notation of 'lipemic specimen' at the bottom of the laboratory report often goes unaddressed — not from negligence, Babirak clarifies, but because the flag is not prominently displayed and sits outside the gastroenterologist's usual diagnostic frame.

Both experts note that a straightforward protocol, ordering a reflex lipid panel on any lipemic specimen, could capture many patients who currently go undiagnosed. Brown points out that FCS ranks as the third most common cause of pancreatitis overall, behind gallstones and alcohol.

Explore how the North American FCS score enables clinical diagnosis when genetic testing is unavailable, and why gastroenterologists remain an undertapped referral source.

Beyond Classic LPL Deficiency: The Genetic Complexity of FCS

The genetic architecture of familial chylomicronemia syndrome extends well beyond classic biallelic LPL mutations, and understanding that broader landscape changes how clinicians recognize and classify patients with severe chylomicronemia.

Stephan P. Babirak, MD, PhD, who was the first to characterize heterozygosity for lipoprotein lipase deficiency in the late 1980s, describes how variants in LPL, apolipoprotein A-V, apolipoprotein C-II, lipase maturation factor, and related loci can individually or in combination substantially reduce LPL activity, producing a phenotype that resembles classic FCS but is far more common in specialty practice. He has also published work suggesting that patients can carry multiple defects across LPL-related genes, compounding their functional LPL impairment.

Alan Brown, MD, MHA, agrees, citing a case of a patient with type III hyperlipidemia carrying a single APOA5 mutation whose chylomicronemia phenotype was indistinguishable from classic FCS. Across his own practice, patients have sorted into 3 broad groups: those with biallelic pathogenic mutations in one of the 5 canonical LPL-pathway genes; a larger group with clinical FCS and a nonclassic genotype; and a third category likely harboring clusters of smaller SNPs that together depress LPL function enough to produce full chylomicronemia without an identifiable large-gene mutation.

Brown notes that splitting hairs over whether a patient has 'true' FCS versus clinical FCS becomes less meaningful when the phenotype is the same: recurrent pancreatitis, no secondary causes, and no response to conventional therapy.

Babirak brings cohort data to the point. In the first 61 consecutive patients he evaluated with chylomicronemia syndrome, 56 had at least one identifiable genetic variant, and virtually all carried at least one additional metabolic or pharmacologic contributor. Each episode of pancreatitis carries roughly a 6% mortality rate, and the cumulative exocrine and endocrine consequences, including secondary diabetes, chronic pancreatic insufficiency, and hepatic steatosis, can permanently alter a patient's life. Both experts note that cascade genetic testing in families is among the most productive diagnostic moves available.

Discover how heterozygous LPL variants, polygenic contributors, and multifactorial presentations complicate FCS classification and the implications for clinical recognition.

Alan S. Brown, MD MHA FACC FAHA MNLA

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