Prevalence of familial chylomicronemia syndrome in a quaternary care center

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by elevated fasting serum triglycerides (TGs)>750 mg/dl that presents with lipemic blood, eruptive xanthomata, lipemia retinalis, and recurrent pancreatitis.1 The disease is genetic, caused by absence of functional lipoprotein lipase in 80% of cases.2 Classical observational data suggest a 1:1,000,000 prevalence of FCS.3,4 However, this estimate has not been rigorously validated. It is unclear the extent to which this rare disorder is correctly identified and treated in clinical practice. Moreover, data are conflicting on the risk of atherosclerotic cardiovascular disease (ASCVD) with FCS. We aimed to assess the prevalence of FCS at Johns Hopkins Hospital using established clinical diagnostic criteria, and compared rates of atherosclerotic cardiovascular and non-cardiovascular events in FCS and hypertriglyceridemic patients with a secondary cause (secondary hypertriglyceridemia (HTG)). We additionally sought to assess rates of referral to lipid specialists and confirmatory genetic testing among FCS patients. We retrospectively reviewed 1,627,763 patients seen at Johns Hopkins Hospital from 2013–2017. FCS patients were defined according to consensus criteria as those with: (a) at least one fasting TG value > 750 mg/dl, (b) personal history of acute pancreatitis, unexplained/recurrent abdominal pain, and/or family history of HTG, and (c) absence of secondary HTG risk factors.5 Secondary risk factors were defined as: alcoholism, smoking, biliary disease, uncontrolled diabetes (hemoglobin A1c ≥ 10%), hypothyroidism, poor diet, nephrotic syndrome, Cushing’s syndrome, lupus, or concurrent use of HTG-provoking medications. Secondary HTG was defined as those who met FCS criteria but had one or more secondary risk factors at the time of HTG. Two-sample t-tests, Wilcoxon rank-sum tests, and Fisher’s exact tests were used for comparison with significance set at p < 0.05. The study was approved by the Johns Hopkins Institutional Review Board. General population demographics are described in Table 1. A total of 21 FCS and 89 secondary HTG patients were identified. FCS prevalence was 13 in 1,000,000 (95% confidence interval (CI): 8–20). FCS patients were more frequently male (p = 0.006) and were less likely to have hypertension (p = 0.04) (Table 1). The frequencies of hospitalization for recurrent acute pancreatitis (27% vs 48%) and chronic pancreatitis (19% vs 29%) were no different among secondary HTG patients and FCS (all p ≥ 0.11). Secondary HTG patients had more acute coronary events (20% vs 0%; p = 0.02), but frequencies of coronary revascularization (17% vs 0%), thrombotic cerebrovascular accident (6% vs 5%), and peripheral arterial disease (9% vs 0%) did not statistically significantly differ among groups (all p ≥ 0.07). The total number of ASCVD events was one in FCS (95% CI: 0–5) as compared to 43 in secondary HTG patients (95% CI: 33–53). Death was observed in one FCS (5%) and three (3%) secondary HTG patients (p = 0.58). Only 29% of FCS patients were seen by a lipid specialist. Two (10%) FCS patients received confirmatory lipoprotein lipase genetic testing. Baseline demographics at time of diagnosis for familial chylomicronemia syndrome (FCS) vs secondary hypertriglyceridemia (HTG) patients. HbA1c: hemoglobin A1c; IQR: interquartile range; SD: standard deviation; TG: triglyceride. “General population” averages represent medians or means of patients’ HbA1c and lipid values across 2013–2017. “FCS” and “Secondary HTG” averages represent medians or means of individual patients’ HbA1c and lipid values at time of diagnosis, i.e. the time at which they have fasting TG > 750 mg/dl and simultaneously meet clinical criteria for FCS diagnosis (at least one of the following: personal history of acute pancreatitis, unexplained/recurrent abdominal pain, and/or family history of HTG). Baseline demographics at time of diagnosis for familial chylomicronemia syndrome (FCS) vs secondary hypertriglyceridemia (HTG) patients. HbA1c: hemoglobin A1c; IQR: interquartile range; SD: standard deviation; TG: triglyceride. “General population” averages represent medians or means of patients’ HbA1c and lipid values across 2013–2017. “FCS” and “Secondary HTG” averages represent medians or means of individual patients’ HbA1c and lipid values at time of diagnosis, i.e. the time at which they have fasting TG > 750 mg/dl and simultaneously meet clinical criteria for FCS diagnosis (at least one of the following: personal history of acute pancreatitis, unexplained/recurrent abdominal pain, and/or family history of HTG). In the largest retrospective review of its kind, we demonstrate a higher prevalence of FCS than classically described. Although this cohort is not directly representative of the general US population, patients were seen in a wide range of inpatient and outpatient settings and were not typically referred to our institution for HTG. Shah et al. recently proposed that HTG in FCS was associated with significant cardiovascular risk independent of genetic predisposition despite the majority of individuals having low-density lipoprotein cholesterol < 70 mg/dl.6 Our study showed that with the exception of one thrombotic stroke, atherosclerotic cardiovascular events were completely absent in FCS. Given that low-density lipoprotein cholesterol (LDL-C) was similar between groups, atherogenic risk in secondary HTG likely derives from excess of very low-density lipoprotein cholesterol in the setting of a type V dyslipidemia. The absence of ASCVD in FCS is consistent with prior research suggesting that primary chylomicron excess in isolation is not atherogenic.1 Finally, we observed a trend toward more pancreatitis in the FCS group, which is likely due to higher TG levels, serving as a proxy for chylomicron burden. One prior study described a linear relationship between acute pancreatitis risk and TG level, such that pancreatitis risk increased by 4% for every 100 mg/dl increase in TG concentration.7 Increased recognition of FCS may lead to more prompt and aggressive management of these patients. The mainstay of treatment is adoption of an extremely restricted, very-low-fat diet, as well as avoidance of offending medications and alcohol.8 A variety of treatments have been described, such as fibrates, omega-3 fatty acids, niacin, and insulin-sensitizing therapies, however their effectiveness are likely limited by extent of residual lipoprotein lipase activity.9 One promising antisense oligonucleotide to apolipoprotein-C3, volanesorsen, was shown to reduce TG by 77% and possibly reduce pancreatitis admissions,10 however, its approval by the US Food and Drug Administration was originally rejected in 2019 due to concern over its adverse effect of thrombocytopenia. Other medications currently in the pipeline for FCS treatment include lipoprotein lipase modulating proteins such as ANGTL3.9 Limitations include that our study is likely underpowered to assess differences in events between FCS and secondary HTG patients. Study criteria may underestimate prevalence by excluding those without documented pancreatitis, abdominal pain, or family history, in addition to not capturing FCS patients with well-controlled TGs. FCS may be ∼ 10-fold more common than classically estimated in a large hospital system, and is likely underdiagnosed. Our data suggest that FCS is frequently complicated by pancreatitis, but not ASCVD. Increasing efforts should be made toward early identification of FCS and specialist referral for this challenging, highly morbid disease.