Multifactorial Chylomicronemia Syndrome Research Articles

High hsCRP concentration is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). However, the risk of AP is very heterogenous in MCS. Previous studies suggested that inflammation might promote disease progression in hyperTG-induced AP. To determine if low-grade inflammation is associated with AP in MCS. This study included 102 subjects with MCS for which high-sensitivity C-reactive protein (hsCRP) concentration was measured at their first visit at the Montreal Clinical Research Institute. MCS subjects with a previous history of AP had a significant higher hsCRP concentration (4.62 mg/L vs. 2.61 mg/L; p=0.003) and high hsCRP concentration (≥3mg/L) was independently associated with AP prevalence (p<0.05). Up to 64% of the variability in AP prevalence was explained by the maximal TG concentration, hsCRP concentration, the presence of rare variants in TG-related genes, and fructose intake based on a stepwise multivariate regression model (p<0.0001). This retrospective study showed for the first time that hsCRP concentration is strongly associated with AP prevalence in MCS. It also suggests that low-grade inflammation may be a driver of AP in severe hypertriglyceridemia. Prospective studies could help determine the causality of this association and assess whether medication known to reduce low-grade inflammation could help prevent AP in individuals with severe hypertriglyceridemia.

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia

Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40mmol/L (OR 5.33 (1.55-18.36); p=0.008 and OR 5.33 (1.28-22.25); p=0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p=0.07 and OR 11.90 (2.54-55.85); p=0.002) compared to MCS patients with high TG-PRS alone. This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

Pancreatitis polygenic risk score is associated with acute pancreatitis in multifactorial chylomicronemia syndrome

Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of acute pancreatitis (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

Understanding Hypertriglyceridemia: Integrating Genetic Insights.

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.

Determinants of coronary artery calcium score in patients with multifactorial chylomicronemia syndrome

Determinants of coronary artery calcium score in patients with multifactorial chylomicronemia syndrome

A patient with severe multifactorial chylomicronemia syndrome treated with volanesorsen, are these peculiar cases neglected and undertreated?

A patient with severe multifactorial chylomicronemia syndrome treated with volanesorsen, are these peculiar cases neglected and undertreated?

Infantile Hyperchylomicronemia Due to A Novel GPIHBP1 Disease-Causing Variant Presenting with Milky Blood: A Rare Case Report

Background: Familial hyperchylomicronemia is a very rare autosomal recessive disorder and the most severe type of pediatric hyperlipidemia. The purpose of this case report is to enhance clinician's insight on the diagnosis and management plan in the case of infantile hyperchylomicronemia presenting with milky blood. Case: We reported a 2-month-old infant with familial chylomicronemia syndrome. The patient was ‘accidentally’ diagnosed by the observation of milky blood. Exome sequencing revealed a homozygous likely pathogenic GPIHBP1 variant (NM_178172.5:c.193T&gt;C p.(Cys65Arg)) confirming the diagnosis. He was treated with low-fat diet, a formula rich in medium-chain triglycerides and fenofibrates. After 4 days, his serum triglycerides decreased markedly. Fenofibrates were stopped at the age of one year and his serum triglycerides were maintained at low level with dietary measures. No complications occurred during two years follow-up period. Discussion: Clinical manifestations of familial chylomicronemia syndrome start in early life with a very high level of hypertriglyceridemia and with monogenetic etiology, in contrast to multifactorial chylomicronemia syndrome that starts in adulthood, with proposed polygenic etiology. The main treatment of familial chylomicronemia syndrome is dietary fat restriction to less than 15% of the total caloric intake and medium-chain triglycerides which can bypass the chylomicron pathway of fat metabolism. Conclusion: The main challenge in this case was the early diagnosis to protect the patient against serious complications. The mainstay of therapy is low-fat diet and medium-chain triglycerides. This case illustrates the relevance of establishing a timely genetic diagnosis and treatment.

Non-alcoholic fatty liver disease in patients with chylomicronemia syndromes

BackgroundChylomicronemia syndrome is a form of severe hypertriglyceridemia (HTG) caused by the familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS). Non-alcoholic fatty liver disease (NAFLD) has been associated with components of the metabolic syndrome and is more prevalent in subjects with elevated triglycerides. ObjectiveThe primary objective was to compare the prevalence of hepatic steatosis assessed by conventional imaging between HTG groups (FSC, MCS and moderate HTG (mHTG)). The secondary objective was to determine the difference in the prevalence of liver fibrosis. MethodsThis cross-sectional observational study was performed on adult patients from the lipid clinic of the Montreal Clinical Research Institute (IRCM). We retrospectively reviewed the imaging reports available in the patients’ files for signs of NAFLD. We also used the FIB-4 index as a surrogate marker of liver fibrosis. ResultsWe reviewed the medical files of 300 patients; 22 with FCS, 82 with MCS and 196 with mHTG. There was significantly more hepatic steatosis in the MCS group compared to the mHTG and FCS groups (79%, 66% and 43% respectively p=0.02). There was a significantly higher prevalence of subjects within the “unlikely fibrosis” category in the mHTG group (91%) compared to the MCS (84%) and FCS groups (59%), p=0.0004. ConclusionWe found that the prevalence of hepatic steatosis was 3-, 2.5-, and 2-fold higher in MCS, mHTG and FCS patients than in the general population. This suggests that patients with elevated triglycerides, regardless of the underlying etiology, are at higher risk of hepatic steatosis and NAFLD.

Abstract #1402734: Next Generation Sequencing Testing for Genetic Causes of Refractory Hypertriglyceridemia in an Outpatient Endocrine Clinic: A Case Series

Endocrinologists often diagnose and treat patients with Hypertriglyceridemia (HTG), but genetic causes like Familial Chylomicronemia Syndrome (FCS) and Multifactorial Chylomicronemia Syndrome (MCS) can be missed in everyday practice. These are caused by mutations in the Lipoprotein Lipase (LPL) gene or genes required for the LPL activity and present with treatment-refractory elevated fasting Triglycerides (TRGs) and recurrent episodes of abdominal pain and/or acute pancreatitis (AP). By testing patients with refractory HTG for genetic variations linked to these syndromes we aimed to offer timely diagnosis and create more personalized treatment plans. Here, we strive to raise awareness over the importance of genetic testing in preventing HTG-related complications. Using Next Generation Sequencing we tested 7 patients presenting in an outpatient endocrine clinic with fasting TRGs above 500 mg/dl for mutations of 7 genes linked to HTG. None of the patients responded to treatment with at least 3 lipid-lowering drug classes and all reported recurrent abdominal pain, while 3 had history of at least 1 episode of AP. Genetic variants of MCS or FCS were found in 5 patients. Three patients had genotypes consistent with MCS, one being heterozygous for a risk mutation (C.-3A >G) of the Apolipoprotein A-V (APOA5) gene, and 2 heterozygous for a likely pathogenic allele (c.888delA and c.823C >T) of the same gene. Two patients had genotypes consistent with FCS, one compound heterozygous for 2 risk mutations of the APOA5 gene, and the other homozygous for a pathogenic variant (c.111delC) of the same gene. Interestingly, all the discovered mutations affected the APOA5 gene, responsible for enhancing the LPL activity, and none the LPL gene, the most common gene linked to FCS. Regarding treatment, strict low-fat diet lowered TRGs more than escalation of medical therapy in 4 patients. In outpatient endocrine clinics, patients with HTG often have a complicated comorbidity profile, which may lead providers to underestimate the potential genetic cause of HTG. A definitive diagnosis could relieve patients from the psychological burden of uncertainty. The diagnosis of genetic HTG makes a personalized treatment plan focusing on strict low-fat diet imperative in preventing complications. This can also help avoid unnecessary polypharmacy. Moreover, the need for more effective medications for FCS and MCS becomes clear. With new genetic treatments under development, the APOA5 gene could be a potential target. Hence, testing for genetic HTG can qualify patients to participate in relevant clinical trials and can direct the treatment towards these medications once they become available.

Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010–2020: a cross-sectional study

Background and aimFamilial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia.MethodsA cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis.ResultsIn total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected.ConclusionThis study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial (NCT03452228) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg−1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228.

Role of lipoprotein lipase activity measurement in the diagnosis of familial chylomicronemia syndrome

Activity assays for lipoprotein lipase (LPL) are not standardised for use in clinical settings. This study sought to define and validate a cut-off points based on a ROC curve for the diagnosis of patients with familial chylomicronemia syndrome (FCS). We also evaluated the role of LPL activity in a comprehensive FCS diagnostic workflow. A derivation cohort (including an FCS group (n=9), a multifactorial chylomicronemia syndrome (MCS) group (n=11)), and an external validation cohort (including an FCS group (n=5), a MCS group (n=23) and a normo-triglyceridemic (NTG) group (n=14)), were studied. FCS patients were previously diagnosed by the presence of biallelic pathogenic genetic variants in the LPL and GPIHBP1 genes. LPL activity was also measured. Clinical and anthropometric data were recorded, and serum lipids and lipoproteins were measured. Sensitivity, specificity and cut-offs for LPL activity were obtained from a ROC curve and externally validated. All post-heparin plasma LPL activity in the FCS patients were below 25.1 mU/mL, that was cut-off with best performance. There was no overlap in the LPL activity distributions between the FCS and MCS groups, conversely to the FCS and NTG groups. We conclude that, in addition to genetic testing, LPL activity in subjects with severe hypertriglyceridemia is a reliable criterium in the diagnosis of FCS when using a cut-off of 25.1 mU/mL (25% of the mean LPL activity in the validation MCS group). We do not recommend the NTG patient based cut-off values due to low sensitivity.

ODP153 Recurrent hypertriglyceridemia-induced pancreatitis due to multifactorial chylomicronemia syndrome in a patient with ketosis-prone diabetes mellitus

Abstract Background Hypertriglyceridemia-induced pancreatitis is associated with significant morbidity and mortality. The triad of diabetic ketoacidosis (DKA), severe hypertriglyceridemia, and acute pancreatitis have been occasionally described in severely obese patients with type 2 diabetes mellitus (T2DM). However, the occurrence of this triad in newly diagnosed ketosis-prone diabetes mellitus (KPDM) is rarely reported. Herein, we report a long-term follow-up of a Thai man with KPDM complicated with recurrent pancreatitis due to multifactorial chylomicronemia syndrome. Case Description A 33-year-old Thai male patient with a history of insulin-independent diabetes mellitus, recurrent hypertriglyceridemic pancreatitis, and recurrent DKA (three times within the past 5 years) came to our hospital in 2020 for the management of plasma triglyceride levels. At the age of 29 years (BMI 31.2 kg/m2), he experienced the first hypertriglyceridemia-induced pancreatitis (plasma triglyceride 8,189 mg/dL) in association with DKA. After resolution of DKA, insulin therapy was successfully discontinued for 3 years. Then, recurrent hypertriglyceridemic pancreatitis in association with multiple organ failures was developed during travelling to India. After treatment with plasmapheresis and continuous intravenous insulin infusion, he was able to extubate but pulmonary embolism at right pulmonary artery was discovered. Subcutaneous low molecular weight heparin was given for 6 months and then discontinued. The last hypertriglyceridemia-induced pancreatitis attack in association with DKA was aggravated by a high fat buffet meal 1 month prior to our hospital visit. He denied any tobacco, alcohol, or substance use. The patient had no known family medical history of lipid disorders. Further investigations revealed preserved beta-cell function by mixed meal stimulation test and negative pancreatic autoantibodies. Genetic testing showed no mutation in lipoprotein lipase (LPL) and its co-factors. Therefore, multifactorial chylomicronemia syndrome with KPDM was diagnosed. The patient was referred to multidisciplinary team for lifelong weight loss, limiting intake of fat and simple carbohydrates, and adherence to lipid-lowering medications. Subsequent follow-up 2 years later showed no recurrent pancreatitis. Conclusion The triad of acute pancreatitis, severe hypertriglyceridemia and DKA constitutes a unique subgroup of patients which insulin deficiency state is the core defect in association with underlying genetic predisposition. Molecular diagnosis of underlying genetic defect should be pursued to exclude familial chylomicronemia syndrome. In patients with multifactorial chylomicronemia syndrome, long-term management with dietary modifications together with pharmacotherapy remains the cornerstone of successful treatment. Presentation: No date and time listed

Abstract #1183744: The challenge of unresolving chylomicronemia and recurring pancreatitis: Lessons learned on the treatment of severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG) in the chylomicronemia (CM) range is associated with acute pancreatitis. Plasma exchange (PEX) has been used for the treatment of chronic CM in the setting of recurrent pancreatitis. We present a patient with multifactorial CM syndrome and recurrent pancreatitis recently started on biweekly sessions of PEX. We share lessons learned on the management of multifactorial CM syndrome and highlight the potential complications associated with chronic apheresis.

The Evolving Story of Multifactorial Chylomicronemia Syndrome.

Multifactorial chylomicronemia syndrome (MCS or type V hyperlipoproteinemia) is the most frequent cause of severe hypertriglyceridemia and is associated with an increased risk of acute pancreatitis, cardiovascular disease, and non-alcoholic steatohepatitis. The estimated prevalence of MCS in the North American population is 1:600–1:250 and is increasing due to the increasing prevalence of obesity, metabolic syndrome, and type 2 diabetes. Differentiating between familial chylomicronemia syndrome and MCS is crucial due to their very different treatments. In recent years, several cohort studies have helped to differentiate these two conditions, and recent evidence suggests that MCS itself is a heterogeneous condition. This mini-review will summarize recent literature on MCS, with a specific focus on the genetic determinants of the metabolic risk and the latest developments concerning the pharmacological and non-pharmacological treatment options for these patients. Possible research directions in this field will also be discussed.

Both low-fat and low-carbohydrate diets reduce triglyceride concentration in subjects with multifactorial chylomicronemia syndrome: a randomized crossover study

Multifactorial chylomicronemia syndrome (MCS) is a complex disease including a genetic component and the presence of lifestyle-related risk factors. We hypothesized that, in subjects with MCS, there would be a greater decrease in plasma triglycerides (TG) with a low-fat (F) diet than with a low-carbohydrate (C) diet. In secondary analyses, we tested the effect of both diets on TG concentration according to the presence or absence of a rare variant in the LPL gene. This randomized crossover dietary intervention included 12 adult subjects with MCS. Subjects followed 2 isocaloric diets, low-C (C, 35%; F, 45%) and low-F (F, 20%; C, 60%), in random order. Each diet lasted 3 weeks, followed by a 6-hour test meal. Diets were separated by a 2-week washout period. TG concentration in fasting subjects decreased by 55% during low-F diet (P = .002) and by 48% during low-C diet (P = .005). The difference between the 2 diets was not significant. However, we observed a more pronounced decrease in TG concentration (65% ± 17%) with the low-F diet compared with the low-C diet (46% ± 31%) (P=.06) in subjects carrying a rare variant in the LPL gene. This is the first study to show that dietary intervention is effective in MCS subjects. In addition, we highlighted the importance of the genetic profile in the choice of treatment by suggesting that subjects with a rare variant of the LPL gene have a greater reduction of TG concentration with a low-F diet than with a low-C diet.

Recurrent Hypertriglyceridemia-Associated Pancreatitis in a Pregnant Woman Complicated by Severe Socioeconomic Insecurity

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis At 26 weeks gestation, a 24-year-old pregnant woman with type 2 diabetes mellitus (T2DM) and hypertriglyceridemia (HTG) was hospitalized for her second episode of acute pancreatitis (AP) associated with triglycerides (TG) > 4000 mg/dL. Medical therapy including plasma exchange resulted in dramatic improvement of TG, and the remaining hospital course was uneventful. She was discharged with plan for twice weekly plasma exchange. However, she did not have adequate childcare or transportation to enable treatment and the tunneled catheter had to be removed due to infection before she could receive any outpatient plasma exchange. This case highlights potential barriers to management of severe HTG and the need for effective therapy. Objective/Purpose To review a clinical scenario where severe inherited lipid abnormality and socioeconomic distress complicate care. Methods Laboratory testing was performed by University of Pennsylvania Health System Cernmill Laboratory. Results A 24-year-old G6P3 woman at 26 weeks gestation with T2DM presented to the hospital with intractable abdominal pain and was found to have diabetic ketoacidosis (DKA) and severe HTG causing AP (Table 1). Her medical history was notable for one prior episode of AP at age 21, during which she was first diagnosed with HTG and T2DM and treated with gemfibrozil and insulin. Subsequent medical care was disrupted by limited financial resources and housing insecurity. Follow-up lipid testing while on this regimen did not achieve TG less than 1000 mg/dl. She was admitted to the obstetrics unit for intravenous fluids and insulin and kept nill per os (NPO) resulting in resolution of the DKA. She underwent plasma exchange resulting in TG reduction and resolution of abdominal pain and elevated pancreatic enzymes. TG levels rose to >1200 mg/dL two days after plasma exchange despite clear liquid diet. A prolonged discussion about the risk of recurrent AP to her and her pregnancy, the interventions to manage HTG-associated AP, and available resources supported the role of once- or twice-weekly plasma exchange until delivery. Unfortunately, this plan was abandoned one week after discharge from the hospital because of inadequate access to appropriate childcare, transportation costs, and difficulty with safe maintenance of her tunneled IV access catheter. Present therapy includes close monitoring, dietary counseling, and combination of gemfibrozil and high dose omega-3 fatty acid supplementation. Conclusions This case illustrates a treatment dilemma stemming from the intersection of lipid biology, pregnancy, diabetes, and social determinants of health. Our patient has features of familial (FCS) and multifactorial chylomicronemia syndrome (MCS). Proper diagnosis may inform expectations from pharmacotherapy (e.g. gemfibrozil and high dose omega-3 fatty acid supplementation). In this case, the decision was made to initiate twice-weekly plasma exchange until delivery. There are no clinical trials to directly inform clinical decision-making for this rare condition. However, HTG-associated AP during pregnancy is reportedly more severe than non-pregnancy associated AP and intensive treatment is sensible given the expectation of worsening HTG in the last trimester and the high stakes for the patient and fetus. Unfortunately, our patient's socioeconomic barriers did not allow for appropriate treatment with plasma exchange and the social safety net could not solve these problems in the time required. This case serves as a reminder that our patients may face barriers to accessing complex healthcare and further highlights the need for more effective, convenient, and reliable HTG treatments for both FCS and MCS. Nothing to disclose.

Abstract 12054: Evinacumab Reduces Atherogenic Lipids and Apolipoprotein B in Patients With Severe Hypertriglyceridemia

Background: Hypertriglyceridemia (HTG) is the consequence of elevated triglyceride-rich lipoproteins (TGRLs) containing apolipoprotein B (apoB), such as VLDL and chylomicrons. Epidemiological and genetic studies indicate that triglycerides (TGs) and the cholesterol within TGRLs causally contribute to coronary heart disease risk (CHD). Evinacumab (EVIN), an angiopoietin-like 3 inhibitor, lowers TGs by derepressing lipoprotein lipase (LPL) and endothelial lipase activity. In a Phase 2 trial in patients (pts) with severe HTG (sHTG, fasting TGs ≥500 mg/dL), EVIN was previously shown to reduce TGs in patients (pts) without familial chylomicronemia syndrome (FCS) and to be generally well tolerated (NCT03452228). This post-hoc analysis reports further details on the efficacy of EVIN in reducing atherogenic lipids/lipoproteins. Methods: Pts (N=51) were treated and assigned to cohorts based on genotype: Cohort 1 (n=17), FCS pts with bi-allelic loss-of-function (LOF) LPL pathway mutations; Cohort 2 (n=15), multifactorial chylomicronemia syndrome (MCS) pts with heterozygous LOF LPL pathway mutations; Cohort 3 (n=19), MCS pts without LPL pathway mutations. Pts were randomized (2:1) to IV EVIN 15 mg/kg or placebo every 4 weeks over a 12-week double-blind treatment (tx) period (DBTP), followed by a 12-week single-blind tx period where all pts received EVIN. Results: Of 51 pts with sHTG treated in the DBTP, 70.6% were categorized as high cardiovascular risk, and 21.6% had a history of CHD. In non-FCS pts (Cohorts 2 and 3), in addition to reducing TGs, EVIN reduced atherogenic lipids and apolipoproteins at Week (W) 12 compared with baseline (Table), including non-HDL-C, remnant cholesterol, and apoB (including apoB100 and apoB48). Overall, reductions observed at W12 were maintained through W24. Conclusions: In this post-hoc analysis, EVIN reduced atherogenic lipids and apoB, indicating it may have the potential to reduce CHD risk in pts with sHTG without genetic FCS.

Rare Variants in Triglycerides-Related Genes Increase Pancreatitis Risk in Multifactorial Chylomicronemia Syndrome.

Severe hypertriglyceridemia (fasting triglycerides [TG] concentration ≥10 mmol/L) can be caused by multifactorial chylomicronemia syndrome (MCS) or familial chylomicronemia syndrome (FCS). Both conditions are associated with an increased risk of acute pancreatitis. The clinical differences between MCS patients with or without a rare variant in TG-related genes have never been studied. To compare the clinical and biochemical characteristics of FCS, positive-MCS patients, and negative-MCS patients, as well as to investigate the predictors of acute pancreatitis in MCS patients. All patients referred at the clinic for severe hypertriglyceridemia underwent genetic testing for the 5 canonical genes involved in TG metabolism (LPL, APOC2, GPIHBP1, APOA5, and LMF1) using next-generation sequencing. A total of 53 variant negative-MCS, 22 variant positive-MCS and 28 FCS subjects were included in this retrospective cross-sectional study. A significant difference was observed in the prevalence of pancreatitis (9%, 41%, and 61%) and multiple pancreatitis (6%, 23%, and 46%) in the negative-MCS, the positive-MCS, and the FCS groups, respectively (P < 0.0001). Predictors of pancreatitis among MCS subjects included the presence of a rare variant, lower apolipoprotein B, as well as higher gamma-glutamyl transferase, maximal TG value, and fructose consumption. We observed that the MCS individuals who carried a rare variant have an intermediate phenotype between FCS and negative-MCS subjects. Since novel molecules such as the antisense oligonucleotide against APOC3 mRNA showed high efficacy in reducing TG levels in patients with multifactorial chylomicronemia, identification of higher-risk MCS patients who would benefit from additional treatment is essential.

Clinical differentiation and mutation spectrum of chylomicronemia patients in a German outpatient clinic

Background and Aims: Severe hypertriglyceridemia (HTG, triglyceride (TG) levels >885 mg/dl) has a prevalence of 1:600. While most cases are multifactorial (multifactorial chylomicronemia syndrome, MCS), a small subset of patients do have the monogenetic familial chylomicronemia syndrome (FCS). So far it remains a challenge to distinguish both forms clinically. Our aim was to characterize our patient's phenotype with respect to MCS and FCS as well as to apply the FCS-score proposed by Moulin and colleagues.