Familial Hypertriglyceridemia Research Articles

#2107 Therapeutic apheresis for the management of lipid disorders: a case series

Abstract Background and Aims Hypertriglyceridemia (HTG) is defined as the plasmatic concentration of triglycerides above 150 mg/dl. With a current prevalence ranging from 15% to 20% in clinical practice, it's a prevalent condition that´s increasing alongside other cardiovascular risk factors such as diabetes mellitus, obesity and hypertension. In most patients HTG is asymptomatic, except in certain circumstances such as hereditary HTG, which can present with skin lesions such as eruptive xanthomas and xanthelasmas. Another exception is severe HTG, which can manifest with pancreatitis. Pharmacological treatment for HTG is typically initiated when serum triglyceride levels exceed 885 mg/dl or when patients with a previous episode of pancreatitis. However, in cases of severe HTG (triglycerides > 1000 mg/dl), conventional pharmacological therapies become less effective. Therefore, alternative therapeutic interventions, such as apheresis, become increasingly relevant for the management of severe HTG. Current guidelines from the American Society of Apheresis (ASFA) consider the use of therapeutic plasmapheresis in patients with acute pancreatitis secondary to severe hypertriglyceridemia as a category III/grade 1C recommendation and that in most cases it is an adjunct to medical treatment. Case series Below, we describe a series of cases in which we used this technique to control metabolic in our center during the last year. Case 1 A 30-year-old man with familial primary hypertriglyceridemia, schizophrenia, and sporadic drinking, was admitted from the Emergency Department with a 24h long severe abdominal pain with difficult management and vomiting. After complementary analysis, acute edematous pancreatitis without necrosis was diagnosed. Given the analytical values (Table 1), therapeutic plasmapheresis was decided, with a plasma volume of 3.5 liters calculated with the patient's weight and hematocrit and using albumin as the replacement fluid. As a complication, and despite administration of heparin, the filter required replacement halfway through the session due to problems with transmembrane pressure. Two sessions were completed on consecutive days until clinical and analytical control of triglycerides was achieved. Case 2 A 55-year-old man with a history of mild dyslipidemia controlled with diet and hypertension, was admitted from the Emergency Department with abdominal pain of 12 hours duration. After completing the study and diagnosis of acute pancreatitis of probable HTG origin, a plasmapheresis session was completed with a volume of 3 liters, albumin replacement fluid and heparinization during the technique, without complications, along with triglyceride control after the procedure maintaining medical treatment. Case 3 A 62-year-old man with a history of familial HTG, bronchial hyperreactivity, and occasional drinking, was admitted with abdominal pain of 72 hours duration accompanied by nausea and vomiting. Complementary studies confirmed acute severe pancreatitis with hemodynamic and respiratory failure. Given the analytical findings, a plasmapheresis session was performed with a volume of 2.5 liters per weight and hematocrit, with albumin replacement and heparin as per protocol. Subsequent HTG control with medical treatment was achieved without the need for further apheresis sessions. Conclusion Cardiovascular disease is responsible for the death of more than 4 million people in Europe each year, 2.2 million women (55%) and 1.8 million men (45%). Lipoprotein apheresis has preventive effects on the progression of atherosclerosis in addition to being an effective technique for reducing LDL, so its indication in groups of patients with severe and primarily familial hypercholesterolemia is well established. In our center, the recent start of the control of apheresis techniques from Nephrology in metabolic diseases, although still with limited experience and a limited number of patients, may constitute a new field of work in the specialty itself and collaboration with the different hospital specialties to improve the prevention, control, and treatment of patients with a high cardiovascular risk.

Wet-Cupping's Impact on Pancreatitis Induced by Hypertriglyceridemia

Familial hypertriglyceridemia is a genetic disorder marked by excessive production of very low-density lipoproteins, resulting in elevated serum triglyceride levels. This can lead to various medical conditions, including acute pancreatitis. In cases of recurrence, it may progress to chronic pancreatitis. Cupping therapy, a traditional treatment practiced in numerous cultures worldwide, is utilized to address various medical conditions. This case report presents a 34-year-old male diagnosed with familial hypertriglyceridemia, subsequently developing chronic pancreatitis. During his last presentation with acute-on-chronic pancreatitis, his lipid profile revealed a notable reduction in serum triglycerides. Interestingly, this reduction coincided with the introduction of cupping therapy into his treatment regimen. Remarkably, following the initiation of cupping therapy, his hospital admissions for acute pancreatitis notably decreased. This case report highlights the potential impact of cupping therapy on familial hypertriglyceridemia, potentially mitigating the risk of acute pancreatitis.
 Keywords: Hyperlipidemia; Hypertriglyceridemia; Pancreatitis.

Heparin-Mediated Extracorporeal Low-Density Lipoprotein Precipitation Apheresis for Treating Peripheral Arterial Disease in Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD), particularly those with end-stage renal disease (ESRD), have a high prevalence of cardiovascular disease and peripheral arterial disease (PAD). Medical treatment is mainly based on risk factor management, and the surgical approach remains the gold standard treatment in specific conditions. Heparin-mediated extracorporeal low-density lipoprotein precipitation (H.E.L.P.) apheresis is effective in reducing circulating lipoprotein, fibrinogen, inflammatory mediators and procoagulant factors, thereby reducing cardiovascular risk in patients with familial hypercholesterolemia and hypertriglyceridemia. These activities may be effective in reducing symptoms and ischemic vascular lesions even in patients with severe PAD. We reported the application of a treatment protocol with H.E.L.P. apheresis in an ESRD patient with severe PAD without clinical improvement after severe revascularization who was not suitable for further surgical approaches, despite normal LDL cholesterol and lipoprotein (a). The H.E.L.P. protocol was characterized by an intensive first phase with weekly treatments followed by a single session every 10-15 days for 6 months of treatment. The overall clinical condition, foot lesions and walking distance improved significantly after the first 2 months of treatment, and foot amputation was avoided. Here, we review the main pathogenetic mechanisms through which LDL apheresis improves microcirculation and clinical outcomes. Its wider application may represent an optimal therapeutic option for patients unresponsive to standard treatment.

FRI089 Massive Hypertriglyceridemia? Think Oral Contraceptive Pills!

Abstract Disclosure: I. Ali: None. M. Hamdi: None. Introduction: Oral contraceptive pills (OCPs) are common cause of Hypertriglyceridemia (TG) that should be recognized early by clinicians. Concern is raised regarding pursing further genetic test for Familial hypertriglyceridemia for female who developed massive hyper triglyceridemic after starting hormonal therapy. Case: A 37-year-old female patient with history of prediabetes with A1c of 5.7% and one attack of pancreatitis. Normal BMI, No regular medications, negative family history for lipid disorder. Rare social intake of alcohol. Routine annual lab showed triglycerides level of 164 in 2016, otherwise normal biochemical evaluation. No treatment pursued. Later She was started on OCPs (Kariva 0.15-0.02 mg) for contraception. Late 2019, blood work-up showed cholesterol level of 979, TG of 3170 and HDL level of 22. She was started on a statin therapy and fenofibrates beside stopping OCP, she maintained normal lipid profile while being off OCPs, until 2022 when she restarted an OCPs (Lo Loestrin 1mg-10 mcg) for 2 months that resulted in elevated cholesterol level of 1222, triglycerides of 5177 and HDL of 10.OCP was stopped, lipids level trended down with cholesterol of 961, triglycerides of 2005 and HDL of 22 then normalized after 2 months. Patient did not have any clinical symptom or complain. Discussion: High triglyceride concentration is an independent predictor of coronary heart disease and ischemic stroke. Many patients with triglycerides >1000 mg/dl have familial hypertriglyceridemia with superimposed additional exogenous factors which further raise triglyceride concentrations like exogenous estrogens, SERMs, hyperestrogenemia of pregnancy, poorly controlled diabetes mellitus, hypothyroidism, alcohol excess, exogenous corticosteroids, and drugs including isotretinoin and protease inhibitors. OCP induced hypertriglyceridemia occurs due to estrogen’s action in decreasing hepatic triglyceride lipase and lipoprotein lipase activity. This causes an overall increase in low and intermediate-density triglycerides and cholesterol that can increase free fatty acids to toxic level. The marked increase of TG and cholesterol in this patient while being on OCP is unusual and strongly indicate underlying familial hypertriglyceridemia exacerbated by starting OCP. Further genetic work up is being done. As OCP or other estrogen therapy are frequently given unwittingly to women with preexisting hypertriglyceridemia that lead to severe clinical consequences. Estrogen containing medication should not be considered if fasting triglyceride is above 500 mg/dl. In women on hormonal treatment with treatment-resistant hypertriglyceridemia, the likelihood that the hormonal treatment is nullifying drug efficacy is high so it should be stopped for a short trial while continuing modifying triglyceride-lowering medications. Presentation: Friday, June 16, 2023

FRI402 “An Unusual Presentation Of Polycystic Ovary Syndrome” - Isolated DHEA-S Elevation In A Patient With Difficulty Conceiving And Recent Onset of Hirsutism

Abstract Disclosure: C. Musurakis: None. J.L. Gilden: None. Background: Isolated DHEA-S levels and worsening hirsutism often prompt the clinician to investigate more serious causes for the elevation, such as an adrenal mass. Clinical Case: A 29-year-old female G0P0 with Norwegian and English heritage and familial hypertriglyceridemia, was referred for elevated DHEA-S levels, and difficulty conceiving for past three years. She had hirsutism of face, chest, and abdomen, worsening over the last two years. Acne had also progressively worsened to cystic type. Menarche was at age 12, and menses were regular. She had never used contraception. Medications: docosahexanoic acid, eicosapentanoic acid, topical azelaic acid, benzoyl peroxide, clindamycin, pantoprazole, prenatal vitamins, and cholecalciferol. There was a family history of acne, but not for hirsutism or menstrual irregularities. Vitals: BP 137/73, HR 81, Ht 165.10 cm, Wt 86.18 Kg, BMI 31.68. Ferriman-Gallwey score was 10 with normal genitalia. Labs (luteal phase): DHEA-S 756 mcg/dL with repeat of 596 mcg/dl(n=35-430), total testosterone 25 ng/dL(n=2-45), free testosterone 4.3 pg/mL(n=0.1-6.4), prolactin 6.6 ng/mL(n=2.2-30.3), LH 5.1 mIU/mL(n=0.6-16.6), FSH 4.7 mIU/mL(n=1.7-12.9), 17-OH progesterone 74 ng/dL(n=139-431), androstenedione 163 ng/dL(n=73-184), estradiol 59.79 pg/mL(n=55.8-214.2), AMH 1.38 ng/mL(n=0.69-13.39), midnight salivary cortisol <0.03 and 0.05 mcg/dL(n<5), IGF-1 258 ng/mL(n=63-373), ACTH 31 pg/mL(n=0-47), AM cortisol 12.58 ug/dL(n=5.3-22.5), TSH 1.27 uIU/mL(n=0.358-3.74), Free T4 0.88 ng/dL (n=0.76-1.46), peroxidase antibodies 49.8 U/m (n=0-60), thyroglobulin antibodies <15(n=0-60), HbA1c 5.5% (n<=5.6%), 25-OH vitamin D 42.7 ng/mL(n=30-100) and negative pregnancy urine test. US pelvis: small follicles in ovaries and normal size. MRI abdomen w/wo contrast: normal bilateral adrenal glands. Cosyntropin stimulation test: baseline cortisol 15.03 ug/dL,17-OH progesterone 168 ng/dL. 30 mins: Cortisol 30.39ug/dL(n>18),17-OH progesterone 130ng/dL(n<200). 60 mins: cortisol 38.95ug/dL(n>18), 17-OH progesterone 153ng/dL(n<200). Non-Classical Congenital Adrenal Hyperplasia was excluded. Polycystic Ovary Syndrome (PCOS) was diagnosed based on clinical and biochemical hyperandrogenism, lack of adrenal mass, and clinical signs of anovulation. Conclusion: As reported by Carmina et al, few patients with PCOS exhibit isolated increase of serum DHEA-S. It is important to recognize that non-classic forms of PCOS (normal ovaries or normal ovulatory cycles) can present with a higher prevalence of adrenal hyperandrogenism than the common classical forms of PCOS. Reference: Carmina E, Longo RA. Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years. Cells. 2022 Oct 17;11(20):3255. doi: 10.3390/cells11203255. PMID: 36291122; PMCID: PMC9601254. Presentation: Friday, June 16, 2023

SAT401 The Aftermath Of Pueraria mirifica: A Case Of Hypertriglyceridemia And Necrotizing Pancreatitis In A Non-binary Individual With Surreptitious Use Of Oral Estrogenic Compounds

Abstract Disclosure: S. Tobolsky: None. F.J. Hayes: None. J. Lo: None. Background Prescription of gender-affirming hormone therapy (GAHT) has become an increasingly prevalent aspect of endocrine care meriting greater attention from our specialty. We report a case where surreptitious use of an unregulated compound with estrogenic activity in a patient with gender dysphoria resulted in severe hypertriglyceridemia and necrotizing pancreatitis. The compound, Pueraria mirifica, is readily available for purchase online. CaseThe patient is a 26yo non-binary individual assigned male at birth who presented to the ED with 1.5 days of abdominal pain and vomiting. CT abdomen showed acute necrotizing pancreatitis. On arrival, serum triglycerides 2,559 mg/dl (nl 40-150 mg/dL) and lipase 481U/L (nl 13-60 U/l). The patient reported no alcohol use. Family history of unspecified hyperlipidemia in father. Patient was admitted, made NPO, and started on insulin/dextrose infusions, continued until serum triglycerides dropped to <1,000 mg/dL. Fenofibrate started and extensive nutritional counseling on low-carbohydrate and low-fat diet given. In absence of clear etiology for hypertriglyceridemia, patient was questioned carefully on supplement use and revealed they took 2 tablets of Pueraria mirifica daily with intent of transitioning without medical guidance given prior negative encounters with healthcare. Patient discharged on fenofibrate 200 mg, atorvastatin 20 mg and omega-3 acid ethyl esters 2 g BID, with plan for endocrinology follow-up for initiation of medically supervised GAHT. At follow-up on this regimen, LDL was 79 mg/dL and triglycerides 160 mg/dL. Goals of transition were discussed with the patient as was importance of avoiding oral estrogens, prescribed or over-the-counter. Given patient’s desire for partial transition, low dose transdermal estradiol 0.05 mg patch and spironolactone 50mg BID started. On above regimen, estradiol was 179 pg/mL and total testosterone suppressed at 72 ng/dL. The patient’s triglycerides remained <150 mg/dL with no further complications. ConclusionThis case highlights a potentially fatal complication of hormone use in a transgender individual with likely underlying familial hypertriglyceridemia. It also illustrates how distrust of the medical system led to surreptitious hormone use and emphasizes the need to create a safe, welcoming environment for individuals with gender dysphoria. Finally, it emphasizes the need to interrogate possible surreptitious hormone use in patients with unusual presentations and for endocrinologists to be aware of the need to avoid oral estrogen use in patients with hypertriglyceridemia. Presentation: Saturday, June 17, 2023

Serum α1-Proteinase Inhibitor, Calprotectin, and S100A12 Concentrations in the Characterization of Pancreatitis in Dogs.

Miniature Schnauzers are predisposed to develop pancreatitis, with familial hypertriglyceridemia (HTG) described as a potential risk factor. Diagnosing pancreatitis in dogs is based on the integration of serum canine-specific pancreatic lipase (cPLI) concentration, clinical presentation, and diagnostic imaging findings. However, markers of systemic inflammation and antiprotease activity have not been extensively investigated in the characterization and prognostication of pancreatitis in dogs. Serum concentrations of alpha1-proteinase inhibitor (α1PI; as a marker of systemic antiprotease response) and calprotectin and S100A12 (as markers of systemic inflammation) were measured in serum samples from 35 Miniature Schnauzers diagnosed with pancreatitis (serum cPLI concentration >400 μg/L, clinical signs, abdominal imaging findings). These markers were evaluated for possible associations with patient characteristics, clinical presentation, risk factors for pancreatitis, and outcome. The study showed that biomarkers of systemic inflammation and antiprotease activity are commonly increased in Miniature Schnauzers with pancreatitis. Whereas serum calprotectin and S100A12 concentrations were found to have limited utility in differentiating pancreatitis presentations, serum α1PI concentrations and potentially also the serum calprotectin-to-S100A12 ratio might be non-invasive surrogate markers of disease severity in dogs with pancreatitis.

Primary Chylomicronemia in Patients with Severe Familial Hypertriglyceridemia Responds to Long-Term Treatment with (n-3) Fatty Acids

Because it disturbs microcirculation, chylomicronemia can cause severe clinical complications such as acute pancreatitis. Dietary measures are very important in the prevention and treatment of this condition. Dietary supplementation with (n-3) fatty acids has been shown to be of benefit in short-term treatment of chylomicronemia. To evaluate the long-term efficacy of (n-3) fatty acids we added 2.16 or 4.32 g/d (for 3 mo) and 3.24 g/d (for a further 8 mo after 1 mo of no treatment (n-3) fatty acids to the diet of eight patients with primary chylomicronemia. Serum triglycerides decreased significantly from 15.0 ± 2.5 to 9.9 ± 2.8 mmol/L (P < 0.01) after 11 mo of treatment, and VLDL triglycerides decreased from 12.3 ± 2.8 to 9.0 ± 2.4 mmol/L (P < 0.01), resulting in a significant decrease of plasma viscosity from 1.56 ± 0.17 mPa·s to 1.47 ± 0.12 mPa·s (P < 0.01). Total cholesterol, HDL and LDL cholesterol as well as lipoprotein (a) and fibrinogen concentrations were not affected by fish oil treatment. The presence of chylomicrons and chylomicron remnants (apolipoprotein B 48 concentration in the lipoprotein fraction with a density lower than 1.006 kg/L) was significantly reduced from 4.82 ± 1.08 to 1.06 ± 0.38 mg/L (P < 0.01). Body weight increased significantly from 71.0 ± 4.6 kg to 75.2 ± 5.3 kg after 11 mo of treatment with (n-3) fatty acids. These data indicate that despite an increase in body weight, long-term supplementation of a diet with (n-3) fatty acids results in a persistent decrease of serum triglyceride concentrations, a pronounced reduction in the number of chylomicrons present in the fasting state, and an improvement in plasma viscosity.

Monoclonal Antibodies, Gene Silencing and Gene Editing (CRISPR) Therapies for the Treatment of Hyperlipidemia-The Future Is Here.

Hyperlipidemia is a significant risk factor for atherosclerotic cardiovascular disease. Undertreatment of elevated lipids persists despite existing therapies. Here, we provide an update on monoclonal antibodies, gene silencing therapies, and gene editing techniques for the management of hyperlipidemia. The current era of cutting-edge pharmaceuticals targeting low density lipoprotein cholesterol, PCSK9, lipoprotein (a), angiopoietin-like 3, and apolipoprotein C3 are reviewed. We outline what is known, studies in progress, and futuristic goals. This review of available and upcoming biotechnological lipid therapies is presented for clinicians managing patients with familial hyperlipidemia, statin intolerance, hypertriglyceridemia, or elevated lipoprotein (a) levels.

Association between atherogenic index of plasma and colorectal neoplasms in patients with hypertension.

Association between atherogenic index of plasma and colorectal neoplasms in patients with hypertension.

Genetic spectrum of familial hypertriglyceridemia from the southeastern region of Turkey

Genetic spectrum of familial hypertriglyceridemia from the southeastern region of Turkey

ODP197 Familial Hypertriglyceridemia Initially Presenting with Hypertriglyceridemia-induced Pancreatitis: A Case Report

Abstract Case Presentation A 28 year old male with a past medical history of diabetes mellitus type 2 (T2DM) and hypertension presented to the emergency room with acute onset, progressive epigastric pain associated with nausea. The pain suddenly started earlier that day after a large meal. He denied alcohol use. He was previously on insulin Glargine 55 units nightly but was not using it for several months. Vitals signs were within normal limits, BMI was 38.5 kg/m 2 . Physical examination revealed marked epigastric tenderness and multiple yellow papules on the abdomen and extensor surfaces of extremities. Lab findings revealed WBC 14.3 k/mm cu, lipase 437 IU/L, triglycerides greater than 3000 mg/dl with VLDL greater than 3000 mg/dl. Computerized tomography of the abdomen was consistent with acute pancreatitis. He was diagnosed with familial hypertriglyceridemia presenting with hypertriglyceridemia-induced pancreatitis and was admitted to the intensive care unit (ICU). Treatment with regular insulin infusion was started. On day 3, triglyceride levels decreased to 543 mg/dl and insulin infusion was stopped. He reported symptomatic improvement and was able to tolerate oral diet. He was counseled on significance of lifestyle modifications and medication compliance and was discharged on Niacin, Omega 3, Fenofibrate, Ezetimibe, and Pravastatin with plans to follow up with an Endocrinologist. Discussion This case of a young male presenting with hypertriglyceridemia-induced pancreatitis due to underlying familial hypertriglyceridemia emphasizes the significance of comprehensive history taking and work up for patients initially presenting to the clinic with risk factors such as obesity and insulin resistance. Our patient classically had a history of T2DM, and as cardiovascular complications are the leading cause of mortality in diabetic patients, screening for and managing dyslipidemia is pivotal. Eruptive xanthomas are erythematous-yellow papules typically located on extensor surfaces which appear when triglyceride levels exceed 1500-2000 mg/dl. This characteristic skin finding led to a prompt suspicion for familial hypertriglyceridemia in our patient. Our patient was stabilized in the ICU and subsequently discharged on multiple oral agents. The current consensus is that single statin therapy is not recommended; however, further research is indicated to specify the optimal combination of triglyceride lowering agents based on the severity of hypertriglyceridemia. Presentation: No date and time listed

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review.

Simple SummaryMetabolic disorders (MD) are a challenge to healthcare systems; the emergence of the modern socio-economic system has led to a profound change in lifestyles in terms of dietary habits, exercise regimens, and behavior, all of which complement the genetic factors associated with MD. Diabetes Mellitus and Familial hypercholesterolemia are two of the 14 most widely researched MD, as they pose the greatest challenge to the public healthcare system and have an impact on productivity and the economy. Research findings have led to the development of new therapeutic molecules for the mitigation of MD as well as the invention of experimental strategies, which target the genes themselves via gene editing and RNA interference. Although these approaches may herald the emergence of a new toolbox to treat MD, the current therapeutic approaches still heavily depend on substrate reduction, dietary restrictions based on genetic factors, exercise, and the maintenance of good mental health. The development of orphan drugs for the less common MD such as Krabbe, Farber, Fabry, and Gaucher diseases, remains in its infancy, owing to the lack of investment in research and development, and this has driven the development of personalized therapeutics based on gene silencing and related technologies.Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors associated with metabolic disorders (MD) and led to interventions that target the underlying genetic causes as well as lifestyle changes and dietary regulation. The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), Niemann-Pick disease, Phenylketonuria (PKU), Porphyria, Tay-Sachs disease, Wilson’s disease, Familial hypertriglyceridemia (F-HTG) and Galactosemia based on genome wide association studies, epigenetic factors, transcript regulation, post-translational genetic modifications and biomarker discovery through metabolomic studies. We will delve into the current approaches being undertaken to analyze metadata using bioinformatic approaches and the emerging interventions using genome editing platforms as applied to animal models.

Severe Hypertriglyceridemia as a Cause of Arterial Thrombosis with Peripheral Embolic Complications.

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Extensive evidence exists in support of a causal association of elevated triglyceride-rich lipoprotein (TRL) levels with the risk of atherosclerosis progression. Hypertriglyceridemia has been established as a risk factor for venous thrombosis, including a 2- fold increase in the risk of venous thrombosis in postmenopausal women. However, there is limited data on the role of hypertriglyceridemia in the arterial thrombosis. Objective/Purpose Not Applicable. Methods Case description: A 51-year-old white female with hypertension and type 2 diabetes (hemoglobin A1C, 7.4%) was transferred for further management of newly diagnosed bilateral renal and splenic infarcts. No risky habits were elicited except for the use of combined hormonal contraceptives over the past two years to control menorrhagia. Family history was significant for hypertriglyceridemia. Her physical exam was unremarkable. Testing for COVID-19 was negative. An extensive hypercoagulable and autoimmune work-up was unremarkable. Fasting lipid profile was significant for elevated levels of triglycerides, 1,274 mg/dL (replicated on two separate occasions), very low-density lipoprotein-cholesterol, 255 mg/dL, and non-high-density lipoprotein-cholesterol, 214 mg/dL, directly measured low-density lipoprotein cholesterol, 39 mg/dL and lipoprotein(a), 6 mg/dL. There was no structural pathology on the echocardiogram, including no interatrial shunt or intracardiac thrombus. Her whole-body computed tomography angiography revealed a focal calcified protruding thrombus in the distal thoracic aorta. No significant plaque was seen elsewhere in the aorta. Results Decision-making. The posterior thrombus in the distal thoracic and proximal abdominal aorta was determined as a culprit for the visceral organ infarcts. Over the course of the hospital stay her abdominal pain gradually resolved. Treatment with low dose aspirin and therapeutic dose of low-molecular weight heparin was initiated followed by apixaban and aspirin on discharge. She was started on atorvastatin 40 mg, fenofibrate 145 mg, icosapent ethyl 4 g, resulting in a 70% reduction in the triglycerides levels (306 mg/dL). In 3 months, her repeat CT angiography showed significant resolution of the aortic atherothrombosis with no signs of aortic wall inflammation. At the 6-month follow-up visit she was switched to dual antiplatelet therapy with a plan to repeat imaging in 6 months. Conclusions This case illustrates challenges in managing patients with arterial thrombosis in the setting of familial hypertriglyceridemia. Apart from severely elevated triglycerides no other etiology was evident. We propose further investigation of the prothrombotic properties of TRL and the role of targeted triglyceride-lowering therapies on atherothrombotic outcomes. Nothing to disclose.

Clinical features and functions of a novel Lpl mutation C.986A>C (p.Y329S) in patient with hypertriglyceridemia

ObjectiveTo investigate and assess the clinical features and functions of a new lipoprotein lipase (Lpl) gene mutation c.986A>C (p.Y329S) found in hypertriglyceridemia(HTG) patients from a Chinese family. MethodsFive members of a family with the proband were diagnosed with HTG were investigated, and fasting peripheral blood was collected . The plasma was then used to measure triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein cholesterol (HDL-C), free fatty acids (FFA), and glucose tolerance. Following that, genomic deoxyribonucleic acid (DNA) was extracted from whole-blood samples using the QIAamp whole-blood DNA kit, and the coding exon regions and flanking regions of 95 dyslipidemia-related genes were captured using GenCap liquid-phase target gene capture technology. The activity of LPL and its mutation were then determined using cell assays, and the newly discovered LPL mutant was functionally analyzed. The binding site of fenofibrate and LPL, as well as the mutation, were subjected to predictive analysis. ResultsThe LPL gene's c.986A>C (p.Y329S) heterozygous mutation was discovered, and patients with the mutation had the typical phenotype of LPL deficiency and weakened LPL activity. Furthermore, this mutant has been treated with fenofibrate, and its triglyceride level is perfectly controlled and stable. The prediction analysis of the fenofibrate and LPL binding sites reveals that the wild-type system, Phe378 contributes most to the binding energy of fenofibrate. In the mutant system, Tyr394, which contributes the most to the binding energy of fenofibrate, the contribution of S329 is greater than that of Y329 (0.9∼0.7 kal/mol) . After Y329 is mutated, the hydrogen bond data of fenofibrate and LPL will also increase to quote H-bond diagrams. ConclusionsA heterozygous mutation c.986A>C (p.Y329S) in exon 6 of Lpl gene occurs in the proband with familial HTG. Lpl c.986A>C (p.Y329S) mutation weakens the activity of the LPL, which may be the pathogenic mutation of HTG. In addition, The proband has been treated with fenofibrate and the triglyceride level is ideally controlled and stable. The prediction analysis of the fenofibrate and LPL binding site shows that the wild-type system, Phe378 contributes most to the binding energy of fenofibrate. In the mutant system, Tyr394, which contributes the most to the binding energy of fenofibrate, the contribution of S329 is greater than that of Y329 (0.9∼0.7 kal/mol). After Y329 is mutated, the hydrogen bond data of fenofibrate and LPL will also increase, which may be one of the reasons why the mutation has no effect on the therapeutic effect of fenofibrate.

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman.

Familial hypertriglyceridemia (F-HTG) is an autosomal disorder that causes severe elevation of serum triglyceride levels. It is caused by genetic alterations in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. The mutation spectrum of F-HTG in Arabic populations is limited. Here, we report the genetic spectrum of six families of F-HTG of Arab ancestry in Oman. Methods: six Omani families affected with triglyceride levels >11.2 mmol/L were included in this study. Ampli-Seq sequencing of the selected gene panels was performed. Whole-exome sequencing and copy number variant analysis were also performed in cases with negative exome results. Three novel pathogenic missense variants in the LPL gene were identified, p.M328T, p.H229L, and p.S286G, along with a novel splice variant c.1322+15T > G. The LPL p.H229L variant existed in double heterozygous mutation with the APOA5 gene p.V153M variant. One family had a homozygous mutation in the LMF1 gene (c.G107A; p.G36D) and a heterozygous mutation in the LPL gene (c.G106A; p.D36N). All affected subjects did not have a serum deficiency of LPL protein. Genetic analysis in one family did not show any pathogenic variants even after whole-exome sequencing. These novel LPL and APOA5 mutations are not reported in other ethnic groups. This suggests that patients with F-HTG in Oman have a founder effect and are genetically unique. This warrants further analysis of patients of F-HTG in the Middle East for preventative and counseling purposes to limit the spread of the disease in a population of high consanguinity.

A Heterozygous LMF1 Gene Mutation (c.1523C>T), Combined With an LPL Gene Mutation (c.590G>A), Aggravates the Clinical Symptoms in Hypertriglyceridemia.

Hypertriglyceridemia is an important contributor to atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Familial hypertriglyceridemia is often caused by mutations in genes involved in triglyceride metabolism. Here, we investigated the disease-causing gene mutations in a Chinese family with hypertriglyceridemia and assessed the functional significance in vitro. Whole-exome sequencing (WES) was performed revealing that the severe hypertriglyceridemic proband carried a missense mutation (c.590G > A) in exon 5 of the LPL gene, as well as a missense mutation (c.1523C > T) in exon 10 of the LMF1 gene. Conservation analysis by Polyphen-2 showed that the 508 locus in the LMF1 protein and 197 locus in the LPL protein were highly conserved between different species. I-TASSER analysis indicated that the LMF1 c.1523C > T mutation and the LPL c.590G > A mutation changed the tertiary structure of the protein. A decrease in mRNA and protein expression was observed in 293T cells transfected with plasmids carrying the LMF1 c.1523C > T mutation. Subcellular localization showed that both wild-type (WT) and mutant LMF1 protein were localized at the cell cytoplasm. In the cell medium and cell lysates, these LMF1 and LPL gene mutations both caused a decreased LPL mass. Moreover, the combination of LMF1 and LPL gene mutations significantly decreased LPL levels compared to their individual effects on the LPL concentration. Both the clinical and in vitro data suggest that severe hypertriglyceridemia was of digenic origin caused by LMF1 and LPL mutation double heterozygosity in this patient.

Cholesterol Lowering Biotechnological Strategies: From Monoclonal Antibodies to Antisense Therapies. A Pre-Clinical Perspective Review.

In recent years, the increase in available genetic information and a better understanding of the genetic bases of dyslipidemias has led to the identification of potential new avenues for therapies. Additionally, the development of new technologies has presented the key for developing novel therapeutic strategies targeting not only proteins (e.g., the monoclonal antibodies and vaccines) but also the transcripts (from antisense oligonucleotides (ASOs) to small interfering RNAs) or the genomic sequence (gene therapies). These pharmacological advances have led to successful therapeutic improvements, particularly in the cardiovascular arena because we are now able to treat rare, genetically driven, and previously untreatable conditions (e.g, familial hypertriglyceridemia or hyperchylomicronemia). In this review, the pre-clinical pharmacological development of the major biotechnological cholesterol lowering advances were discussed, describing facts, gaps, potential future steps forward, and therapeutic opportunities.

Colon cancer in a 12-year-old girl with hypertriglyceridemia

Colorectal cancer is usually considered a disease of the elderly; however, in a small fraction of patients (2%-3% of all affected individuals), colorectal malignancies may develop earlier. The reasons whereby some individuals develop colorectal cancer at a young age are poorly understood. In a 12-year-old girl, a malignancy was diagnosed in the ascending colon. There was no familial history of Lynch syndrome or familial adenomatous polyposis. The metabolic profile of the patient revealed hypertriglyceridemia and low high-density lipoprotein cholesterol levels at nine years, then diagnosed as familial hypertriglyceridemia due to a constitutional mutation in the APOA5 gene (c.427delC). Moreover, variants possibly increasing the risk of cancer were detected in MSH6 (c.3438+11_3438+14delCTTA, intron 5) and APC (I1307K). The patient showed a rather unusual dietary pattern, since her basic alimentation from weaning consisted almost exclusively of meat homogenates and, subsequently, roasted meat or cutlets. Other foods, including fish, vegetables, sweets, and pasta, were refused. In this case, genetic and environmental factors could have acted in a particularly accelerated manner. Indeed, the genetic background of the patient (familial hypertriglyceridemia and polymorphisms predisposing to colorectal cancer) may have favored a dietary-driven colorectal carcinogenesis, resulting in an extremely early onset development of malignancy.

Human Angiopoietin-like Protein 3/ANGPTL3 Antibodies: Adding to the Armamentarium in the Management of Dyslipidemia.

Cardiovascular (CV) disease remains the leading cause of death in the United States. In addition to lifestyle modifications, current guidelines primarily focus on lowering low-density lipoprotein cholesterol (LDL-C) to reduce atherosclerotic CV disease risk. However, despite aggressive management, a degree of residual risk remains, suggesting that focusing on lowering LDL-C alone may be inadequate and that other lipid parameters may need to be targeted. In patients who remain at high risk despite current pharmacologic options either because of inadequate response, elevated levels of other lipoproteins, or those who have genetic variants predisposing them to atherosclerotic CV disease, additional treatment strategies continue to be sought. One such group is the homozygous familial hypercholesterolemia population, especially those patients carrying the null low-density lipoprotein receptor mutation as they often fail to derive the same benefit from traditional LDL-C lower strategies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitors that work by upregulating the LDL receptor. Emerging data also suggest that patients with increased levels of triglyceride-rich lipoproteins are also at increased risk as elevated levels are proposed to have a role in various pathways promoting atherogenesis. Angiopoietin-life protein 3 (ANGLTPL3) has recently become a target of interest because of the discovery that inhibiting its action leads to reductions in lipid parameters. Although the mechanism of action of ANGLTPL3 inhibitors is independent of the LDL receptor, their ability to significantly lower triglycerides and LDL-C make them an attractive option particularly in patients with homozygous familial hypercholesterolemia and hypertriglyceridemia. The efficacy and safety of 2 ANGLTPL3 inhibitor agents have been evaluated in clinical trials. In this review, the lipid lowering, metabolic effects, and safety are reported. Ongoing trials assessing CV outcomes as well as long-term safety data are still needed to provide a more definitive role for these agents in the overall management in these populations.