Sirolimus-induced Hypertriglyceridemia Leads to Acute Pancreatitis and Diabetic Ketoacidosis Post Stem Cell Transplant for Sickle Cell Disease.

Sirolimus (mammalian target of rapamycin inhibitor) is a potent immunosuppressive agent, used in patients receiving hematopoietic stem cell transplant (HSCT) for Graft vs Host disease prophylaxis. Compared to calcineurin inhibitors, sirolimus has no neurotoxicity or nephrotoxicity, but sirolimus causes dose-dependent thrombocytopenia, leukopenia, delayed wound healing, hyperlipidemia, and hypertriglyceridemia. Here we report a case of acute pancreatitis and diabetic ketoacidosis in a patient with sickle cell disease post haploidentical family donor HSCT which was managed conservatively without plasmapheresis. Based on our review of the literature, this is the first reported case of developing acute pancreatitis as an adverse effect of sirolimus-induced hypertriglyceridemia leading to diabetic ketoacidosis in a recipient of HSCT.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Very severe hypertriglyceridemia complicating pediatric acute lymphoblastic leukemia treatment: a call for management guidelines.

OBJECTIVES: Severe and very severe hypertriglyceridemia although rare within the pediatric population occur more often among oncology patients, secondary to chemotherapeutic agents. Currently there exists minimal literature to guide management of severe hypertriglyceridemia among pediatric patients. Very-low-fat dietary restriction should be considered over nil per os (NPO) for initial management of severe hypertriglyceridemia in stable pediatric patients. Pediatricians caring for oncology patients must consider chylomicronemia as a potential etiology for presenting symptoms. Pediatric severe hypertriglyceridemia management guidelines are needed as pediatricians must currently rely on anecdotal experiences for management decisions. CASE PRESENTATION: Three children receiving treatment for acute lymphoblastic leukemia required hospitalization for very severe hypertriglyceridemia. Management varied among the cases but included: NPO or very-low-fat diet, insulin, intravenous fluids, fibrates, and omega-3 fatty acids. CONCLUSIONS: These cases suggest that pediatric severe hypertriglyceridemia management, in the absence of pancreatitis should allow a very-low-fat diet initially rather than NPO followed by pharmacologic therapies.

Inhibition of TRAF6 improves hyperlipidemic acute pancreatitis by alleviating pyroptosis in vitro and in vivo rat models.

OBJECTIVE: Hypertriglyceridemia (HTG) is one of the common causes of acute pancreatitis (AP). Hyperlipidemic acute pancreatitis (HTG-AP) is associated with higher mortality owing to its tendency for greater severity and rapid progression. The purpose of this study was to explore the mechanism of involvement of tumor necrosis factor receptor-related factor 6 (TRAF6) in pyroptosis during HTG-AP. METHODS: The HTG environment was simulated with palmitic acid treatment in vitro and a high-fat diet in vivo. Cerulein was used to establish the HTG-AP model, followed by genetic and pharmacological inhibition of TRAF6. Pyroptosis activation, inflammatory reaction, and the interaction between TRAF6 and pyroptosis in HTG-AP were assessed. RESULTS: HTG was found to aggravate the development of pancreatitis, accompanied by increased pyroptosis and enhanced inflammatory response in HTG-AP models. Mechanistically, TRAF6 downregulation decreased the activation of pyroptosis in cerulein-induced HTG-AP. CONCLUSION: Collectively, inhibition of TRAF6 improved HTG-AP and the associated inflammation by alleviating pyroptosis.

Plasmapheresis compared with conventional treatment for hypertriglyceridemia-induced acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: The treatment of acute pancreatitis (AP) induced by hypertriglyceridemia (HTG) remains controversial with regard to plasmapheresis vs conventional treatment. We reviewed relevant articles to explore the efficacy of plasmapheresis in the management of HTG-induced AP. METHODS: We systematically reviewed studies that compared plasmapheresis with conventional treatment for HTG-induced AP using three databases: PubMed, Embase, and Cochrane Library, as well as relevant references. The primary outcomes were 24 h triglyceride reduction rate and in-hospital mortality. RESULTS: A total of 791 articles were retrieved. Finally, 15 observational studies (1080 participants) were included, most of which were historical cohort studies. Compared with conventional treatment, plasmapheresis assisted in the reduction of serum triglyceride (TG) levels in the first 24 h after hospital admission (standardized mean difference [SMD]: 0.58; 95% confidence interval [CI]: 0.17 to 0.99; P = 0.005). However, it resulted in increased hospitalization costs (thousand yuan) (weighted mean difference [WMD]: 24.32; 95% CI: 12.96 to 35.68; P < 0.001). With regard to in-hospital mortality, although the mortality rate in the plasmapheresis group was higher than that in the conventional treatment group (relative risk [RR]: 1.74; 95% CI: 1.03 to 2.94; P = 0.038), the result was disturbed by confounding factors as per the subgroup and sensitivity analysis, as well as trial sequential analysis (TSA). No significant differences were found in other outcomes, including systematic complications, local complications, the requirement for surgery, and hospitalization duration. CONCLUSION: The effect of plasmapheresis in HTG-induced AP is not superior to that of conventional treatment, even resulting in a greater economic burden to patients and health care system. High quality randomized control trials are required to obtain a more a definitive understanding of this issue.

Double filtration plasmapheresis for hypertriglyceridemic acute pancreatitis caused by fat overload syndrome.

WHAT IS KNOWN AND OBJECTIVE: Severe hypertriglyceridemia (HTG) can cause acute pancreatitis (AP). CASE SUMMARY: We report a patient with acute lymphoblastic leukaemia who received long-term intravenous parenteral nutrition solution without monitoring of the serum triglyceride (TG) level, which resulted in fat overload syndrome and HTG-AP. WHAT IS NEW AND CONCLUSION: Double filtration plasmapheresis was performed to eliminate the TGs and treat the AP.

The Role of High Triglycerides Level in Predicting Cognitive Impairment: A Review of Current Evidence.

The burden of cognitive disorders is huge and still growing, however the etiology and the degree of cognitive impairment vary considerably. Neurodegenerative and vascular mechanisms were most frequently assessed in patients with dementia. Recent studies have shown the possible involvement of triglycerides levels in cognitive function through putative mechanisms such as brain blood barrier dysfunction or amyloid metabolism imbalance, but not all research in the field found this association. Several clinical studies evaluated the relationship between different forms of cognitive decline and levels of serum triglycerides, independent of other cardiovascular risk factors. This review focuses on the role of triglycerides in cognitive decline, cerebral amyloidosis and vascular impairment. Considering that the management of hypertriglyceridemia benefits from lifestyle modification, diet, and specific drug therapy, future studies are requested to appraise the triglycerides-cognitive impairment relationship.

Using fresh frozen plasma as an emergency treatment modality for hypertriglyceridaemic acute pancreatitis in a resource-constrained environment: A case report and review of literature.

Hypertriglyceridaemia is associated with severe disease such as coronary disease, cerebral vascular accidents and acute pancreatitis. Severe hypertriglyceridaemia is defined as a serum triglyceride value of >55 mmol/L. Hypertriglyceridaemic acute pancreatitis, often found in pregnancy, has a higher mortality rate than the other causes of acute pancreatitis. The cornerstone of treatment is to lower the triglyceride level as quickly as possible. In a resource-constrained environment, plasma exchange is not a viable option. Therefore, exploring the possible efficacity of directly infusing fresh frozen plasma is applicable to rural emergency medicine and may lead to more definitive research. In our case study, we used fresh frozen plasma to enhance the removal of triglyceride because it contains lipoprotein lipase.

Hipertrigliceridemia severa refractaria a tratamiento médico y pancreatitis aguda recurrente: uso de plasmaféresis crónica ambulatoria en el Hospital San Pablo de Coquimbo. Reporte de un caso

Severe Hypertriglyceridemia (HTG) is associated with complications such as acute pancreatitis (AP) with high morbidity and mortality rates. We report a 42 years-old man with refractory HTG diagnosed at 19 years of age, and multiple episodes of AP, admitted with the suspicion of a new AP episode. Serum triglycerides were over 2000 mg/dl. His body mass index was 18 kg/m2, there was no evidence of xanthomas or xanthelasmas, but lipemia retinalis was found. Management included heparin and insulin, added to his usual treatment with fibrates, statins, omega-3 fatty acids, and orlistat. Due to lack of response, apheresis was started. After five sessions, triglycerides decreased to 588 mg/dl (82% reduction) and levels remained below 1000 mg/dl with daily apheresis. The patient continued with weekly sessions as outpatient with a sustained good response.

Lipid Apheresis to Manage Severe Hypertriglyceridemia during Induction Therapy in a Child with Acute Lymphoblastic Leukemia.

PEG asparaginase is an important and established drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). Severe hypertriglyceridemia is a rare complication of PEG asparaginase in combination with glucocorticoids. We report a case of excessive hypertriglyceridemia in a child during ALL induction therapy successfully treated by lipid apheresis and give a literature review on the management of hypertriglyceridemia in children treated for ALL.

Anti-lipid therapy and risk factor management for triglyceridaemia-induced acute pancreatitis.

BACKGROUND: Pancreatitis secondary to hypertriglyceridaemia is rare, accounting for less than 5% of pancreatitis presentations. We reviewed our institutional experience with triglyceridaemia induced acute pancreatitis to report the clinical presentation, patient demographics and clinical management. METHODS: The Acute Surgical Unit database at a high-volume general surgical referral centre was queried to identify cases of acute pancreatitis secondary to hypertriglyceridaemia between 2016 and 2019. Patient demographics, clinical manifestations, biochemical derangements and treatment regimens were analysed. Current related literature was reviewed. RESULTS: There were 496 presentations for acute pancreatitis of which 14 presentations (2.8%), amongst 12 patients were due to hypertriglyceridaemia. The mean triglyceride level at presentation was 92.46 (standard deviation 46.9) mmol/L. Ten patients (83%) had poorly controlled type 2 diabetes. All patients were managed using conservative therapy combined with a restricted fat diet and commenced on long-term anti-lipid therapy to manage associated risk factors. In addition, 10 patients received an insulin infusion and one patient received insulin infusion, plasmapheresis and heparin infusion in combination. The median length of hospital stay was 5.5 (range 3-13) days. Two patients (16%) developed a recurrent episode related to non-compliance to medical therapy. CONCLUSION: Hypertriglyceridaemia is a rare cause of acute pancreatitis. Successful management involves the treatment of acute pancreatitis in conjunction with long-term anti-lipid therapy and optimisation of associated risk factors.

[Refractory severe hypertriglyceridemia treated with apheresis. Report of one case]. / Hipertrigliceridemia severa refractaria a tratamiento médico y pancreatitis aguda recurrente: uso de plasmaféresis crónica ambulatoria en el Hospital San Pablo de Coquimbo. Reporte de un caso.

Severe Hypertriglyceridemia (HTG) is associated with complications such as acute pancreatitis (AP) with high morbidity and mortality rates. We report a 42 years-old man with refractory HTG diagnosed at 19 years of age, and multiple episodes of AP, admitted with the suspicion of a new AP episode. Serum triglycerides were over 2000 mg/dl. His body mass index was 18 kg/m2, there was no evidence of xanthomas or xanthelasmas, but lipemia retinalis was found. Management included heparin and insulin, added to his usual treatment with fibrates, statins, omega-3 fatty acids, and orlistat. Due to lack of response, apheresis was started. After five sessions, triglycerides decreased to 588 mg/dl (82% reduction) and levels remained below 1000 mg/dl with daily apheresis. The patient continued with weekly sessions as outpatient with a sustained good response.

Triglycerides as a Metabolic Target in Afrocaribbean Infertile Women with Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is classically associated with insulin resistance, metabolic syndrome, or type 2 diabetes. Infertile Afrocaribbean (AC) women with PCOS may have metabolic features that could help to better target their management. Objective: To evaluate the characteristics of PCOS in this population and their metabolic profile to target the worst metabolic parameter. Methods: A retrospective study including infertile AC women for 4 years. PCOS was diagnosed using Rotterdam criteria and compared with non-PCOS women referred consecutively for infertility during the same period. Results: Among 981 AC women evaluated for infertility, PCOS was found in 17%. PCOS women were younger than non-PCOS women. After age and body mass index (BMI) matching, only fasting blood glucose and triglyceride levels were higher in PCOS women compared with non-PCOS women. PCOS was positively correlated with triglyceride levels and negatively with vitamin D levels. PCOS women with obesity had low high-density lipoprotein-cholesterol and increased triglyceride levels compared with those without obesity. No correlation was found between lipids or glucose levels and androgen levels. Multivariate analysis showed that only triglycerides were independently related to PCOS after adjustment for age and BMI. Conclusions: In the AC population where the prevalence of obesity and diabetes is increased, the metabolic profile of infertile women with PCOS is mainly characterized by hypertriglyceridemia, with a higher risk of visceral obesity and nonalcoholic fatty liver disease. Interventional studies would be useful to evaluate the predictive value of hypertriglyceridemia on diabetes and cardiovascular diseases in this population.

Severe drug-induced hypertriglyceridemia treated with plasmapheresis in children with acute lymphoblastic leukemia.

Asparaginase (ASP) and steroids are a main part of treatment for ALL, in both front-line and relapse setting. It is known, that ASP can cause several toxicities such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances. Administered steroids can result in diabetes, obesity, hyponatremia and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased. We report two patients who were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland and developed severe hypertriglyceridemia after receiving asparaginase and steroid therapy for acute lymphoblastic leukemia. These patients were treated using plasmapheresis. This procedure was performed with a venous catheter in the femoral vein and 5% albumin or fresh frozen plasma as the replacement fluid. We analysed the laboratory and clinical data of these children. Plasmapheresis was well tolerated in both cases and a decrease of hypertriglyceridemia was quickly observed. However, the girl developed pancreatitis. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.

Long-Term Comparison of Ethyl Icosapentate vs. Omega-3-Acid Ethyl in Patients With Cardiovascular Disease and Hypertriglyceridemia (DEFAT Trial).

BACKGROUND: Numerous studies have demonstrated a reduction in cardiovascular events when the low-density lipoprotein cholesterol (LDL) level is decreased by statin therapy. However, despite good control of LDL, cardiovascular events may increase if the triglyceride (TG) level is high. We conducted a long-term comparison of treatment of hypertriglyceridemia with ethyl icosapentate (EPA) vs. omega-3-acid ethyl (EPA+docosahexaenoic acid [DHA]).Methods and Results:Cardiac surgery patients with hypertriglyceridemia were randomized to an EPA group (1.8 g t.i.d.) or an EPA+DHA group (2 g s.i.d.) and observed for 3 years. The primary endpoints were the serum TG level and its percent change. Secondary endpoints included lipid markers, fatty acid parameters, serum creatinine, cystatin-C, oxidized LDL, high-sensitivity C-reactive protein, and MACCE. An interview to assess study drug adherence was conducted 6 months after completing the study. TG levels were significantly lower in the EPA+DHA group than in the EPA group. Levels of remnant-like particles-cholesterol, oxidized LDL, and cystatin-C were also significantly lower in the EPA+DHA group than in the EPA group. Compliance with treatment was significantly worse in the EPA group. CONCLUSIONS: Better results were obtained in the EPA+DHA group, but more patients showed poor compliance with treatment in the EPA group, making detailed comparison of the 2 groups difficult. Even so, TG were reduced while EPA and DHA levels were increased in the EPA+DHA group, together with a reduction in oxidative stress and remnant-like particles-cholesterol. Decreased compliance with medication in the EPA group significantly affected the results of this study, clearly indicating the importance of good compliance.

The Chylomicronemia Syndrome Is Most Often Multifactorial: A Narrative Review of Causes and Treatment.

The chylomicronemia syndrome occurs when triglyceride levels are severely elevated (usually >16.95 mmol/L [1500 mg/dL]) and is characterized by such clinical features as abdominal pain, acute pancreatitis, eruptive xanthomas, and lipemia retinalis. It may result from 1 of 3 conditions: the presence of secondary forms of hypertriglyceridemia concurrent with genetic causes of hypertriglyceridemia, termed multifactorial chylomicronemia syndrome (MFCS); a deficiency in the enzyme lipoprotein lipase and some associated proteins, termed familial chylomicronemia syndrome (FCS); or familial partial lipodystrophy. Most chylomicronemia syndrome cases are the result of MFCS; FCS is very rare. In all these conditions, triglyceride-rich lipoproteins accumulate because of impaired plasma clearance. This review describes the 3 major causes of the chylomicronemia syndrome; their consequences; and the approaches to treatment, which differ considerably by group.

Clinical Characteristics and Sequelae of Severe Hypertriglyceridemia in Pediatrics.

OBJECTIVE: Severe hypertriglyceridemia (HTG) (i.e., plasma triglycerides [TGs] >1,000 mg/dL) in children is a rare but pernicious and understudied condition. Our objective was to evaluate the etiology, characteristics, and sequelae of severe pediatric HTG. METHODS: This was a retrospective electronic medical record review of pediatric patients with severe HTG at a tertiary referral Children's hospital over a 17-year period. RESULTS: There were a total of 124 patients with severe HTG. The etiology varied: hemato-oncologic (n = 48), diabetes and insulin resistance-related (n = 46), total parenteral nutrition (TPN)-related (n = 6), renal (n = 12), and miscellaneous (n = 12). There was considerable variability in the number of days for the plasma TGs to decrease to <1,000 mg/dL (147.7 ± 567.3 days) and to further decrease to <500 mg/dL (136.84 ± 230.9 days). Patients with diabetes required the longest time to improve their plasma TGs (165.8 ± 305.7 days) compared to other groups. There were 11 cases of pancreatitis, comorbid with diabetes (n = 5), hemato-oncologic conditions (n = 3), and TPN (n = 3). Sixty-seven patients (54%) had persistent HTG. CONCLUSION: Severe HTG in pediatrics is commonly due to secondary causes. Patients with diabetes tend to have a longer course of dyslipidemia. A substantial number of patients had persistent dyslipidemia, indicating underlying genetic susceptibility to HTG that is phenotypically expressed consequent to a secondary metabolic insult. ABBREVIATIONS: DKA = diabetic ketoacidosis; EMR = electronic medical record; GSD = glycogen storage disorder; HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; HTG = hypertriglyceridemia; ICD-9 = International Classification of Diseases-Ninth Revision; IV = intravenous; LCHAD = long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency; LPL = lipoprotein lipase; NPO = nothing by mouth; PCOS = polycystic ovary syndrome; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TG = triglyceride; TPN = total parenteral nutrition; VLDL = very-low-density lipoprotein.