La importancia de la genética en el estudio de la hipertrigliceridemia / The importance of genetics in the study of hypertriglyceridemia

La hipertrigliceridemia engloba un conjunto de trastornos lipídicos comunes en la práctica clínica, generalmente definidos como una concentración superior a 150mg/dL en ayunas. Existen diversas clasificaciones de la gravedad de la hipertrigliceridemia en función de sus valores séricos, considerándose por norma general moderada cuando los niveles son inferiores a 500mg/dL y severa cuando son mayores de 1.000mg/dL. Su importancia radica en su asociación con otras alteraciones del perfil lipídico, contribuyendo al aumento del riesgo cardiovascular y de pancreatitis aguda, fundamentalmente con concentraciones superiores a 500mg/dL.(AU)

Hypertriglyceridemia encompasses a set of lipid disorders common in clinical practice, generally defined as a fasting concentration above 150mg/dL. There are various classifications of the severity of hypertriglyceridaemia based on serum values, with levels generally considered moderate when below 500mg/dL and severe when above 1000mg/dL. Its importance lies in its association with other alterations in the lipid profile, contributing to increased cardiovascular risk and increased risk of acute pancreatitis, mainly with concentrations above 500mg/dL.(AU)

Connecting impaired fibrinolysis and dyslipidemia.

A State of the Art lecture entitled "Connecting Fibrinolysis and Dyslipidemia" was presented at the International Society on Thrombosis and Haemostasis Congress 2023. Hemostasis balances the consequences of blood clotting and bleeding. This balance relies on the proper formation of blood clots, as well as the breakdown of blood clots. The primary mechanism that breaks down blood clots is fibrinolysis, where the fibrin net becomes lysed and the blood clot dissolves. Dyslipidemia is a condition where blood lipid and lipoprotein levels are abnormal. Here, we review studies that observed connections between impaired fibrinolysis and dyslipidemia. We also summarize the different correlations between thrombosis and dyslipidemia in different racial and ethnic groups. Finally, we summarize relevant and new findings on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress. More studies are needed to investigate the mechanistic connections between impaired fibrinolysis and dyslipidemia and whether these mechanisms differ in racially and ethnically diverse populations.

Diagnostic and Therapeutic Ambiguities in Diabetic Ketoacidosis With Overlapping Acute Pancreatitis and Hypertriglyceridemia.

This case report discusses the diagnostic challenges and management complexities in a patient presenting with symptoms of diabetic ketoacidosis (DKA) and severe pancreatitis, complicated by concurrent hypertriglyceridemia (HTG) and superior mesenteric vein (SMV) thrombosis. The presence of DKA in acute pancreatitis suggests very severe impact on the pancreas. Hence, it calls for screening with CT imaging for complications like hemorrhagic pancreatitis, necrotizing pancreatitis, or even thrombus. Despite typical reliance on clinical presentation and serum lipase for diagnosing pancreatitis, this case emphasizes the necessity of contrast-enhanced CT imaging in ambiguous cases to identify critical complications like thrombosis and necrotizing pancreatitis. Furthermore, the patient's management involved insulin therapy for DKA and HTG-induced acute pancreatitis, deferring plasmapheresis and anticoagulation due to the risk of hemorrhagic transformation in pancreatitis. This approach highlights the need for individualized treatment strategies, especially in complex presentations with overlapping pathologies. The case also explores the potential for insulin as a first-line treatment in HTG-induced pancreatitis over plasmapheresis, contributing to evolving guidelines.

Clinical Efficacy and Safety of Low-Dose Pemafibrate in Patients With Severe Renal Impairment: A Retrospective Study.

BACKGROUND: The management of hypertriglyceridemia in patients with chronic kidney disease (CKD) is important. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator with less toxic effects on liver and kidney function than those of other fibrates, has recently been approved for the treatment of patients with an estimated glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m2. However, the efficacy and safety of pemafibrate in patients with severe renal impairment have not yet been established. METHODS: This single-center, retrospective observational study included 12 outpatients with CKD and hypertriglyceridemia, who were newly started on low-dose pemafibrate (0.1 mg/day) treatment between December 2021 and May 2023 and whose eGFRs were less than 30 mL/min/1.73 m2 at baseline. Blood samples were collected before and at 12 weeks after pemafibrate treatment. RESULTS: After 12 weeks of treatment, the serum triglyceride level was significantly decreased, whereas the high-density lipoprotein cholesterol level was significantly increased. The serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and uric acid levels were also significantly decreased, without worsening of the eGFR and serum creatinine levels. In the subgroup analysis, there were no significant differences in the changes in clinical parameters regardless of statin use and CKD stage at baseline. CONCLUSIONS: Low-dose pemafibrate administration in patients with severe renal impairment resulted in significant improvements in triglyceride, high-density lipoprotein cholesterol, and serum uric acid levels, and liver function, without adverse events.

Early detection of severe hypertriglyceridemia using teleconsultation in a clinical laboratory setting.

BACKGROUND: Teleconsultation in the context of clinical laboratories is a valuable tool for the early detection of dyslipidemia and prevention of cardiovascular risk. Here, we describe a patient who was referred to the Lipid Unit of the Virgen Macarena Hospital due to an alert for severe hypertriglyceridemia through its teleconsultation program. CASE PRESENTATION: A comprehensive clinical and biochemical study of the patient was carried out, and genetic testing was performed on the patient and his family. The proband and his family showed mild to severe hypertriglyceridemia and various secondary factors, together with a genetic background associated with a triglyceride-raising effect. CONCLUSION: This extensive study has identified a family at high risk of cardiovascular disease and acute pancreatitis. These findings can help maximize lifestyle changes and improve the clinical management of their dyslipidemia.

Sex Differences in Severity and Risk Factors for Ischemic Stroke in Patients With Hyperlipidemia.

Objective: This study aims to determine sex differences in poststroke hypertriglyceridemia (serum triglyceride levels ⩾ 200 mg/dl) and high stroke severity in ischemic stroke patients. Method: Our study analyzed data from 392 males and 373 females with hypertriglyceridemia. Stroke severity on admission was measured using the National Institute of Health Stroke Scale (NIHSS) with a value ⩽7 indicating a more favorable post-stroke prognosis while a score of >7 indicates poorer post-stroke outcomes. Logistic regression models adjusted for demographic and risk factors. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each clinical risk factor were used to predict the increasing odds of an association of a specific clinical baseline risk factor with the male or female AIS with hypertriglyceridemia. Results: In the adjusted analysis, male patients with hypertriglyceridemia, diastolic blood pressure (OR = 1.100, 95% CI, 1.034-1.171, P = .002), and Ischemic stroke mortality (OR = 6.474, 95% CI, 3.262-12.847, P < .001) were significantly associated with increased stroke severity. In female patients with hypertriglyceridemia, age (OR = 0.920, 95% CI, 0.866-0.978, P = .008) was associated with reduced stroke severity, while ischemic stroke mortality score (OR = 37.477, 95% CI, 9.636-145.756, P < .001) was associated with increased stroke severity. Conclusion: Increased ischemic stroke mortality risk score was associated with increased severity in both male and female AIS patients with hypertriglyceridemia. Our findings provide information about sex differences in specific risk factors that can be managed to improve the care of male and female ischemic stroke patients with hypertriglyceridemia.

Carotid intimamedia thickness in patients with severe hypertriglyceridemia.

Background and aims: Severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD. Methods: We studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.6 mmol/L), 271 patients with familial hypercholesterolemia (FH) as a contrast group, and 70 normolipidemic controls. Carotid IMT was measured using standardized ultrasound imaging. Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare mean IMT values, analysis of covariance (ANCOVA) to adjust for confounding variables, specifically age and sex, as well as Spearman pairwise correlation analysis between variables. Results: Unadjusted mean carotid IMT was greater in severe HTG and FH groups compared to controls, however, this was no longer significant for severe HTG after adjustment for age and sex. In contrast, adjusted carotid IMT remained significantly different between the FH and control groups. Conclusions: Our findings suggest that extreme TG elevations in severe HTG patients are not significantly associated with carotid IMT, in contrast to the increased IMT seen in FH patients. These findings add perspective to the complex relationship between severe HTG and ASCVD risk.

The association between pregnancy levels of blood lipids and the risk of preterm birth.

Preterm labor, a condition associated with various risk factors such as a history of prior preterm birth (PTB) and multiple pregnancies, has recently seen an increasing focus on its potential link with dyslipidemia. This study aims to investigate the relationship between dyslipidemia in expectant mothers and the risks of PTB. We studied 6963 mothers who gave birth at the International Peace Maternal and Child Health Hospital of Shanghai Jiaotong University School of Medicine in 2020, among which, 437 women had PTB. We extracted clinical and lipid data from electronic records, using multivariable logistic regression and restricted cubic spline models to explore the link between lipid concentrations (by quartiles) in pregnancy stages and PTB risk. The PTB rate was 6.3%. Early pregnancy in the PTB group showed elevated ApoA, ApoB, CHOL, LDL, and TG levels compared to controls (all P < 0.05). Late pregnancy showed no notable lipid differences. Multivariable analysis revealed elevated ApoA, TG, higher age, BMI ≥ 28 kg/m2, hypertension, assisted reproductive technology and gestational diabetes as PTB risk factors (all P < 0.05). After adjustments, higher ApoA, ApoB, CHOL and TG levels correlated with increased PTB risk. Using the lowest quartile, the adjusted ORs for early pregnancy's highest quartile of ApoA, ApoB, CHOL and TG were 1.348, 1.442, 1.442 and 2.156, respectively. Our findings indicate that dyslipemia in early pregnancy, including elevated levels of ApoA, ApoB, CHOL and TG, are associated with PTB. Managing lipid abnormalities during pregnancy may help reduce the risk of PTB.

Validation of Nutritional Approaches to Modulate Cardiovascular and Diabetic Risk Factors in Patients with Hypertriglyceridemia or Prediabetes-The MoKaRi II Randomized Controlled Study.

Hypertriglyceridemia and diabetes mellitus type 2 are among the most important metabolic diseases globally. Diet plays a vital role in the development and progression of both clinical pictures. For the 10-week randomized, controlled, intervention study, 67 subjects with elevated plasma triglyceride (TG) concentrations (≥1.7 mmol/L) and 69 subjects with elevated fasting glucose concentrations (≥5.6 < 7.0 mmol/L) were recruited. The intervention groups received specially developed, individualized menu plans and regular counseling sessions to lower (A) TG or (B) fasting glucose and glycated hemoglobin A1c as well as other cardiovascular and diabetic risk factors. The hypertriglyceridemia intervention group was further supplemented with fish oil (3.5 g/d eicosapentaenoic acid + docosahexaenoic acid). The two control groups maintained a typical Western diet. Blood samples were taken every 2 weeks, and anthropometric data were collected. A follow-up examination was conducted after another 10 weeks. In both intervention groups, there were comparable significant reductions in blood lipids, glucose metabolism, and anthropometric parameters. These results were, with a few exceptions, significantly more pronounced in the intervention groups than in the corresponding control groups (comparison of percentage change from baseline). In particular, body weight was reduced by 7.4% (6.4 kg) and 7.5% (5.9 kg), low-density lipoprotein cholesterol concentrations by 19.8% (0.8 mmol/L) and 13.0% (0.5 mmol/L), TG concentrations by 18.2% (0.3 mmol/L) and 13.0% (0.2 mmol/L), and homeostatic model assessment for insulin resistance by 31.8% (1.1) and 26.4% (0.9) (p < 0.05) in the hypertriglyceridemia and prediabetes intervention groups, respectively. Some of these changes were maintained until follow-up. In patients with elevated TG or fasting glucose, implementing individualized menu plans in combination with regular counseling sessions over 10 weeks led to a significant improvement in cardiovascular and diabetic risk factors.

Approach to the Management of Hypertriglyceridemia Complicated With Acute Pancreatitis in Pregnancy: A Case Report.

This is a case of a 32-year-old woman, Gravida 3 para 2, previous two cesarean sections, who presented to our emergency department at 24+3 weeks of gestation complaining of severe epigastric pain radiating to the back. She was diagnosed with severe hypertriglyceridemia complicated with acute pancreatitis and was managed by a multi-disciplinary team, which included obstetrics, gastroenterology, endocrinology, hematology, nutrition, and ICU team. Initially, conservative treatment was employed for her management. She was placed on nil per oral status and initiated on a normal saline infusion at a rate of 150 ml/hour, along with insulin infusion at 0.1 unit/kg/hour and dextrose (D5) at 80 ml/hour. Additionally, she received omeprazole, meropenem, clexane (40 mg once daily subcutaneous injection), iron, vitamin supplements, and analgesics as required. Subsequently, due to the failure of the initial conservative medical management, the patient was admitted to the ICU. Plasmapheresis was performed after the insertion of a vascath, using 3000 ml of albumin 5% as replacement fluid and oral calcium. Following this, she was prescribed Omacor (Omega 3) at a dosage of 2 grams orally twice daily, along with a low carbohydrate and fat diet, to manage her triglyceride levels. After the removal of the central line, her triglycerides increased to 14.3 mmol/L, leading to the initiation of fenofibrate at a daily dose of one tablet. With persistent elevation to 16.4 mmol/L, Lipitor at 40 mg once daily was introduced. Following this intervention, her triglyceride levels stabilized, and her overall condition improved. She was discharged at 25+1 weeks with a prescribed regimen, and scheduled follow-ups were arranged in the endocrine and obstetrics clinics. At 36 weeks of gestation, she presented to the emergency room with abdominal, back, and leg pain. Fetal distress, indicated by fetal tachycardia (170-180 bpm) on cardiotocography, prompted an urgent category 1 cesarean section, which proceeded without complications.

Acute Pancreatitis during and after Pregnancy: A Review.

During pregnancy and in the post-partum period, several diseases may arise or become exacerbated. Acute pancreatitis is an inflammatory disease with an increasing incidence in Western countries. The incidence of acute pancreatitis during pregnancy is not different with respect to the general population, but this incidence increases in the first 2 years after delivery. Biliary sludge and stones are the most frequent aetiologies, followed by hypertriglyceridemia. Taking care of the mother and foetus through a potentially severe disease requires a team consisting of an obstetrician, a gastroenterologist, an anaesthesiologist, and a surgeon. It is necessary to monitor the health of the foetus/child and the mother during pregnancy, childbirth, and puerperium. The management of this care depends on the systemic and local complications, the severity of the acute pancreatitis, and the trimester of pregnancy. Some diagnostic tools and many drugs are not safe for foetuses, while interventional endoscopy and surgery have limitations and can only be used after an accurate evaluation of benefit/risk ratios. Despite these limitations, maternal mortality due to acute pancreatitis is low during pregnancy, mainly thanks to multidisciplinary approaches for these patients. A careful diet to prevent obesity, alcohol abstinence, routine serum triglyceride control, and breastfeeding for at least three months may prevent acute pancreatitis during and after pregnancy.

Factors affecting clinical outcomes of continuous and intermittent plasmapheresis in patients with severe hypertriglyceridemia.

INTRODUCTION: Acute hypertriglyceridemia is considered a category III indication for plasmapheresis. The use of plasma as replacement fluid (RF) has been suggested to replace the consumed lipoprotein lipase. Heparin when used as an anticoagulant could possibly release lipoprotein lipase, thereby increasing triglyceride clearance. METHODS: The impact of RF (albumin vs fresh frozen plasma (FFP) and anticoagulant (ACD-A vs. heparin) on triglycerides following plasmapheresis in 27 patients with severe hypertriglyceridemia (SHTG) was investigated. A paired study of four patients with recurrent SHTG was conducted, evaluating continuous (Optia) versus intermittent flow plasmapheresis (Haemonetics). RESULTS: Shorter procedures positively impacted triglycerides (TG) drop post-sessions p < 0.05. In albumin sessions, patients who used heparin demonstrated significantly greater drop in TG and required less sessions than did those with citrate p < 0.05. In heparin sessions, patients who used albumin demonstrated significantly greater drop in triglycerides and required less sessions than did those with FFP p < 0.05. Three of six patients who used FFP and heparin showed a triglyceride drop of 11.7% following three sessions and a 50% drop with one albumin session. Compared with Haemonetics, Optia removed comparable volumes of plasma in less time, processing smaller blood volumes and using less citrate p < 0.05. Patients demonstrated significantly lower drop in TG and required more sessions with Haemonetics than they did with Optia p < 0.05. CONCLUSION: Shorter procedure was the main predictor for effective TG clearance. This can be achieved by continuous apheresis technology, particularly when using albumin as RF. TG removal via Optia seems to be optimized by using heparin.

Epidemiology and Prevalence of Dyslipidemia Among Adult Population of Tehran: The Tehran Cohort Study.

BACKGROUND: Dyslipidemia is among the leading risk factors for cardiovascular diseases (CVDs), with an increasing global burden, especially in developing countries. We investigated the prevalence of dyslipidemia and abnormal lipid profiles in Tehran. METHODS: We used data from 8072 individuals aged≥35 from the Tehran Cohort Study (TeCS) recruitment phase. Fasting serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglyceride were measured. Dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, and high LDL/HDL was defined as a ratio>2.5. The age-sex standardized prevalence rates were calculated based on the 2016 national census. Furthermore, the geographical distribution of dyslipidemia and lipid abnormalities was investigated across Tehran's zip code districts. RESULTS: The age-sex standardized prevalence was 82.7% (95% CI: 80.1%, 85.0%) for dyslipidemia, 36.9% (95% CI: 33.8%, 40.1%) for hypertriglyceridemia, 22.5% (95% CI: 19.9%, 25.4%) for hypercholesterolemia, 29.0% (95% CI: 26.1%, 32.1%) for high LDL-C, 55.9% (95% CI: 52.6%, 59.2%) for low HDL-C, and 54.1% (95% CI: 50.9%, 57.3%) for high LDL/HDL ratio in the Tehran adult population. The prevalence of dyslipidemia, low HDL-C, and high LDL/HDL ratio was higher in the northern regions, hypercholesterolemia was higher in the southern half, and high LDL-C was more prevalent in the middle-northern and southern areas of Tehran. CONCLUSION: We found a high prevalence of dyslipidemia, mainly high LDL/HDL in the Tehran adult population. This dyslipidemia profiling provides important information for public health policy to improve preventive interventions and reduce dyslipidemiarelated morbidity and mortality in the future.

Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). CASE PRESENTATION: A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient's parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. CONCLUSION: These siblings' case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants-beyond next-generation sequencing-as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

Resolution of Extensive Xanthomas Associated With Severe Hypertriglyceridemia via Modified Therapeutic Plasma Exchange.

Severe hypertriglyceridemia can be manifested by xanthomas. Therapeutic plasma exchange (TPE) is an invasive medical procedure that has been documented as a viable approach for severe hypertriglyceridemia when cases would be refractory to conventional therapies. TPE is mainly an optional therapeutic modality for cases of severe acute pancreatitis or preventing the recurrence of pancreatitis. Beyond this clinical application, data are scarce on TPE utilization in managing cutaneous lesions associated with hypertriglyceridemia. We present a case of severe hypertriglyceridemia accompanied by extensive xanthomas of various types and a history of recurrent pancreatitis. After conventional therapy failed, a modified plasmapheresis regimen was used and was able to achieve a fast and marked reduction in the patient's serum triglyceride levels with complete resolution of the extensive cutaneous lesions, providing him a newfound comfort he had not experienced in some time and suggesting the regimen potentially could be considered in the treatment of refractory severe hypertriglyceridemia with debilitating cutaneous complications.

Hypertriglyceridemia-induced acute necrotizing pancreatitis: Poor clinical outcomes requiring revisiting management modalities.

Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is the third most common cause of AP after gallstones and alcohol. Supportive measures, intravenous insulin, and plasmapheresis are possible treatment modalities for HTG-AP; however, definitive guidelines evaluating the best therapeutic approach are not clearly established. We present a rare case of a 42-year-old male without known comorbidities who was found to have HTG-AP. Despite early initiation of intravenous insulin and plasmapheresis and the initial decline in his triglycerides level, his condition was complicated by necrotizing pancreatitis and subsequent multi-organ failure. Future studies are warranted to evaluate the role of plasmapheresis in HTG-AP and its efficacy.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

Acute pancreatitis associated with pembrolizumab-induced hypertriglyceridemia.

INTRODUCTION: Acute pancreatitis (AP) following drug-induced hypertriglyceridemia is a rare clinical phenomenon. Immune checkpoint inhibitors have revolutionized treatment for a variety of solid organ and hematological malignancies. Pembrolizumab is a programmed cell death receptor-1 (PD-1) inhibitor that has shown promising responses in many advanced cancers. However, a constellation of immune-related adverse events has also been described. There are reports of pembrolizumab-induced hypertriglyceridemia, but AP as a result of this side effect remains an exceedingly rare clinical sequela. CASE REPORT: We delineate a case of a patient with stage IVB non-small-cell lung cancer who developed progressive abdominal pain and nausea following administration of pembrolizumab for four months. Laboratory studies revealed increased serum lipase and triglyceride levels at 12,562 IU/L and 16,901 mg/dL, respectively. The diagnosis of AP was made based on the revised Atlanta classification criteria. After ruling out alternative causes, pembrolizumab-induced hypertriglyceridemia was considered the likely etiology of AP. MANAGEMENT AND OUTCOME: The patient was transferred to the medical intensive care unit for close monitoring. Treatment was initiated with intravenous fluids, pain medications, and an insulin infusion. However, her hypertriglyceridemia levels remained persistently elevated, necessitating therapeutic apheresis. She recovered well with no complications after triglyceride apheresis. DISCUSSION: AP following pembrolizumab-associated hypertriglyceridemia remains a rare clinicopathologic entity. Given the widespread clinical use of immune checkpoint inhibitors, knowledge of such rare adverse events is crucial. Evaluation of serum triglyceride levels before and after initiating pembrolizumab therapy may be mandated, especially in patients with metabolic comorbidities.

Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

BACKGROUND: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). AIMS: To explore the role of HTG in the pathogenesis of AP. METHODS: Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. RESULTS: In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1ß, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). CONCLUSIONS: HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.