暂无摘要。

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

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was to describe biochemical-clinical characteristics and variants in the APOA5, GPIHBP1, LMF1, and LPL genes in patients with primary hypertriglyceridemia. Thirty DNA fragments were analyzed using PCR and Sanger sequencing in 58 unrelated patients. The patients\' main clinical-biochemical features were hypoalphalipoproteinemia (77.6%), pancreatitis (18.1%), and a TG median value of 773.9 mg/dL. A total of 74 variants were found (10 in APOA5, 16 in GPIHBP1, 34 in LMF1, and 14 in LPL), of which 15 could be involved in the development of PHTG: 3 common variants with significative odds and 12 heterozygous rare pathogenic variants distributed in 12 patients. We report on the first Mexican patient with hyperchylomicronemia syndrome due to GPIHBP1 deficiency caused by three variants: p.R145*, p.A154_G155insK, and p.A154Rfs*152. Moreover, eleven patients were heterozygous for the rare variants described as causing PHTG and also presented common variants of risk, which could partially explain their phenotype. In terms of findings, two novel genetic variants, c.-40_-22del LMF1 and p.G242Dfs*10 LPL, were identified.

Recent studies have reported that patients with autoimmune hyperchylomicronemia caused by glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) autoantibodies are associated with rheumatoid arthritis, systemic lupus erythematosus, Sjogren\'s syndrome, Hashimoto\'s thyroiditis, Basedow\'s disease, and immune thrombocytopenia. We report a rare case of hyperchylomicronemia due to GPIHBP1 autoantibodies and fluctuating thyroid autoimmune disease. A 28-year-old woman, diagnosed with Hashimoto\'s thyroiditis at 26 years of age, started taking 50 µg/day of levothyroxine sodium. She had an episode of acute pancreatitis at 27 years of age; her serum triglyceride (TG) level was 1291 mg/dL at that time. The patient was referred to our hospital because her hyperchylomicronemia (hypertriglyceridemia) did not improve on treatment with pemafibrate and eicosapentaenoic acid (EPA). Serum total cholesterol and TG levels were 237 mg/dL and 2535 mg/dL, respectively, while plasma pre-heparin lipoprotein lipase (LPL) mass was 15 ng/mL (26.5-105.5 ng/mL). We diagnosed her as Basedow\'s disease based on autoimmune antibodies and ultrasound examination. Targeted exome sequencing revealed no pathogenic variants in the LPL or GPIHBP1 genes. The serum GPIHBP1 autoantibody level was 686.0 U/mL (<58.4 U/mL) and GPIHBP1 mass was 301.9 pg/mL (570.6-1625.6 pg/mL). The patient showed hyperchylomicronemia during periods of hypothyroidism and hyperthyroidism, whereas GPIHBP1 autoantibodies were positive during episode of hyperchylomicronemia but negative during periods of normal TG levels. Based on these findings, the patient was diagnosed with hyperchylomicronemia due to GPIHBP1 autoantibodies and treated with rituximab. GPIHBP1 autoantibodies remained undetectable and TG levels were controlled at approximately 200 mg/dL.

A 37-year-old pregnant woman, was diagnosed with acute pancreatitis whilst being infected with COVID-19. Additionally, she had a hyperchylomicronemia and an uncontrolled (most probably, pre-gestational) type 2 diabetes. The coronavirus is able to enter the pancreatic cells through ACE-2 receptors. On the pancreatic level, ACE- 2 receptor expression is present but not as abundant as on pulmonary level. However, with inflammation (due to hyperchylomicronemia), the ACE-2 receptor expression may change and hypothetically make the pancreas more susceptible for a Covid-19 surinfection. Here it is difficult to conclude whether the COVID-19 infection contributed substantially to the development of pancreatitis. Late term pregnancy, uncontrolled glycaemia and the heterozygote mutation in the GPIHBP1 gene (c.523G>C p; Gly175Arg), all contribute to increased TG levels, a principal factor in the development of pancreatitis. This case shows a rare but serious clinical presentation late in pregnancy that could have interesting consequences postpartum.

BACKGROUND: The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown.
OBJECTIVE: The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population.
METHODS: Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up.
RESULTS: Patients with FCS were younger than those with MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, P < 0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least 1 episode of acute hypertriglyceridemic pancreatitis (AHP) (hazard ratio [HR] = 3.6; P < 0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HR = 0.3; P = 0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (odds ratio [OR] = 22.8; P < 0.01 in FCS and OR = 30.3; P < 0.01 in MCS).
CONCLUSIONS: The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.

Landmark studies have convincingly demonstrated that atherosclerosis begins in youth. While generally asymptomatic, an increasing number of youth with disorders of lipid and lipoprotein metabolism, such as familial hypercholesterolemia, are being identified through selective and universal screening. While a heart healthy lifestyle is the foundation of treatment for all youth with dyslipidemia, lipid-lowering therapy may be required by some to prevent morbidity and premature mortality, especially when initiated at a young age. When appropriate, use of statins has become standard of care for reducing low-density lipoprotein cholesterol, while fibrates may be beneficial in helping to lower triglycerides. Many therapeutic options commonly used in adults are not yet approved for use in youth less than 18 years of age. Although currently available lipid-lowering therapy is well tolerated and safe when administered to youth, response to treatment may vary and some conditions lack an efficient therapeutic option. Thus, newer agents are needed to aid in management. Many are in development and clinical trials in youth are currently in progress but will require FDA approval before becoming commercially available. Many utilize novel approaches to favorably alter lipid and lipoprotein metabolism. In the absence of long-term outcome data of youth who were treated beginning at an early age, clinical registries may prove to be useful in monitoring safety and efficacy and help to inform clinical decision-making. In this manuscript, we review currently available and novel therapeutic agents in development for the treatment of elevated cholesterol and triglycerides.

Currently available treatments have only been partly successful in patients with severe hypertriglyceridemia, including those with high serum triglycerides above 1,000 mg/dL (11.3 mmol/L), who often suffer from acute pancreatitis. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) which has been developed as an affordable oral tablet in Japan. We herein report the first three patients with severe hypertriglyceridemia who were successfully treated with pemafibrate.
Three patients with fasting serum triglyceride (TG) levels above 1,000 mg/dL (11.3 mmol/L) were treated with pemafibrate (0.2-0.4 mg/day, 0.1-0.2 mg BID).
Serum TGs decreased from 2,000-3,000 mg/dL (22.6-33.9 mmol/L) to < 250 mg/dL (2.8 mmol/L) without adverse effects in all three patients. Serum TGs in Patient 1 and 2 decreased from 1,326 mg/dL (15.0 mmol/L) to 164 mg/dL (1.9 mmol/L) and from 2,040 mg/dL (23.1 mmol/L) to 234 mg/dL (2.6 mmol/L), respectively. Patient 3 with type 2 diabetes and 12.1% (109 mmol/mol) hemoglobin A1c had a TG level of 2,300 mg/dL (26.0 mmol/L). Even after glycemic control improved, TG remained high. After pemafibrate administration, TG decreased to 200 mg/dL (2.3 mmol/L). All patients showed no serious adverse events.
Pemafibrate demonstrated potential efficacy and safety for severe hypertriglyceridemia which may contribute to the prevention of acute pancreatitis, in a manner that can be easily prescribed and used as an oral tablet.

The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown.
The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population.
Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up.
Patients with FCS were younger than those with MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, P < 0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least 1 episode of acute hypertriglyceridemic pancreatitis (AHP) (hazard ratio [HR] = 3.6; P < 0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HR = 0.3; P = 0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (odds ratio [OR] = 22.8; P < 0.01 in FCS and OR = 30.3; P < 0.01 in MCS).
The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.

暂无摘要。