Disappearance of recurrent pancreatitis after splenectomy in familial chylomicronemia syndrome

Background and aims: Recurrent pancreatitis is a severe complication of familial chylomicronemia syndrome (FCS) mainly secondary to lipoprotein lipase deficiency. The mechanism and interindividual variability of pancreatitis in FCS are not fully understood, but abnormalities in the drainage system of pancreatic veins could be involved. Methods and results: Two cases of typical FCS are described with a past history of recurrent pancreatitis that dramatically improved after splenectomy performed in both cases for reasons non-related to FCS. Conclusions: These are the first reports of the disappearance of pancreatitis after splenectomy in FCS and they should be considered of anecdotal nature at this time. The disappearance of pancreatitis following splenectomy could be in part due to subsequent improvements in pancreatic drainage. Extrahepatic portal hypertension induced by hypertriglyceridemic splenomegaly leading to pancreatic congestion could also be a contributing factor

Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors

ANGPTL3 gene variants in subjects with familial combined hyperlipidemia

Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans. Loss-of-function variants in ANGPTL3 cause a monogenic disease named familial combined hypolipidemia. However, the potential contribution of ANGPTL3 gene in subjects with familial combined hyperlipidemia (FCHL) has not been studied. For that reason, the aim of this work was to investigate the potential contribution of ANGPTL3 in the aetiology of FCHL by identifying gain-of-function (GOF) genetic variants in the ANGPTL3 gene in FCHL subjects. ANGPTL3 gene was sequenced in 162 unrelated subjects with severe FCHL and 165 normolipemic controls. Pathogenicity of genetic variants was predicted with PredictSNP2 and FruitFly. Frequency of identified variants in FCHL was compared with that of normolipemic controls and that described in the 1000 Genomes Project. No GOF mutations in ANGPTL3 were present in subjects with FCHL. Four variants were identified in FCHL subjects, showing a different frequency from that observed in normolipemic controls: c.607-109T>C, c.607-47_607-46delGT, c.835+41C>A and c.*52_*60del. This last variant, c.*52_*60del, is a microRNA associated sequence in the 3'UTR of ANGPTL3, and it was present 2.7 times more frequently in normolipemic controls than in FCHL subjects. Our research shows that no GOF mutations in ANGPTL3 were found in a large group of unrelated subjects with FCHL

Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia

Background and aims: The effect of LDLc lowering with PCSK9 antibodies on tendon xanthomas (TX) is unknown. Methods: TX was measured in 24 heterozygous familial hypercholesterolemia (HeFH) cases and in 24 HeFH controls with or without PCSK9 inhibitors for at least one year. Results: Exposure to PCSK9 inhibitors in cases was 2.96 ± 1.33 years. LDLc decreased 80.8 ± 7.66% in cases and 56.9 ± 11.1% in controls. There was a decrease in maximum (-5.03%) and mean (-5.32%) TX in cases but not in controls (+3.97%, +3.16, respectively, p = 0.01). PCSK9 inhibitor treatment was independently associated with TX reduction. Conclusion: Addition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and TX after 3 years of treatment

Bile acid synthesis precursors in subjects with genetic hypercholesterolemia negative for LDLR/APOB/PCSK9/APOE mutations. Association with lipids and carotid atherosclerosis

Some oxysterols are precursors of bile acid synthesis and play an important role in cholesterol homeostasis. However, if they are involved in the pathogeny of genetic hypercholesterolemia has not been previously explored. We have studied non-cholesterol sterol markers of cholesterol synthesis (lanosterol and desmosterol) and oxysterols (7a-hydroxy-4-cholesten-3-one, 24S-hydroxycholesterol and 27-hydroxycholesterol) in 200 affected subjects with primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH) and 100 normolipemic controls. All studied oxysterols and cholesterol synthesis markers were significantly higher in affected subjects than controls (P < 0.001). Ratios of oxysterols to total cholesterol were higher in non-FH GH than in controls, although only 24S-hydroxycholesterol showed statistical significance (P < 0.001). Cholesterol synthesis markers had a positive correlation with BMI, triglycerides, cholesterol and apoB in control population. However, these correlations disappeared in non-FH GH with the exception of a weak positive correlation for non-HDL cholesterol and apoB. The same pattern was observed for oxysterols with high positive correlation in controls and absence of correlation for non-FH GH, except non-HDL cholesterol for 24S-hydroxycholesterol and 27-hydroxycholesterol and apoB for 27-hydroxycholesterol. All non-cholesterol sterols had positive correlation among them in patients and in controls. A total of 65 (32.5%) and 35 (17.5%) affected subjects presented values of oxysterols ratios to total cholesterol above the 95th percentile of the normal distribution (24S-hydroxycholesterol and 27-hydroxycholesterol, respectively). Those patients with the highest levels of 24S-hydroxycholesterol associated an increase in the carotid intima media thickness. These results suggest that bile acid metabolism is affected in some patients with primary hypercholesterolemia of genetic origin, negative for mutations in the candidate genes, and may confer a higher cardiovascular risk. Our results confirm that cholesterol synthesis overproduction is a primary defect in non-HF GH and suggest that subjects with non-FH GH show high levels of oxysterols in response to hepatic overproduction of cholesterol

Lipid-lowering response in subjects with the p.(Leu167del) mutation in the APOE gene

Background and aims: The aim of this work was to compared the effect of lipid lowering drugs among familial hypercholesterolemia (FH) subjects with a functional mutation in LDLR (LDLR FH) and FH with the p.(Leu167del) mutation in APOE. Methods: We retrospectively selected all adults with the p.(Leu167del) mutation on lipid-lowering treatment (n = 22) attending the Lipid Unit at the Hospital Miguel Servet. Age and sex matched LDLR FH from the same Unit were randomly selected as a control group (n = 44). Results: The mean percentage reduction in LDLc was significantly higher in the p.(Leu167del) carriers (-52.1%) than in the LDLR FH (-39.7%) (p = 0.040) when on high intensity statins. Similar differences between groups were observed in non-HDLc -49.4% and -36.4%, respectively (p = 0.030). Conclusions: Subjects with p.(Leu167del) mutation have a higher lipid-lowering response to statins with or without ezetimibe than LDLR FH. This supports the use of genetics for a more efficient management of FH

Frequency of rare mutations and common genetic variations in severe hypertriglyceridemia in the general population of Spain

Background: Hypertriglyceridemia (HTG) is a common complex metabolic trait that results of the accumulation of relatively common genetic variants in combination with other modifier genes and environmental factors resulting in increased plasma triglyceride (TG) levels. The majority of severe primary hypertriglyceridemias is diagnosed in adulthood and their molecular bases have not been fully defined yet. The prevalence of HTG is highly variable among populations, possibly caused by differences in environmental factors and genetic background. However, the prevalence of very high TG and the frequency of rare mutations causing HTG in a whole non-selected population have not been previously studied. Methods: The total of 23, 310 subjects over 18 years from a primary care-district in a middle-class area of Zaragoza (Spain) with TG >500 mg/dL were selected to establish HTG prevalence. Those affected of primary HTG were considered for further genetic analisys. The promoters, coding regions and exon-intron boundaries of LPL, LMF1, APOC2, APOA5, APOE and GPIHBP1 genes were sequenced. The frequency of rare variants identified was studied in 90 controls. Results: One hundred ninety-four subjects (1.04 %) had HTG and 90 subjects (46.4 %) met the inclusion criteria for primary HTG. In this subgroup, nine patients (12.3 %) were carriers of 7 rare variants in LPL, LMF1, APOA5, GPIHBP1 or APOE genes. Three of these mutations are described for the first time in this work. The presence of a rare pathogenic mutation did not confer a differential phenotype or a higher family history of HTG. Conclusion: The prevalence of rare mutations in candidate genes in subjects with primary HTG is low. The low frequency of rare mutations, the absence of a more severe phenotype or the dominant transmission of the HTG would not suggest the use of genetic analysis in the clinical practice in this population

The effects of high-intensity interval training on glucose metabolism, cardiorespiratory fitness and weight control in subjects with diabetes: systematic review a meta-analysis

Aim: The objective of this meta-analysis was to explore the effects of high-intensity interval training (HIIT) compared with control conditions (CON) or moderate intensity continuous training (MICT) on glycemic parameters in diabetes subjects. Methods: Pubmed, Embase and Google Scholar databases were searched for HIIT interventions that were carried out in diabetic subjects and exploring fasting glucose, glycated haemoglobin (HbA1c), fasting insulin and/or HOMA-IR. Results: This systematic review retrieved a total of 1741 studies of which 32 articles fulfilled the eligibility criteria. Nineteen trials were included in the meta-analysis since they compared HIIT intervention with CON or MICT group. There was a significantly reduction of fasting glucose of 13.3 mg/dL (p < 0.001), Hb1Ac -0.34% (p < 0.001), insulin -2.27 UI/L (p = 0.003), HOMA-IR -0.88 (p = 0.005) in the HIIT-group compared with CON-group. Nevertheless, this reduction was not significantly different when comparing HIIT with MICT (p = 0.140, p = 0.315, p = 0.520 and p = 0.389). Besides, there was a significant increase of absolute VO2max of 0.21 L/min (p < 0.001) and relative VO2max of 2.94 ml/kg/min (p < 0.001) in the HIIT-group compared with the CON-group and the MICT-group (0.22 L/min, p = 0.025) and (0.97 ml/kg/min, p = 0.045). Conclusions: These findings revealed that HIIT intervention led to significant improvement in glycemic control and insulin resistance in subjects with diabetes compared with CON-group

Effect of Lifestyle Intervention in the Concentration of Adipoquines and Branched Chain Amino Acids in Subjects with High Risk of Developing Type 2 Diabetes: Feel4Diabetes Study

Introduction: The global prevalence of type 2 diabetes (T2D) is increasing rapidly, especially in low- and middle-income countries and has a high number of associated comorbidities. Plasmatic concentrations of branched chain amino acids (BCAA) and retinol-binding protein 4 (RBP4) have been shown to be elevated in T2D subjects in cross-sectional studies. However, the effect of lifestyle community-based interventions on BCAA and RBP4 concentrations has not yet been analyzed. Material and methods: The Feel4Diabetes study is a school and community-based intervention that identified 360 European families with a high risk of developing T2D according to the FINDRISC questionnaire. Families were randomized in control and intervention groups were followed-up from 2016 to 2018. In the Spanish families, the concentration of BCAA and RBP4 was determined in 266 subjects (115 control and 151 intervention group) that attended the three time-point assessments by colorimetric and ELISA reaction, respectively. Results: Baseline BCAA levels showed positive correlations with the FINDRISC score and glucose impairment (baseline glucose, insulin, and glycated hemoglobin), body mass index, and body weight. The participants receiving the community-based intervention showed a significant decrease in glycated hemoglobin and BCAA levels compared to the control group (p = 0.011 and p < 0.001, respectively). However, baseline RBP4 did not show significant correlations with anthropometric and glycemic parameters, and no significant change was observed in anthropometric parameters and RBP4 concentrations throughout the follow-up. Conclusion: A community-based intervention on lifestyle led to a significant reduction in BCAA levels regardless of weight loss. These findings suggest that this interventional approach could be promising in T2D prevention

Energy-restricted, high-protein diets more effectively impact cardiometabolic profile in overweight and obese women than lower-protein diets

Background & aims High-protein energy-restricted diets have demonstrated efficacy in promoting weight loss in overweight and obesity. However, the protein percentage that achieves optimal efficacy and acceptability remains unknown. We sought to assess the effects of three energy-reduced diets with different percentages of calories from protein (20%, 27%, and 35%) on weight loss and lipids. Secondary outcomes included diet acceptability and compliance. Methods Six-month, randomized study included women aged 18–80 years with BMI of 27.5–45 kg/m2 and who were not taking lipid-lowering drugs. We randomly assigned 91 women to one of three calorie-reduced diets with: protein, 20%, 27%, or 35% (80% from animal protein); carbohydrates, 50%, 43%, or 35%; fat, 30%. Dietary intervention involved individual visits with a nutritionist every 2 weeks during the first 3 months. We performed a follow-up visit at 6 months. Results Eighty women aged 44.0 ± 9.08 years with BMI of 37.7 ± 3.39 kg/m2 completed the study. At 3 months, weight loss was -8.16 ± 4.18 kg, -9.66 ± 5.28 kg, and -10.7 ± 4.28 kg in the 20%, 27%, and 35%-protein groups, respectively (P = 0.16). These figures slightly and homogeneously increased at 6 months. Around 65% of women following 35%-protein diet lost =10% of body weight vs. ~33% in 20%-protein group (P = 0.023). Significant decreases occurred in fat mass, lipids and insulin resistance, especially in the 35%-protein group (P < 0.05 vs. 20% protein). This improvement was not fully explained by weight loss. Triglyceride change was negatively correlated with animal-protein intake. All groups provided similar responses to an acceptance, palatability, and satisfaction questionnaire. Conclusions An energy-restricted diet with 35% protein, mostly of animal origin, more effectively impacts cardiometabolic profile than an energy-restricted diet with lower protein content although no clear benefit between diets in terms of overall weight loss was observed. The high-protein diet displayed an excellent safety profile and acceptability. This trial was registered in ClinicalTrials.gov as NCT02160496. Clinical trial registration The clinical trial has been registered in ClinicalTrials.gov (Identifier: NCT02160496)