Severe Hypercholesterolemia Research Articles

The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Severe hypercholesterolaemia--when to use the proprotein convertase subtilisin-kexin type 9 protease inhibitors (PCSK9 inhibitors)? Polish Society of Cardiology experts' group statement

The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i.e. one in every 250 people. As HeFH is a wellknown cause of premature coronary heart disease the rigorous treatment targets for LDL-C have been established in clinical guidelines. Their achievements, even with a high dose of high efficacy statin therapy is difficult or even impossible. New strong hypolipidaemic drugs i.e. PCSK9 inhibitors have been initiated against this chalange. Both drugs, evolocumab and alirocumab, have been extensively studied in numerous phase 2 and phase 3 trials. Fewer studies with bococizumab are available until now. The PCSK9 inhibitors, as monotherapy as well in combination with statins were associated with mean LDL-C reduction about 60%. It means that the majority of patients (70-90%) with severe hypercholesterolaemia (including HeFH), treated with statins, after addition of PCSK9 inhibitors were able to achieve an LDL-C < 2.5 mmol/L (< 100 mg/dL) or < 1.8 mmol/L (< 70 mg/dL) level. Another group of patients who may benefit from PCSK9 inhibitors include those who need lipid lowering therapy, but who are statin intolerant, especially because of statin-associated muscle symptoms (SAMS). In our statement we have accepted the diagnosis of SAMS proposed recently by European Atherosclerosis Society. Today the longest clinical trial with evolocumab (11 months) was the open OSLER study, and with alirocumab ODYSSEY LONG TERM (78 weeks). In the first one the reduction of cardiovascular events by 53% (95% Cl 22-72%) was observed, and in the second one by 48% (10-69%). Neurocognitive events were reported more frequently with both drugs than with placebo. This adverse effect will be the subject of observation in ongoing studies. We still await the results of 4 ongoing large placebo controlled phase 3 trials investigating whether PCSK9 inhibitors on background of statin therapy reduce cardiovascular events. Meanwhile evolocumab, as well as alirocumab have been accepted to use in clinical practice by European Medicine Agency. In this situation the experts of Polish Society of Cardiology have prepared the statement on the use PCSK9 inhibitors with indication in the first place for HeFH patients, statin intolerant and those at high risk who are not able to reach LDL-C target level with a high potent high dose statin.

Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

BackgroundApproximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. ObjectivesThis study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. MethodsThree genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. ResultsAmong 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. ConclusionsAmong participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

Novel therapies for severe dyslipidemia originating from human genetics.

Novel therapies for severe dyslipidemia target a wide range of unmet medical needs: severe familial hypercholesterolemia, severe hypertriglyceridemia and chylomicronemia, elevated lipoprotein (a), lipodystrophies, high-density lipoprotein particle diseases, lysosomal acid lipase deficiency and storage diseases, nonalcoholic fatty liver disease and others. The purpose of this review is to describe the contribution of human genetics to the development of therapeutic approaches targeting severe dyslipidemia. Recent advances in human genetics and the identification of rare genetic variants having strong effects on disease risk not only accelerated the development of therapies for severe dyslipidemia, they also revealed new pathways, genes and mechanisms of health, disease or drug response, and facilitated molecular diagnosis, which may prove essential as the authorized use of some of these novel drugs is limited to specific conditions. In addition, the dissection of the gene and cell machinery gave rise to new technologies, gene-based therapies and biodrugs covering a broad range of novel agents currently available or in clinical development to treat severe lipid disorders. Several novel therapies are recently available or under development to treat severe dyslipidemia and associated risk stem directly from genetic research. Altogether, these therapies target a broad variety of severe dyslipidemia pathways or mechanisms and illustrate that clinical lipidology has now entered the era of precision medicine.

Prior renovascular hypertension does not predispose to atherosclerosis in mice

BackgroundHypertension is a major risk factor for development of atherosclerotic cardiovascular disease (ASCVD). Although lowering blood pressure with antihypertensive drugs reduces the increased risk of ASCVD, residual increased risk still remains, suggesting that hypertension may cause chronic changes that promote atherosclerosis. Thus, we tested the hypothesis that hypertension increases the susceptibility to atherosclerosis in mice even after a period of re-established normotension. MethodsWe used the 2-kidney, 1-clip (2K1C) technique to induce angiotensin-driven renovascular hypertension, and overexpression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene to cause severe hypercholesterolemia and atherosclerosis. ResultsFirst, we performed 2K1C (n = 8) or sham surgery (n = 9) in PCSK9 transgenic mice before they were fed a high fat diet for 14 weeks. As expected, 2K1C did not affect cholesterol levels, but induced cardiac hypertrophy and significantly increased the atherosclerotic lesion area compared to sham mice (1.8 fold, p < 0.01). Next, we performed 2K1C (n = 13) or sham surgery (n = 14) in wild-type mice but removed the clipped/sham-operated kidney after 10 weeks to eliminate hypertension, and subsequently induced hypercholesterolemia by way of adeno-associated virus-mediated hepatic gene transfer of PCSK9 combined with high-fat diet. After 14 weeks of hypercholesterolemia, atherosclerotic lesion areas were not significantly different in mice with or without prior 2K1C hypertension (0.95 fold, p = 0.35). ConclusionRenovascular hypertension in mice does not induce pro-atherogenic changes that persist beyond the hypertensive phase. These results indicate that hypertension only promotes atherogenesis when coinciding temporally with hypercholesterolemia.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits

IntroductionSeveral studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits. MethodsJapanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks. ResultsDietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment. ConclusionsWe demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function.

Lipoprotein-X in a Patient with Lymphoplasmacytic Sclerosing Cholangitis: An Unusual Cause of Secondary Hypercholesterolemia

ABSTRACT Objective: To describe the presence of lipoprotein-X in a patient with obstructive liver disease and review the available literature on secondary hypercholesteremia occurring in the presence of lipoprotein-X. Methods: Reported is the case of a 40-year-old man who presented with severe hypercholesterolemia due to obstructive cholestasis secondary to lymphoplasmacytic sclerosing cholangitis. A literature search was conducted through PubMed for references from 1976 to 2013 regarding the appearance of lipoprotein-X in plasma secondary to cholestasis. Twenty-eight articles were found that addressed the physiology, pathogenesis, complications, or treatments of lipoprotein-X in the context of cholestasis. Results: Severe hypercholesterolemia was found in a patient with lymphoplasmacytic sclerosing cholangitis. His elevated plasma cholesterol level was due to the presence of lipoprotein-X, which is a particle with a density similar to low-density lipoprotein (LDL) that does not contain apolipoprotein B. ...

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management.

Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients with sitosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic individuals to those with severe hypercholesterolemia leading to accelerated atherosclerosis and premature cardiac death. Hematologic manifestations include hemolytic anemia with stomatocytosis, macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols and the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay should be performed in patients with normocholesterolemic xanthomas, hypercholesterolemia with unexpectedly good response to dietary modifications or to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to statins, or those with unexplained hemolytic anemia and macrothrombocytopenia. Because prognosis can be improved by proper management, it is important to find these patients out and diagnose correctly. This review article aimed to summarize recent publications on sitosterolemia, and to suggest clinical indications for plant sterol assay.

A descriptive retrospective study on children with newly diagnosed nephrotic syndrome presented to Tripoli Children Hospital during the period between Jan. to Dec. 2014

Abstract Introduction: Nephrotic syndrome (NS) is a clinical picture characterized by severe proteinuria, hypoalbuminemia, edema and hypercholesterolemia. A retrospective study was carried out in order to describe disease pattern in newly diagnosed NS of children admitted to Tripoli children hospital during the year 2014. Methods: The medical data of 56 patients aged between 1 year and 11 years diagnosed with idiopathic nephrotic syndrome were analysed using SPSS software. The data included gender differences, sensitivity to steroid therapy, relapses withen six months of follow up and the effect of variable factors such as family history, hypertension, hematuria, serum urea on the degree of relapse. Results: Out of 56 patients with newly diagnosed NS, 60.7% were boys and 39.3% were girls, with a mean age 4.2±2.2 years. Age was related significantly to the response to steroid therapy, where 79.5% of patients aged between 2-8 years (group 1) had steroid sensitive NS (SSNS) compared with only 41.7% of patients aged less than 2 years or more than 8 years (group 2) (P&lt;0.001). Although girls relapsed more than boys (70.5% versus 57.1%) during six months of therapy, this difference was not statistically significant. Similarly, no other factors measured such as family history of NS, hypertension, hematuria, serum complement and urea had any effect on the percentage of relapse in patients with newly diagnosed NS. Conclusion: NS is one of the commonest reasons for admission to nephrology ward. It is more common in boys than girls. The age at presentation related significantly to the response to steroidal therapy. Regarding relapses, girls seems to relapse more frequent than boys and relapses was seen more in age group 1 than group 2, however, these differences were not significant. Other factors studied seems to have no effect on the relapse rate of children with newly diagnosed NS.

Severe hypercholesterolemia and liver disease in a 3-year old

Lipoprotein-X, which is composed of phospholipids and non-esterified cholesterol, is an abnormal lipoprotein with a density range similar to LDL-C. The two most common ways which lipoprotein-X accumulates is from reflux of bile salts into plasma or deficiency in lecithin cholesterol acyltransferase. This is a case of severe hypercholesterolemia and liver disease in a 3- year old male that presented with pruritus, pale stool, scleral ictus, and abdominal distention. He was diagnosed with primary sclerosing cholangitis which was confirmed by liver biopsy. Our patient was treated with steroids and immunomodulator therapy which was associated with significant reduction in cholestasis and LDL-C levels. Lipoprotein-X has several properties that make it anti-atherogenic, which raises the question if treatment for hypercholesterolemia should be initiated.

Genetic Dissection of Tissue-Specific Apolipoprotein E Function for Hypercholesterolemia and Diet-Induced Obesity.

ApoE deficiency in mice (Apoe −/−) results in severe hypercholesterolemia and atherosclerosis. In diet-induced obesity, Apoe −/− display steatohepatitis but reduced accumulation of triacylglycerides and enhanced insulin sensitivity in white adipose tissue (WAT). Although the vast majority of apoE is expressed by hepatocytes apoE is also abundantly expressed in WAT. As liver and adipose tissue play important roles for metabolism, this study aims to outline functions of both hepatocyte- and adipocyte-derived apoE separately by investigating a novel mouse model of tissue-specific apoE deficiency. Therefore we generated transgenic mice carrying homozygous floxed Apoe alleles. Mice lacking apoE either in hepatocytes (Apoe ΔHep) or in adipose tissue (Apoe ΔAT) were fed experimental diets. Apoe ΔHep exhibited slightly higher body weights, adiposity and liver weights on diabetogenic high fat diet (HFD). Accordingly, hepatic steatosis and markers of inflammation were more pronounced compared to controls. Hypercholesterolemia evoked by lipoprotein remnant accumulation was present in Apoe ΔHep mice fed a Western type diet (WTD). Lipidation of VLDL particles and tissue uptake of VLDL were disturbed in Apoe ΔHep while the plasma clearance rate remained unaltered. Apoe ΔAT did not display any detectable phenotype, neither on HFD nor on WTD. In conclusion, our novel conditional apoE deletion model has proven here the role of hepatocyte apoE for VLDL production and diet-induced dyslipidemia. Specific deletion of apoE in adipocytes cannot reproduce the adipose phenotype of global Apoe −/− mice, suggesting that apoE produced in other cell types than hepatocytes or adipocytes explains the lean and insulin-sensitive phenotype described for Apoe −/− mice.

Assessment of Subclinical Atherosclerosis Using Computed Tomography Calcium Scores in Patients with Familial and Nonfamilial Hypercholesterolemia

The aim of this study was to compare coronary calcium scores and aortic calcium scores between patients with severe hypercholesterolemia having a DNA-based diagnosis of FH (FH group) versus patients with severe hypercholesterolemia without the FH gene mutation (NFH group). A total of 89 FH and 50 NFH patients underwent CT with coronary and thoracic aorta calcium scoring. Their CCS and TCS in ascending aorta (TCSasc) and descending aorta (TCSdesc) were determined and compared between the two patient groups. TCSasc was significantly higher in the FH group when compared to the NFH group (30.6± 59 vs 4.7±13.4, p＜0.001. After adjusting for age, sex, smoking, blood pressure, history of diabetes mellitus and LDL cholesterol levels, FH gene mutation was an independent risk factor of having non-zero TCSasc 3.6 (95% CI, 1.4-9.5, p＜0.01), high TCSasc 9.6 (95% CI, 2.4-38.2, p＜0.01) and high CCS of 4.1 (95% CI, 1.2-13.2. p＜0.05). We found that when computed tomography calcium scores were used as an assessment, patients with familial hypercholesterolemia displayed an increased burden of ascending aorta atherosclerosis when compared to patients with nonfamilial severe hypercholesterolemia. This phenomenon appears to be more dependent on the presence of FH genotype than hypercholesterolemia itself.

The hinterland of familial hypercholesterolaemia: what do we not know?

Familial hypercholesterolaemia is the commonest autosomal dominant disorder in man, but many questions about familial hypercholesterolaemia remain to be answered. Guidelines are increasing in importance as healthcare becomes standardized. The review suggests areas that require more investigation or where pertinent guidelines may need to be reviewed. Familial hypercholesterolaemia is commoner than previously thought, but its epidemiology needs further investigation against a background of changing environmental and lifestyle factors that may bear on its phenotypic expression. Screening for familial hypercholesterolaemia may be more difficult than might be thought as cascade testing may not capture all cases effectively and universal screening appears compelling, but requires testing and evaluation. Cardiovascular disease guidelines are moving to being risk based, but familial hypercholesterolaemia stands alone as defined by large database of lipids-cholesterol criteria. A risk-based approach may need to be considered for familial hypercholesterolaemia, but a good evidence base is required. The effects of older therapies on prognosis in familial hypercholesterolaemia are based on surrogate as opposed to cardiovascular disease outcomes. Novel efficacious but expensive therapies are on the horizon, but no specific outcome trials in familial hypercholesterolaemia are planned and they may not be cost-effective outside very severe familial hypercholesterolaemia. Further research is also required to trial and test different models of care for familial hypercholesterolaemia. Despite familial hypercholesterolaemia being a common genetic condition, aspects of basic epidemiology, risk assessment, treatment, and models of care remain uncertain.

Defining the Role of PCSK9 Inhibitors in the Treatment of Hyperlipidemia.

Statins remain the mainstay of medical cardiovascular risk reduction because of their effectiveness in decreasing low-density lipoprotein cholesterol (LDL-C) as well as some other potentially beneficial effects. The latest US 2013 lipid guidelines essentially recommend only the prescription of a high-dose statin for the high-risk patient. However, both quite old and quite new outcomes evidence, such as reported for ezetimibe, emphasize that LDL-C lowering is, in and of itself, quite important for cardiovascular risk reduction. It appears that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a major new contribution to this effort, especially for patients with severe familial hypercholesterolemia, proven clinical cardiovascular disease, statin intolerance, or failure to attain an acceptably low LDL-C goal despite maximum available medical management. Very recent clinical trials have proven overwhelmingly the effectiveness and safety of PCSK9 inhibitors for lowering LDL-C. Both alirocumab and evolocumab have now been approved by the US FDA and there are some initial favorable outcomes data. This review is intended to summarize available evidence and emphasize the possible clinical role of these inhibitors following the approval of alirocumab and evolocumab. Understanding the negative receptor feedback of PCSK9 and the mechanism and beneficial effect of PCSK9 inhibitors for cardiovascular risk reduction is essential for the up-to-date practitioner of cardiovascular medicine. There is every reasonable hope for significant cardiovascular benefit from these new additions to our medical cardiovascular armamentarium.

Apheresis Treatment In German Patients With Severe Hypercholesterolemia - A Psychodrama Market Research

Apheresis Treatment In German Patients With Severe Hypercholesterolemia - A Psychodrama Market Research

Gallstone and Severe Hypertriglyceride-Induced Pancreatitis in Pregnancy.

Patients with biliary disease or underlying dyslipidemias are at risk for pancreatitis in pregnancy. Appropriate treatment can decrease the risk of recurrence and perinatal complications. Prevention of severe lipid elevations can prevent the development of pancreatitis in pregnancy. To review the pathophysiology, diagnosis and treatment of gallstone and severe hypertriglyceride-induced pancreatitis in pregnancy. We performed a literature search regarding pancreatitis, gallstones, hyperlipidemia, and the treatment of both severe hypertriglyceride-induced pancreatitis and gallstone pancreatitis in pregnancy. In the setting of acute pancreatitis, removal of the offending agent, either gallstones or serum lipids, can lead to improved status and decrease recurrence risk. Patients with acute pancreatitis should be treated with analgesia and fluid resuscitation and maintain a nothing-per-os status. In cases of gallstone pancreatitis, removal of the offending stone through endoscopic retrograde cholangiopancreatography or cholecystectomy can decrease recurrence risk. Severe hypertriglyceride-induced pancreatitis includes similar management. Lipopheresis may be considered in refractory cases. Patients with severe hypercholesterolemia should maintain a low-fat diet and can continue lipid-lowering agents outside the statin class of medications. Preventing severe dyslipidemia in gestation can decrease the risk of pancreatitis and improve maternal and neonatal outcomes.

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

BackgroundThere is clinical interest in identifying novel lipid biomarkers for evaluating cardiovascular risk and targeting lipid-lowering treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in the dysregulated cholesterol transfer from modified lipoproteins to human coronary vascular smooth muscle cells (hVSMCs), promoting hVSMC-derived foam cell formation. LRP1 has a soluble and circulating form (sLRP1) generated from LRP1. Cholesterol modulates the release of the soluble form of LRP1. Using in vitro, ex vivo and patient-based approaches, we tested the association between circulating sLRP1 concentrations and hypercholesterolemia and the potential of sLRP1 as a biomarker of atherosclerosis. Methods and resultsCirculating sLRP1 concentrations were higher in severe hypercholesterolemia compared to moderate hypercholesterolemia or normocholesterolemia (Study 1). Circulating sLRP1 was significantly associated with established pro-atherogenic lipid parameters in two different hypercholesterolemic populations (Studies 2 and 3). sLRP1 concentrations decreased after statin treatment and increased after statin withdrawal (Study 3). In vitro experiments showed that native LDL, aggregated LDL and VLDL+IDL lipoproteins induced the release of sLRP1 from hVSMC. sLRP1 levels were increased in the conditioned medium of coronary atherosclerotic plaque areas extracted from patients compared to non-atherosclerotic areas of the same coronary artery and patient. Circulating sLRP1 concentrations were independently associated with the occurrence of carotid atherosclerosis in a hypercholesterolemic population (Study 2). The later association was higher than that observed for other classical or novel lipid parameters. ConclusionsCirculating sLRP1 is a new lipid-related parameter potentially useful as a biomarker for atherosclerosis.

Erratum: Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing

Familial hypercholesterolaemia (FH) is a serious genetic metabolic disease. We identified a specific family in which the proband had typical homozygous phenotype of FH, but couldn’t detect any mutations in usual pathogenic genes using traditional sequencing. This study is the first attempt to use whole exome sequencing (WES) to identify the pathogenic genes in Chinese FH. The routine examinations were performed on all parentage members, and WES on 5 members. We used bioinformatics methods to splice and filter out the pathogenic gene. Finally, Sanger sequencing and cDNA sequencing were used to verify the candidate genes. Half of parentage members had got hypercholesterolaemia. WES identified LDLR IVS8[−10] as a candidate mutation from 222,267 variations. The Sanger sequencing showed proband had a homozygous mutation inherited from his parents, and this loci were cosegregated with FH phenotype. The cDNA sequencing revealed that this mutations caused abnormal shearing. This mutation was first identified in Chinese patients, and this homozygous mutation is a new genetic type of FH. This is the first time that WES was used in Chinese FH patients. We detected a novel genetic type of LDLR homozygous mutation. WES is powerful tools to identify specific FH families with potentially pathogenic gene mutations.

Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis.

Lipoprotein X (LpX) is an abnormal lipoprotein found in conditions such as lecithin:cholesterol acyltransferase deficiency and cholestatic states (e.g., primary biliary cirrhosis and primary sclerosing cholangitis). Management of severe hypercholesterolemia due to LpX with drugs and physical removal methods is not well established in the literature. A case is discussed of a 51-year-old woman who presented with multiple electrolyte abnormalities, xanthomas and neuropathy found to be secondary to LpX in the setting of primary sclerosing cholangitis. This case highlights that oral medications, including statins, may be insufficient to normalize lipid levels or improve clinical symptoms of LpX and presents therapeutic plasma exchange as a safe and effective therapeutic option to treat the morbid sequela of LpX hyperlipidemia.