Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease involving lysosomal accumulation of cholesteryl esters and triglycerides. The International Lysosomal Acid Lipase Deficiency Registry (NCT01633489), established in 2013 to understand LAL-D natural history and long-term outcomes, is accessible to centres caring for patients diagnosed by deficient LAL activity and/or biallelic pathogenic LIPA variants. We describe the registry population enrolled through 2 May 2022. METHODS: In this prospective observational study, we analysed demographic and baseline clinical characteristics of children (ages ≥6 months to <18 years) and adults diagnosed with LAL-D. RESULTS: Of 228 patients with confirmed disease, 61% were children; 202/220 (92%) with data on race were white. Median age was 5.5 years at sign/symptom onset and 10.5 years at diagnosis; median time from sign/symptom onset to diagnostic testing was 3.3 years. The most common manifestations raising suspicion of disease were elevated alanine (70%) and aspartate aminotransferase levels (67%) and hepatomegaly (63%). Among 157 with reported LIPA mutations, 70 were homozygous and 45 were compound heterozygous for the common exon 8 splice junction pathogenic variant (E8SJM-1). Seventy percent (159/228) of patients had dyslipidaemia. Among 118 with liver biopsies, 63% had microvesicular steatosis exclusively, 23% had mixed micro- and macrovesicular steatosis and 47% had lobular inflammation. Of 78 patients with fibrosis-stage data, 37% had bridging fibrosis and 14% had cirrhosis. CONCLUSIONS: Although LAL-D signs/symptoms occur early, diagnosis is often delayed. Abnormal transaminase levels associated with hepatomegaly and dyslipidaemia should raise suspicion and prompt earlier diagnosis of LAL-D. TRIAL REGISTRATION NUMBER: NCT01633489.

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8-10 years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population. RECENT FINDINGS: Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth. Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in children and adults: Consensus recommendations from an international collaborative working group.

BACKGROUND: Lysosomal acid lipase (LAL) deficiency is an ultra-rare, progressive, autosomal recessive disorder. Functional mutations in LIPA, the gene that encodes LAL, result in accumulation of cholesteryl esters and triglycerides in hepatocytes and in the macrophages of the intestines, vascular endothelial system, and numerous other organs. LAL deficiency has a broad clinical spectrum; children and adults can present with dyslipidemia, liver enzyme elevations, hepatosplenomegaly, hepatic steatosis, liver fibrosis and/or cirrhosis, and vascular disease, which may lead to significant morbidity and premature mortality in some patients. Given the systemic involvement and the wide range of healthcare specialists who manage patients with LAL deficiency, there is a need for guidelines to assess and monitor disease involvement. OBJECTIVES: To provide a set of recommendations for the initial assessment and ongoing monitoring of patients with LAL deficiency to help physicians in various disciplines effectively manage the disease based on the observed presentation and progression in each case. METHODS: A group of internationally recognized healthcare specialists with expertise in clinical genetics, pathology, hepatology, gastroenterology, cardiology, and lipidology convened to develop an evidence-based consensus of best practices for the initial assessment and ongoing monitoring of children and adults with LAL deficiency, regardless of treatment status; infants with LAL deficiency have been excluded from these guidelines because they require specialized care. RESULTS: The authors present guidance for the assessment and monitoring of patients with LAL deficiency based on age and disease manifestations that include the hepatic, cardiovascular, and gastrointestinal systems. A schedule for ongoing monitoring of disease progression is provided. In addition, the need to establish an interdisciplinary and integrated care team to optimize the approach to managing this systemic disease is highlighted. CONCLUSIONS: There is currently no published guidance on the assessment and monitoring of patients with LAL deficiency. These consensus recommendations for the initial assessment and ongoing monitoring of children and adults with LAL deficiency are intended to help improve the management of these patients.

Reverse Cascade Screening for Familial Hypercholesterolemia.

PROBLEM: Cardiovascular disease (CVD) is the leading cause of death in the U.S. and in most Western countries. Early identification and treatment of individuals with elevated levels of atherogenic cholesterol, a major contributor to CVD, have been shown to be effective and safe in reducing premature morbidity and mortality, especially in familial hypercholesterolemia (FH). Cholesterol screening of youth also provides a unique means of identifying affected family members through reverse cascade screening (RCS). ELIGIBILITY CRITERIA: A PubMed review of all relevant articles from 2000 to 2016 was conducted of familial hypercholesterolemia and cholesterol screening of youth. RESULTS: We provide an overview of cholesterol screening, outline the role of the pediatric nurse in the lipid clinic, and discuss effectiveness and potential barriers, including cost and confidentiality considerations of RCS. CONCLUSIONS: Early identification and effective intervention of youth with FH, including adoption of a heart-healthy lifestyle, has the potential of 1) markedly reducing or eliminating atherosclerotic cardiovascular disease and related events in future generations and 2) provides a unique means of identifying affected family members. IMPLICATIONS: Pediatric nurses play a vital role in the education and care coordination of children diagnosed with FH and screening of relatives. Identification of a child with FH with effective screening of relatives combines the benefits of universal and cascade screening, and has the potential of detecting all living cases of FH. While potentially providing significant benefit to those at risk for premature CVD, a RCS program needs to carefully consider ethical, psychological, and financial implications as well.

Diabetes management mediating effects between diabetes symptoms and health-related quality of life in adolescents and young adults with type 1 diabetes.

OBJECTIVES: The primary objective was to investigate the mediating effects of diabetes management in the relationship between diabetes symptoms and generic health-related quality of life (HRQOL) in adolescents and young adults (AYAs) with type 1 diabetes. The secondary objective explored patient health communication and perceived treatment adherence barriers as mediators in a serial multiple mediator model. METHODS: The PedsQL 3.2 Diabetes Module 15-item diabetes symptoms summary score, 18-item diabetes management summary score, and PedsQL 4.0 generic core scales were completed in a 10-site national field test study by 418 AYA aged 13 to 25 years with type 1 diabetes. Diabetes symptoms and diabetes management were tested for bivariate and multivariate linear associations with overall generic HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of diabetes management as an intervening variable between diabetes symptoms and generic HRQOL. RESULTS: The predictive effects of diabetes symptoms on HRQOL were mediated in part by diabetes management. In predictive analytics models utilizing multiple regression analyses, demographic and clinical covariates, diabetes symptoms, and diabetes management significantly accounted for 53% of the variance in generic HRQOL (P < 0.001), demonstrating a large effect size. Patient health communication and perceived treatment adherence barriers were significant mediators in an exploratory serial multiple mediator model. CONCLUSIONS: Diabetes management explains in part the effects of diabetes symptoms on HRQOL in AYA with type 1 diabetes. Patient health communication to healthcare providers and perceived treatment adherence barriers further explain the mechanism in the relationship between diabetes symptoms and overall HRQOL.

Diabetes symptoms predictors of health-related quality of life in adolescents and young adults with type 1 or type 2 diabetes.

OBJECTIVES: The objective was to investigate the patient-reported diabetes symptoms predictors of generic health-related quality of life (HRQOL) in adolescents and young adults (AYA) with type 1 or type 2 diabetes. METHODS: The 15-item PedsQL™ 3.2 Diabetes Module Diabetes Symptoms Summary Score and PedsQL™ 4.0 Generic Core Scales were completed in a 10-site national field test study by 513 AYA ages 13-25 years with type 1 (n = 424) or type 2 (n = 89) diabetes. Diabetes symptoms were tested for bivariate and multivariate linear associations with generic HRQOL. RESULTS: Diabetes symptoms were associated with decreased HRQOL in bivariate analyses. In predictive analytics models utilizing hierarchical multiple regression analyses controlling for relevant demographic and clinical covariates, diabetes symptoms accounted for 38 and 39% of the variance in patient-reported generic HRQOL for type 1 and type 2 diabetes, respectively, reflecting large effect sizes. The diabetes symptoms facets hyperglycemia symptoms, hypoglycemia symptoms, and nonspecific diabetes symptoms individually accounted for a significant percentage of the variance in separate exploratory predictive analytics models after controlling for demographic and clinical covariates, with small-to-large effect sizes. CONCLUSIONS: Diabetes symptoms are potentially modifiable predictors of generic HRQOL in AYA with diabetes. Identifying specific diabetes symptoms or symptoms facets that are the most important predictors from the patient perspective facilitates a patient-centered approach in clinical research, clinical trials, and practice designed to enhance overall generic HRQOL in AYA with diabetes.

Genetics of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.

Pediatric dyslipidemia: recommendations for clinical management.

During the last 50 years, it has become evident that atherosclerosis originates in childhood. Although cardiovascular disease (CVD) events are rare in children, autopsy data and imaging studies have documented subclinical disease in association with measurable risk factors during childhood. When present at a young age, risk factors track into adulthood and have been associated with a moderate to high risk of future CVD. As such, the ability to identify this vulnerable population creates the opportunity to prevent the development of risk factors and future CVD events with effective management of genetic and acquired risk factors. In 2011, the National Heart, Lung, and Blood Institute Expert Panel published comprehensive guidelines summarizing the current evidence and providing developmentally appropriate recommendations for screening, treatment, and follow-up of children and adults younger than 21 years at risk for premature CVDs such as myocardial infarction and stroke. In addition to screening individuals with a family history of hypercholesterolemia and/or premature CVD, the Expert Panel recommended universal screening of all children between 9 and 11 years of age and then again between 17 and 21 years of age. Although the recommendation for universal screening, regardless of general health or the presence/absence of risk factors of CVD, is not without controversy, this review serves to create awareness among healthcare providers, elected officials, and the lay public about the burden of CVD, the opportunity for prevention, and the benefits of early and effective therapeutic intervention with lifestyle changes and lipid-lowering medications.

A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice.

Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification. Individuals with Lp(a) levels <75 nmol/L (30 mg/dL) are considered low risk, individuals with Lp(a) levels ≥125 nmol/L (50 mg/dL) are considered high risk, and individuals with Lp(a) levels between 75 and 125 nmol/L (30-50 mg/dL) are at intermediate risk. Cascade screening of first-degree relatives of patients with elevated Lp(a) can identify additional individuals at risk who require intervention. Patients with elevated Lp(a) should receive early, more-intensive risk factor management, including lifestyle modification and lipid-lowering drug therapy in high-risk individuals, primarily to reduce low-density lipoprotein cholesterol (LDL-C) levels. The U.S. Food and Drug Administration approved an indication for lipoprotein apheresis (which reduces both Lp(a) and LDL-C) in high-risk patients with familial hypercholesterolemia and documented coronary or peripheral artery disease whose Lp(a) level remains ≥60 mg/dL [∼150 nmol/L)] and LDL-C ≥ 100 mg/dL on maximally tolerated lipid-lowering therapy. Although Lp(a) is an established independent causal risk factor for cardiovascular disease, and despite the high prevalence of Lp(a) elevation (∼1 of 5 individuals), measurement rates are low, warranting improved screening strategies for cardiovascular disease prevention.

Medical student research opportunities: a survey of osteopathic medical schools in the United States.

CONTEXT: It is important for colleges of osteopathic medicine (COMs) to provide opportunities for osteopathic medical students (OMSs) to conduct research under the guidance of professional researchers. However, COMs historically lag behind allopathic medical schools in research offerings for medical students. The literature would benefit from a synopsis of research opportunities for OMSs at COMs. OBJECTIVES: This study aims to assess the availability of research opportunities currently offered to OMSs and to identify structured research programs (SRPs) to provide data that may help COMs expand such opportunities. METHODS: Two online surveys were developed. The General Survey asked about general research opportunities, research requirements, and SRPs, which we define as optional, intramural, and mentored research programs. The follow-up SRP Survey sought to understand the history, funding, and organizational structure of SRPs. Between February and June 2021, the General and SRP Surveys were sent to all COMs in the United States. Response data were analyzed descriptively. RESULTS: Responses were received from 32 (84.2%) of 38 COMs. Nearly all COMs offered research symposia, offered third- or fourth-year research elective rotations, and provided some form of funding for OMSs to participate in research. Fourteen (43.8%) COMs had mandatory research requirements. Twenty COMs (62.5%) offered 31 SRPs, and surveys were completed for 25 (80.6%) SRPs. SRPs were founded a median (range) of 7 (1-43) years prior and accommodated 20 (4-50) OMSs annually. Among the responding SRPs, 12.0% had external funding, 96.0% required applications, 50.0% interviewed applicants prior to acceptance into the program, 72.0% required OMSs to identify their own mentors, 68.0% offered stipends to OMSs, 28.0% offered course credits, 96.0% had clinical research opportunities, and 68.0% offered research-oriented didactics. In 84.0% of SRPs, OMSs worked predominantly in the summer after OMS-I; for these SRPs, students had 4-10 weeks of dedicated time for participation in research. CONCLUSIONS: Findings from our surveys provide a synopsis of the research opportunities currently provided by COMs in the United States. Our data demonstrated wide variability of research opportunities among COMs.

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

Nutrition interventions for youth with dyslipidemia: a National Lipid Association clinical perspective.

A heart-healthy lifestyle, beginning at an early age and sustained throughout life, may reduce risk for cardiovascular disease in youth. Among youth with moderate to severe dyslipidemia and/or those with familial hypercholesterolemia, lipid-lowering medications are often needed for primary prevention of cardiovascular disease. However, lifestyle interventions are a foundation for youth with dyslipidemia, as well as those without dyslipidemia. There are limited data supporting the use of dietary supplements in youth with dyslipidemia at this time. A family-centered approach and the support of a multi-disciplinary healthcare team, which includes a registered dietitian nutritionist to provide nutrition counseling, provides the best opportunity for primary prevention and improved outcomes. While there are numerous guidelines that address the general nutritional needs of youth, few address the unique needs of those with dyslipidemia. The goal of this National Lipid Association Clinical Perspective is to provide guidance for healthcare professionals caring for youth with disorders of lipid and lipoprotein metabolism, including nutritional guidance that complements the use of lipid lowering medications.

Novel therapeutic targets and agents for pediatric dyslipidemia.

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.

Expert position statements: comparison of recommendations for the care of adults and youth with elevated lipoprotein(a).

PURPOSE OF REVIEW: Summarize recent recommendations on clinical management of adults and youth with elevated lipoprotein(a) [Lp(a)] who are at-risk of or affected by cardiovascular disease (CVD). RECENT FINDINGS: There is ample evidence to support elevated Lp(a) levels, present in approximately 20% of the general population, as a causal, independent risk factor for CVD and its role as a significant risk enhancer. Several guidelines and position statements have been published to assist in the identification, treatment and follow-up of adults with elevated levels of Lp(a). There is growing interest in Lp(a) screening and strategies to improve health behaviors starting in youth, although published recommendations for this population are limited. In addition to the well established increased risk of myocardial infarction, stroke and valvular aortic stenosis, data from the coronavirus pandemic suggest adults with elevated Lp(a) may have a particularly high-risk of cardiovascular complications. Lp(a)-specific-lowering therapies are currently in development. Despite their inability to lower Lp(a), use of statins have been shown to improve outcomes in primary and secondary prevention. SUMMARY: Considerable differences exist amongst published guidelines for adults on the use of Lp(a) in clinical practice, and recommendations for youth are limited. With increasing knowledge of Lp(a)'s role in CVD, including recent observations of COVID-19-related risk of cardiovascular complications, more harmonized and comprehensive guidelines for Lp(a) in clinical practice are required. This will facilitate clinical decision-making and help define best practices for identification and management of elevated Lp(a) in adults and youth.

Mentors' experiences in an osteopathic medical student research program.

CONTEXT: Medical students, especially at osteopathic medical schools, have limited research exposure. Systematic instruction in research, supervised by qualified mentors, could motivate osteopathic medical students to pursue research in their careers, thereby increasing the number of future clinician-scientists. Recruiting and retaining suitable research mentors are crucial to sustaining such programs, but this task is also particularly challenging for osteopathic medical schools. OBJECTIVES: To assess mentors' experiences in a voluntary student-mentor medical research program. METHODS: An online survey was sent to 76 university- or hospital-based participants who previously mentored 219 medical students between 2014 and 2019. The questionnaire consisted of 13 items with responses in checklist, five-point Likert scale, and categorical multiple-choice formats, assessing motivation for participation, satisfaction with the program, and interest in future participation. Data were analyzed descriptively, and responses from mentors at the university and hospital were compared using univariate logistic and ordinal regression analyses. RESULTS: Among 70 (92.1%) mentors who responded to the survey, 61 (87.1%) reported being motivated by a desire to help medical students learn research. Forty-nine (70.0%) mentors indicated that furthering their own research productivity was a motivation, and hospital-based mentors were statistically significantly more likely to endorse this source of motivation (OR=2.02; 95% CI=1.18-3.45; p=0.01). Most respondents were satisfied with the quality of the students' work (59 [84.3%]) and with the program (59 [85.5%]). However, 46 (65.7%) suggested the program could be enhanced by requiring medical students to be physically present in the clinic or laboratory for a minimum amount of time. Importantly, most (58 [84.1%]) mentors reported that they would be interested in participating in future mentored research programs. CONCLUSIONS: Mentors were motivated to participate in the voluntary research program for both altruistic and professional reasons. Since most mentors reported being satisfied with the program, it is likely they would participate in future mentored research programs. Our results suggest that mentors viewed this voluntary research program as mutually beneficial.