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Lancet Child Adolesc Health. 2024 Jul;8(7):491-499. doi: 10.1016/S2352-4642(24)00073-7. Epub 2024 May 14.
ABSTRACT
BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence.
METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis.
FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037).
INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life.
FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.
PMID:38759658 | DOI:10.1016/S2352-4642(24)00073-7
Glob Heart. 2024 May 3;19(1):43. doi: 10.5334/gh.1316. eCollection 2024.
ABSTRACT
Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.
PMID:38708402 | PMC:PMC11067975 | DOI:10.5334/gh.1316
Atherosclerosis. 2024 May;392:117525. doi: 10.1016/j.atherosclerosis.2024.117525. Epub 2024 Mar 27.
ABSTRACT
Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.
PMID:38598969 | DOI:10.1016/j.atherosclerosis.2024.117525
medRxiv [Preprint]. 2023 Nov 15:2023.11.14.23298547. doi: 10.1101/2023.11.14.23298547.
ABSTRACT
Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is well established since three decades, lowering serum LDL-C levels by more than 70% per session. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment targets and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.
PMID:38014132 | PMC:PMC10680892 | DOI:10.1101/2023.11.14.23298547
Eur Heart J. 2023 Jul 1;44(25):2277-2291. doi: 10.1093/eurheartj/ehad197.
ABSTRACT
This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.
PMID:37130090 | PMC:PMC10314327 | DOI:10.1093/eurheartj/ehad197
J Am Heart Assoc. 2023 May 2;12(9):e029175. doi: 10.1161/JAHA.122.029175. Epub 2023 Apr 29.
ABSTRACT
Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.
PMID:37119068 | PMC:PMC10227232 | DOI:10.1161/JAHA.122.029175
Stem Cells Dev. 2021 Jun 15;30(12):632-640. doi: 10.1089/scd.2021.0004. Epub 2021 May 21.
ABSTRACT
Homozygous familial hypercholesterolemia (hoFH) is a rare disorder caused primarily by pathological mutations in the low-density lipoprotein receptor (LDLR), which disrupts LDL-cholesterol (LDL-C) metabolism homeostasis. hoFH patients are at extremely high risk for cardiovascular disease and are resistant to standard therapies. LDLR knockout animals and in vitro cell models overexpressing different mutations have proved useful, but may not fully recapitulate human LDLR mutation biology. We and others have generated induced pluripotent stem cells (iPSC) from hoFH patient's fibroblasts and T cells and demonstrated their ability to recapitulate hoFH biology. In this study, we present the generation and characterization of a cohort of seven hoFH-iPSC lines derived from peripheral blood mononuclear cells (PBMC) collected from four homozygous and three compound heterozygous patients. The hoFH-iPSC cohort demonstrated a wide range of LDLR expression and LDL-C internalization in response to rosuvastatin that correlated with the predicted pathogenicity of the mutation. We were able to confirm that hoFH-iPSC cohort were pluripotent by differentiation toward all three germ layers and specifically to hepatocyte-like cells (HLC), the cell with primary LDL-C metabolic regulatory control, by expression of hepatocyte markers. hoFH patient PBMC-derived iPSC recapitulate the LDLR dysfunction of their specific mutation. They were capable of differentiating to HLC and could be useful for early developmental studies, pharmacology/toxicology, and potentially autologous cell therapy.
PMID:34029164 | PMC:PMC8215406 | DOI:10.1089/scd.2021.0004
J Pediatr. 2021 Feb;229:70-77. doi: 10.1016/j.jpeds.2020.09.042. Epub 2020 Sep 22.
ABSTRACT
OBJECTIVE: To describe enrollment characteristics of youth in the Cascade Screening for Awareness and Detection of FH Registry.
STUDY DESIGN: This is a cross-sectional analysis of 493 participants aged <18 years with heterozygous familial hypercholesterolemia recruited from US lipid clinics (n = 20) between April 1, 2014, and January 12, 2018. At enrollment, some were new patients and some were already in care. Clinical characteristics are described, including lipid levels and lipid-lowering treatments.
RESULTS: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest Low-density lipoprotein cholesterol (LDL-C) was 238 (61) mg/dL before treatment. Lipid-lowering therapy was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with lipid-lowering therapy; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on lipid-lowering therapy reached both goals.
CONCLUSIONS: Among youth enrolled in the Cascade Screening for Awareness and Detection of FH Registry, diagnosis occurred relatively late, only 77% of children eligible for lipid-lowering therapy were receiving treatment, and only 39% of those treated met their LDL-C goal. Opportunities exist for earlier diagnosis, broader use of lipid-lowering therapy, and greater reduction of LDL-C levels.
PMID:32976895 | DOI:10.1016/j.jpeds.2020.09.042
J Lipid Res. 2020 Nov;61(11):1365-1376. doi: 10.1194/jlr.R120001116. Epub 2020 Sep 18.
ABSTRACT
Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.
PMID:32948662 | PMC:PMC7604722 | DOI:10.1194/jlr.R120001116
J Clin Lipidol. 2019 Jan-Feb;13(1):89-99. doi: 10.1016/j.jacl.2018.09.007. Epub 2018 Sep 18.
ABSTRACT
BACKGROUND: Triglyceride (TG) concentrations >2000 mg/dL are extremely elevated and increase the risk of pancreatitis.
OBJECTIVES: We characterized five cases and two kindreds and ascertained prevalence in a reference laboratory population.
METHODS: Plasma lipids and DNA sequences of LPL, GPIHBP1, APOA5, APOC2, and LMF1 were determined in cases and two kindreds. Hypertriglyceridemia prevalence was assessed in 440,240 subjects.
RESULTS: Case 1 (female, age 28 years) had TG concentrations >2000 mg/dL and pancreatitis since infancy. She responded to diet and medium-chain triglycerides, but not medications. During two pregnancies, she required plasma exchange for TG control. She was a compound heterozygote for a p.G236Gfs*15 deletion and a p.G215E missense mutation at LPL, as was one sister with hypertriglyceridemia and pancreatitis during pregnancy. Her father was heterozygous for the deletion and had hypertriglyceridemia and recurrent pancreatitis. Other family members had either the missense mutation or the deletion, and had hypertriglyceridemia but no pancreatitis. In kindred 2, three preschool children had severe hypertriglyceridemia and were homozygous for a GPIHBP1 p.T108R missense mutation. Case 5 (male, age 43 years) presented with pancreatitis and TG levels >5000 mg/dL and had heterozygous GPIHBP1 p.G175R and APOC2 intron 2-4G>C mutations. On diet, fenofibrate, fish oil, and atorvastatin, his TG concentration was 2526 mg/dL, but normalized to <100 mg/dL with added pioglitazone. In our population study, 60 subjects (0.014%) of 440,240 had TG concentrations >2000 mg/dL, and 66.7% were diabetic and had elevated insulin levels.
CONCLUSIONS: Extreme hypertriglyceridemia is rare (0.014%); and during pregnancy, it may require plasma exchange.
PMID:30352774 | DOI:10.1016/j.jacl.2018.09.007
Lipids Health Dis. 2018 May 28;17(1):127. doi: 10.1186/s12944-018-0769-6.
ABSTRACT
BACKGROUND: Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. Since apoproteins are now known to have important roles in host defense, we have separated these subclasses according to their apoprotein content and characterized their changes during experimental endotoxemia in human volunteers.
METHODS: We have studied apoB- and apoA containing lipoprotein subclasses in twelve healthy male volunteers before and for 8 h after a single dose of endotoxin (ET; 2 μg/kg) to stimulate inflammation.
RESULTS: After endotoxin, TG, TC, apoB and the apoB-containing lipoprotein cholesterol-rich subclass LpB and two of the three triglyceride-rich subclasses (TGRLP: Lp:B:C, LpB:C:E+ LpB:E) all declined. In contrast, the third TGRLP, LpA-II:B:C:D:E ("complex particle"), after reaching a nadir at 4 h rose 49% above baseline, p = .006 at 8 h and became the dominant particle in the TGRLP pool. This increment exceeds the threshold of > 25% change required for designation as an acute phase protein. Simultaneous decreases in LpA-I:A-II and LpB:C:E + LpB:E suggest that these subclasses undergo post-translational modification and contribute to the formation of new LpA-II:B:C:D:E particles.
CONCLUSIONS: We have identified a new acute phase lipoprotein whose apoprotein constituents have metabolic and immunoregulatory properties applicable to host defense that make it well constituted to engage in the APR.
PMID:29807532 | PMC:PMC5972402 | DOI:10.1186/s12944-018-0769-6
Mol Metab. 2016 Nov 23;6(1):14-21. doi: 10.1016/j.molmet.2016.11.008. eCollection 2017 Jan.
ABSTRACT
OBJECTIVE: Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.
METHODS: We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.
RESULTS: Hepatic expression of ChREBP-β and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-β and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.
CONCLUSIONS: In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.
PMID:28123933 | PMC:PMC5220398 | DOI:10.1016/j.molmet.2016.11.008
Clin Endocrinol (Oxf). 2017 Mar;86(3):361-366. doi: 10.1111/cen.13293. Epub 2017 Jan 16.
ABSTRACT
OBJECTIVE: South Asians have higher rates of type 2 diabetes and cardiovascular disease compared to most other racial/ethnic groups. Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar may accelerate the development of these chronic diseases in this population.
STUDY DESIGN: Hepatic DNL in response to a calorically sweetened beverage was measured in an outpatient setting in 15 South Asians and 15 Caucasians with similar and normal body mass indexes, waist circumferences, glucose tolerance and lipid profiles. Blood was sampled before and hourly for 4 h after the ingestion of a single beverage made with glucose (1·5 g/kg) and fructose (1·5 g/kg). The main outcome, DNL, was measured as the increase in %palmitate (16:0) in very low-density lipoprotein (VLDL) triglyceride (TG) over 4 h.
RESULTS: After the sugar dose, the increase in %16:0 in VLDL TG was significantly greater in South Asians vs Caucasians (P = 0·01). VLDL and total TG also increased to a significantly greater extent in South Asians (P = 0·04 and <0·001, respectively). Although the fasting and postsugar levels of insulin and glucose did not differ between groups, the DNL response significantly correlated with the insulin response to sugar in South Asians (r = 0·56, P = 0·03).
CONCLUSIONS: Hepatic DNL in response to a sugar challenge was greater in healthy, young South Asians compared to Caucasians despite normal indices of insulin sensitivity, and it correlated with the insulin response. These findings suggest an early, insulin-related, gene-nutrient interaction contributing to the high prevalence of diabetes and coronary disease in this population.
PMID:27988942 | DOI:10.1111/cen.13293
J Clin Lipidol. 2016 Sep-Oct;10(5):1223-9. doi: 10.1016/j.jacl.2016.07.011. Epub 2016 Aug 6.
ABSTRACT
BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.
OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry.
METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other.
RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry.
CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.
PMID:27678440 | PMC:PMC5381273 | DOI:10.1016/j.jacl.2016.07.011
Am J Cardiol. 2016 Aug 15;118(4):504-10. doi: 10.1016/j.amjcard.2016.05.042. Epub 2016 May 28.
ABSTRACT
Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited, life-threatening, metabolic disorder of low-density lipoprotein (LDL) receptor function characterized by elevated serum LDL cholesterol (LDL-C) and rapidly progressive atherosclerotic cardiovascular disease (ACVD). Since LDL receptors are predominantly found on hepatocytes, orthotopic liver transplantation (OLT) has emerged as a viable intervention for HoFH because LDL receptor activity is restored. This study assessed the effects of OLT on ACVD and ACVD risk factors in pediatric patients with HoFH. We analyzed lipids, lipoproteins, body mass index, glucose, blood pressure, and cardiovascular imaging in 8 pediatric patients who underwent OLT for HoFH. Total serum cholesterol, LDL-C, lipoprotein (a), and apolipoprotein B/apolipoprotein A1 ratio decreased to normal values in all subjects (p values <0.001) at 1 month after OLT and were maintained for the length of follow-up (2 to 6 years). There were few complications related to surgery or immunosuppressive therapy. Two patients developed mild hypertension. In the first 4 subjects monitored for 4 to 6 years after OLT, coronary artery disease did not develop or progress except in 1 minor artery in 1 subject and actually regressed in 2 subjects with >50% stenosis. However, aortic valve stenosis progressed in 2 of 4 subjects. In conclusion, OLT is an effective therapeutic option for patients with HoFH with coronary artery disease and persistently elevated serum LDL-C despite maximum medical therapy. Aortic valvular disease may progress. Long-term data are needed to evaluate the true risk-benefit ratio of this surgical approach.
PMID:27365335 | DOI:10.1016/j.amjcard.2016.05.042
