Estimating health state utilities associated with a rare disease: familial chylomicronemia syndrome (FCS).

Aims: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with no currently approved therapies. Treatments are in development, and cost-utility analyses will be needed to examine their value. These models will require health state utilities representing FCS. Therefore, the purpose of this study was to estimate utilities for FCS and an associated episode of acute pancreatitis (AP).Methods: Because it is not feasible to gather a large enough sample of patients with this extremely rare condition to complete standardized preference-based measures, vignette-based methods were used to estimate utilities. In time trade-off interviews, general population participants in the UK and Canada valued health state vignettes drafted based on literature review, clinician input, and interviews with patients. Four health states described variations of FCS. A fifth health state, describing AP, was added to one of the other health states to evaluate its impact on utility.Results: A total of 308 participants provided utility data (208 UK; 100 Canada). Mean utilities for FCS health states ranged from 0.46 to 0.83, with higher triglycerides, more severe symptoms, and a history of AP associated with lower utility values. The disutility (i.e. utility decrease) of AP ranged from -0.17 to -0.25, with variations depending on the health state to which it was added. Utility means were similar in the UK and Canada.Conclusions: The vignette-based approach is useful for estimating utilities of a rare disease. The health state utilities derived in this study would be useful in models examining cost-effectiveness of treatments for FCS.

PROMIS® and Neuro-QoLTM measures are valid measures of health-related quality of life among patients with familial chylomicronemia syndrome.

Background: FCS significantly affects health-related quality of life (HRQOL). Legacy patient-reported outcome measures are often not sensitive to FCS's impact. NIH PROMIS and Neuro-QoL measures may accurately capture HRQOL in FCS patients. This study assessed a broad range of PROMIS and Neuro-QoL measures covering physical, mental, and social HRQOL to determine their suitability for the FCS population.Methods: Adult FCS patients in the United States (N = 25) were recruited to an online survey study and completed several PROMIS short forms and Neuro-QoL computer adaptive tests.Results: Scores were more than 0.5 standard deviations (SD) worse than the normative mean on 10 of 16 normed measures, and more than 0.75 SDs worse than the normative mean on two measures. Responses at the floor and ceiling were occasionally observed, marginal reliabilities were strong, and significant differences across performance status (ps < 0.05) provided preliminary support for construct validity. The measures correlated with each other strongly and as expected.Conclusion: Results support the ability of PROMIS and Neuro-QoL measures to detect HRQOL impairment among patients with FCS. PROMIS and Neuro-QoL measures captured the functional impact and symptom burden associated with FCS, and the broad range of symptom severity experienced by patients with FCS.

Nuevos tratamientos en la hipertrigliceridemia y en la hiperquilomicronemia / Novel therapeutics in hypertriglyceridaemia and chylomicronaemia

Existen evidencias del papel de la hipertrigliceridemia como factor de riesgo independiente de ateromatosis. Cuando es severa, la hiperquilomicronemia puede asociarse a pancreatitis aguda grave y recurrente. En la mayoría de las hipertrigliceridemias se combina una base predisponente poligénica con diversos factores ambientales u otras patologías precipitantes. Algunas hiperquilomicronemias son formas familiares monogénicas autosómicas recesivas. Una característica de los triglicéridos plasmáticos es la marcada variabilidad y su descenso con ajustes en la dieta y el estilo de vida. Los fármacos disponibles contribuyen también a su control, pero es más controvertida la disminución del riesgo vascular o de pancreatitis. Los avances en el conocimiento del metabolismo lipídico a nivel molecular y en la tecnología farmacológica posibilitan el desarrollo de nuevas estrategias terapéuticas que pueden facilitar el tratamiento de pacientes en los que las medidas convencionales no son efectivas. En algunos casos, el elevado coste podría limitar su acceso y su sostenibilidad

Currently there is evidence on hypertriglyceridaemia as an independent risk factor of atherosclerosis. Chylomicronaemia associated with very high concentration of triglycerides may cause severe and recurrent acute pancreatitis. The cause of most cases is a combination of a polygenetic basis with some lifestyles and pathological conditions. Some rare and familial chylomicronaemias are mendelian diseases with an autosomal recessive pattern. On the other hand, plasma triglycerides have considerable biological variability and usually descend with non-pharmacological interventions alone. In some cases, drugs are also required for their control, but their impact on vascular risk reduction or pancreatitis prevention is more controversial. The recent advances in knowledge of molecular lipid metabolism and pharmacological technologies are resulting in the development of new therapeutic strategies, which can be applied to patients with refractory hypertrigliceridaemia. The challenge may be how the health systems can cover its high costs

Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome.

INTRODUCTION: A spectrum of disorders, ranging from rare severe cases of homozygous null lipoprotein lipase deficiency (LPLD)-familial chylomicronemia syndrome (FCS) to heterozygous missense LPLD or polygenic causes, result in hypertriglyceridemia and pancreatitis. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy, and insulin resistance. Areas covered: In this review, authors discuss chronic treatment of FCS by ultra-low fat diets allied with the use of fibrates, omega-3 fatty acids, niacin, statins, and insulin-sensitizing therapies depending on the extent of residual lipoprotein lipase (LPL) activity; novel therapies in development target triglyceride (TG)-rich lipoprotein particle clearance. Previously, a gene therapy approach to LPL-alipogene tiparvovec showed that direct targeting of LPL function reduced pancreatitis events. An antisense oligonucleotide to apolipoprotein-C3, volanesorsen has been shown to decrease TGs by 70-80% and possibly to reduce rates of pancreatitis admissions. Studies are underway to validate its long-term efficacy and safety. Other approaches investigating the role of LPL modulating proteins such as angiopoietin-like petide-3 (ANGPTL3) are under consideration. Expert opinion: Current therapeutic options are not sufficient for management of many cases of FCS. The availability of antisense anti-apoC3 therapies and, in the future, ANGPTL3 therapies may remedy this.

Gene Therapy in Lipoprotein Lipase Deficiency: Case Report on the First Patient Treated with Alipogene Tiparvovec Under Daily Practice Conditions.

One-year results are reported of the first lipoprotein lipase deficiency (LPLD) patient treated with alipogene tiparvovec, which is indicated for the treatment of patients with genetically confirmed LPLD suffering from acute and recurrent pancreatitis attacks (PAs) despite dietary restrictions and expressing >5% of lipoprotein lipase (LPL) mass compared to a healthy control. During clinical development, alipogene tiparvovec has shown improvement of chylomicron metabolism and reduction of pancreatitis incidence up to 5.8 years post treatment. A 43-year-old female presented with severe hypertriglyceridemia (median triglyceride [TG] value of 3,465 mg/dL) and a history of 37 PAs within the last 25 years, despite treatment with fibrates, omega 3 fatty acids, and-since 2012-twice-weekly lipid apheresis. LPLD was confirmed by identification of two different pathogenic variants in the LPL gene located on separate alleles and therefore constituting a compound heterozygous state. With a detectable LPL mass level of 55.1 ng/mL, the patient was eligible for alipogene tiparvovec treatment, and in September 2015, she receved 40 injections (1 × 1012 genome copies/kg) in the muscles of her upper legs under epidural anesthesia and immunosuppressive therapy. Alipogene tiparvovec was well tolerated: no injection site or systemic reactions were observed. Median TG values decreased by 52%, dropping to 997 mg/dL at month 3 and increasing thereafter. Within the first 18 months post treatment, the patient discontinued plasmapheresis and had no abdominal pain or PAs. In March 2017, the patient suffered from a PA due to diet violation. Within the first 12 months post treatment, overall quality of life improved, and no change in humoral or cellular immune response against LPL or AAV-1 was observed. In conclusion, alipogene tiparvovec was well tolerated, with a satisfactory response to treatment. Long-term effects on the recurrence of pancreatitis continue to be monitored.

A case of severe acquired hypertriglyceridemia in a 7-year-old girl.

We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis.

The burden of familial chylomicronemia syndrome from the patients' perspective.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives. METHODS: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS. RESULTS: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS. CONCLUSIONS: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.

The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study.

BACKGROUND: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients' lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature. METHODS: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains. RESULTS: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease. CONCLUSION: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.

Type 1 Hyperlipoproteinemia Due to Compound Heterozygous Rare Variants in GCKR.

BACKGROUND: Type 1 hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme elevations in serum triglyceride (TG) levels. Despite considerable progress in identifying several causal genes for T1HLP, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1, the molecular basis of some extremely rare patients presenting with T1HLP remains obscure. CASE DESCRIPTION: We report a 58-year-old Hispanic female who initially presented with serum TG of 4740 mg/dL at age 23 years when she was 3 weeks postpartum and was taking an oral contraceptive for 2 weeks. Over a period of 35 years, she has had recurrent episodes of extreme hypertriglyceridemia (fasting serum TG exceeding 2000 mg/dL), which responded to a reduction of dietary fat, fibrates, and fish oil therapy. Sanger sequencing of the known T1HLP genes in this patient did not reveal any disease-causing mutations. Whole-exome sequencing revealed compound heterozygous rare variants (p.Val103Met and p.Arg540Gln) in the glucokinase regulator (GCKR) gene. CONCLUSIONS: GCKR encodes glucokinase regulatory protein, which is an inhibitor of glucokinase, an enzyme that drives glucose uptake in the liver. Loss of function GCKR variants, by enhancing glucose uptake in hepatocytes, may induce de novo lipogenesis and TG biosynthesis, resulting in extreme hypertriglyceridemia. We conclude that compound heterozygous rare variants in GCKR cause an extremely rare unique T1HLP, most likely by inducing excessive hepatic lipogenesis.

Improved visual function with dietary intervention in a child with lipemia retinalis.

We present a 4.8-year-old female with grade 3 lipemia retinalis due to lipoprotein lipase deficiency, an abnormal electroretinogram, and bilateral decreased visual acuity. Strict dietary intervention resulted in reversal of lipemia retinalis, normalization of her electroretinogram, and improved visual acuity in both eyes.

Impaired synaptic vesicle recycling contributes to presynaptic dysfunction in lipoprotein lipase-deficient mice.

Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons, but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study, we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPL-deficient neurons, which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling, which is known to play an important role in maintaining the RRP size in active synapses, is impaired in LPL-deficient neurons. Moreover, lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice; exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from deficient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-deficient neurons.

Lipoprotein lipase deficiency: clinical, biochemical and molecular characteristics in three patients with novel mutations in the LPL gene.

Lipoprotein lipase (LPL) deficiency, caused by mutations in the LPL gene, is a rare autosomal recessive disorder manifesting in early childhood with recurrent abdominal pain, hepatosplenomegaly, acute pancreatitis, lipaemia retinalis and eruptive xanthomas. Typical laboratory findings are lactescent serum, extreme hypertriglyceridaemia and hypercholesterolaemia. The diagnostics is based on postheparin serum LPL assay and DNA analyses of the LPL gene. We report clinical, biochemical and molecular data of three children with LPL deficiency. One child manifested since the first week of life with recurrent abdominal pain (Patient 1), the second with abdominal distension and hepatosplenomegaly since the second month of life (Patient 3) and patient 2, asymptomatic younger brother of patient 1, was diagnosed in the first week of life. Lipaemia retinalis and splenomegaly were present in two symptomatic children, hepatomegaly in patient 3 and acute pancreatitis in patient 1. All children had lactescent serum, profound hypertriglyceridaemia (124 ± 25 mmol/l; controls < 2.2), hypercholesterolaemia (22.8 ± 7.3 mmol/l, controls < 4.2) and their LPL immunoreactive mass in serum did not increase after heparin injection. Molecular analyses revealed that both siblings are homozygous for novel mutation c.476C > G in the LPL gene changing the conserved amino acid of the catalytic centre. The third patient is a compound heterozygote for mutations c.604G>A and c.698A>G in the LPL gene, both affecting highly conserved amino acids. We conclude that LPL deficiency must be considered in neonates and young infants with abdominal pain and hypertriglyceridaemia because early treatment might prevent development of life-threatening acute pancreatitis.

Alipogene tiparvovec for the treatment of lipoprotein lipase deficiency.

Alipogene tiparvovec is the first adeno-associated virus (AAV)-mediated gene therapy to be approved for the treatment of a metabolic disorder. Lipoprotein lipase (LPL) deficiency (LPLD) is a rare autosomal-recessive disorder in which gene mutations cause the production of a catalytically inactive enzyme required for plasma triglyceride hydrolysis. The resultant hypertriglyceridemia causes frequent abdominal pain, fatty deposits in the skin and retina, and can lead to potentially fatal pancreatitis. In addition, patients with LPLD can develop diabetes and cardiovascular disease. Past therapies to lower plasma triglycerides in these patients have been ineffective. Intramuscular injection of alipogene tiparvovec delivers a natural gain-of-function LPL gene variant, LPLS447X, to muscle tissue and has demonstrated efficacy in animal models of LPLD. In phase I/II and phase II/III clinical evaluations, alipogene tiparvovec significantly lowered plasma triglycerides and increased LPL activity, resulting in a reduction in plasma chylomicron and a decrease in the frequency of pancreatitis episodes. The therapy is well tolerated in animals and humans and produces no serious treatment-related adverse effects.

Acute pancreatitis and hypertriglyceridemia.

Pancreatitis is a condition characterized by painful inflammation of the pancreas and can be either chronic or acute. The most common causes of acute pancreatitis (AP) in the United States are gallstones and excessive alcohol consumption. In addition, significantly elevated serum triglyceride levels can precipitate episodes of AP. Genetic defects are associated with severe elevations in serum triglyceride levels, whereas poorly controlled diabetes, obesity, and high-fat diets can contribute to elevated triglyceride levels substantial enough to provoke pancreatitis (secondary hypertriglyceridemia). Treatment of hypertriglyceridemia-induced AP consists of immediate reduction in serum triglyceride levels and long-term medications and lifestyle modifications. Nurses are instrumental in patient education about lifelong treatment strategies.

Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis.

CONTEXT: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by LPL gene mutation and is characterized by severe hyperchylomicronemia. Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, but the underlying mechanisms are not fully understood. CASE REPORT: A 22-yr-old male Japanese patient with severe hyperchylomicronemia was admitted to our hospital in 1973. He had no consanguinity and no family history of hyperlipidemia. He was genetically diagnosed as LPL deficiency (homozygous for LPL(Arita)) with no LPL mass or activity in postheparin plasma. He has experienced recurrent acute pancreatitis 22 times during our 31-yr clinical follow-up, but no pancreatic pseudocyst, irregularity of the pancreatic duct, or abnormal pancreatic calcification was observed in computed tomography. Moreover, his pancreatic endocrine function, as assessed by the oral glucose tolerance test, has preserved more than 30 yr. Although he was a current smoker, no clinically significant atherosclerotic lesion had been observed. CONCLUSIONS: From the long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

Lipoprotein lipase and its role in regulation of plasma lipoproteins and cardiac risk.

For over 50 years, biologists and clinicians have studied lipoprotein lipase (LPL) and learned about its structure, function, cellular production, physiology, and human genetics. LPL is the principal enzyme that removes triglyceride from the bloodstream. It also determines plasma levels of high-density lipoprotein. Surprisingly, within the past several years, a number of new and unexpected proteins have been discovered that regulate the actions of LPL. These include the very low-density lipoprotein receptor, angiopoetin-like protein 3, and apolipoprotein A-V. In addition, mouse genetic studies have confirmed tissue culture findings of nonenzymatic roles of LPL both in lipid metabolism and atherogenesis. These basic observations are now being related to new information on human genetic polymorphism in this gene that is likely to affect clinical evaluation of lipoprotein disorders and cardiac risk.

Insulin sensitivity is impaired in heterozygous carriers of lipoprotein lipase deficiency.

AIMS/HYPOTHESIS: Several studies have investigated the lipoprotein phenotype in heterozygous carriers of a defective lipoprotein lipase allele. We studied whether heterozygosity for lipoprotein lipase deficiency also affects glucose metabolism beyond its effect on plasma lipids. METHODS: To address this question 85 heterozygous carriers of either a missense mutation (Gly188Glu) or a splice site mutation (C-->A in position -3 at the acceptor splice site of intron 6) in the LPL gene which both result in a catalytically inactive product were compared with 108 unaffected subjects from the same families. RESULTS: Carriers for one of these mutations had higher fasting insulin levels but only a trend towards increased fasting blood glucose concentrations could be detected. HOMA index values were significantly higher in carriers than in non-carriers. Furthermore, in carriers, a significantly higher BMI and a trend towards higher systolic and diastolic blood pressure were observed. Carriers also had significantly higher fasting triglycerides, lower HDL cholesterol, and lipoprotein lipase particles of smaller size, confirming previous reports. Among carriers, subjects with one rare allele of the SstI polymorphism in the apo CIII gene had significantly higher plasma triglyceride levels than those with two common SstI alleles. This difference could not be observed in non-carriers of a mutant lipoprotein-lipase allele. The mean intima media thickness of the carotid arteries was slightly, but not significantly higher in carriers when compared with non-carriers. CONCLUSION/INTERPRETATION: This study shows that carrier status of one defective lipoprotein-lipase allele is associated with impaired insulin sensitivity, an atherogenic lipoprotein profile and other characteristics of the metabolic syndrome, which are risk factors for atherosclerotic vascular disease. A higher incidence of atherosclerotic vascular disease, however, could not be firmly established in carriers of this study population.