Whats in the Name Lipase D deficiency Lipoprotein lipase deficiency LPLD Chylomicronemia syndrome Chylomicronemia familial Familial chylomicronemia Hyperchylomicronemia familial Hyperlipemia ID: 777167
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Slide1
Slide2Slide3Slide4Slide5Familial Chylomicronemia Syndrome (FCS): What’s in the Name?
Lipase D deficiencyLipoprotein lipase deficiency (LPLD)Chylomicronemia syndromeChylomicronemia, familialFamilial chylomicronemiaHyperchylomicronemia familialHyperlipemia idiopathic Burger-Grutz typeBurger-Grutz syndrome
Endogenous hypertriglyceridemiaFamilial fat-induced hypertriglyceridemiaFamilial hyperchylomicronemiaFamilial LPL deficiencyHyperlipidemia Type I (Fredrickson)Hyperlipoproteinemia Type IHyperlipoproteinemia Type IA
US Department of Health & Human Services. National Center for Advancing Translational Services. Genetic and Rare Diseases Information Center. Familial lipoprotein lipase deficiency. Available at: https://rarediseases.info.nih.gov/diseases/12241/familial-lipoprotein-lipase-deficiency; Genetics Home Reference. Familial lipoprotein lipase deficiency. Available at: http://ghr.nlm.nih.gov/condition/familial-lipoprotein-lipase-deficiency;
Brahm
AJ
Hegele
RA.
Nat Rev
Endocrinol
.
2015;11:352-362.
Slide6What is Familial Chylomicronemia Syndrome?
Familial Chylomicronemia Syndrome (FCS)Rare autosomal recessive disorderLeads to buildup of chylomicrons in blood, severe hypertriglyceridemia, and recurrent pancreatitisSeverely elevated levels of plasma triglycerides10 to 100 times greater than normalUnresponsive to lipid-lowering therapies (statins, fibrates, niacin, fish oils)Al Azkawi H, et al. Case Rep Med. 2010;2010:807434.Gaudet D, et al. N Engl J Med. 2014; 371:2200-2206.
Slide7Epidemiology
Autosomal recessive genetic disorder1 to 2 people affected per millionMales and females equally affectedMutations in the LPL gene account for most cases of FCS Usually manifests in childhood Overall mortality: 5% to 6%30% in subgroups with severe complicationsLPL = lipoprotein lipase.Stroes E, et al. Atheroscler Suppl. 2017;23:1-7. Brunzell JD. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2011 Dec 15]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/.
Slide8Pathophysiology of FCS
Slide9What are Chylomicrons?
Chylomicrons are one of 5 major types of lipoproteins.The other 4 are: VLDL, IDL, LDL, HDLChylomicrons are very large lipoproteins that contain basic dietary TGs. Surface consists of phospholipids and apolipoproteins.Main Function: Transport dietary lipids from intestines to adipose tissue and muscle for energy utilizationOnce the chylomicron is delivered into plasma, it is exposed to LPL which hydrolyzes TGs into FFAs.FFAs are then absorbed by the target tissue and used for energy utilization.Once TG is hydrolyzed, it becomes a “chylomicron remnant” which re-enters circulation or is taken up by the liver.TG = triglycerides; VLDL = very-low-density lipoprotein; IDL = intermediate density lipoprotein; LDL = low-density lipoprotein;HDL = high-density lipoprotein; FFA = free fatty acids. Feingold KR, Grunfeld C. Introduction to Lipids and Lipoproteins [updated in June 2015]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK305896/.
Slide10What is the Structure of a Chylomicron?
ApoB
ApoB
ApoA
ApoC
ApoE
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
TG
C
C
C
C
C
C
C
Phospholipids
Apolipoproteins
Triglycerides and
cholesterol
for transport
Slide11What is Lipoprotein Lipase?
Lipoprotein lipase (LPL): Rate-limiting catalytic enzyme involved in the hydrolysis of:Circulating chylomicrons VLDLFunctions to internalize free fatty acid into:Muscle (cardiac, skeletal)Adipose tissueStroes E, et al. Atheroscler Suppl. 2017;23:1-7. Benlian P, et al. N Engl J Med. 1996;335:848-854.
Slide12Chylomicron Metabolism
HDLHDL
LPL
Free fatty acids
ApoC
-III
ApoC
-II
ApoE
ApoB-48
ApoA-1
Tissues
(adipose, muscle)
Liver
Gut
Remnant receptor (LRP)
ApoC
-II
ApoC
-III
ApoE
Chylomicron remnant
Chylomicron
Apo = apolipoprotein.
Adapted from: http://www.myhealthywaist.org/the-concept-of-cmr/intra-abdominal-adipose-tissue-the-culprit/complications-of-intra-abdominal-obesity/atherogenic-dyslipidemia/print.html.
ApoA
I, IV
ApoC
II, III
Slide13Lipoprotein Biology
Lusis AJ, et al. Nat Genet. 2008;40:129-130.
Slide14Pathway to Lower Triglycerides
byGonzales JC, et al. J Clin Invest. 2013;123:2742-2751; Feingold KR, Grunfeld C. Introduction to Lipids and Lipoproteins [updated in June 2015]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK305896/.
TG hydrolyzed to
free fatty acids &
monoacylglycerol
Lipases
ApoC
-II
ApoC
-III
ApoA
-V
TG-rich lipoproteins must interact with lipases
Lipoprotein lipase
Endothelial lipase
Hepatic lipase
regulated
by
Slide15LMF1 and LPL Maturation
LMF1 = Lipase maturation factor-1.Doolittle MH, et al. Curr Opin Lipidol. 2010;21:198-203.
Slide16Sequence of FactorsInvolved in LPL Function
LMF1 = Lipase maturation factor 1GPIHBP1 = Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1Stroes E, et al. Atheroscler Suppl. 2017;23:1-7. LMF1GPIHBP1ApoC2ApoA5 enhances LPL activity
Slide17Physiologic and Therapeutic Role of ApoC3
ApoC3 inhibits ApoC2-mediated LPL activationWhen ApoC3 levels are elevated, LPL activity is reducedRegulates plasma TG clearance through both LPL-dependent and LPL-independent pathwaysCurrent therapeutic target for FCSGaudet D, et al. N Engl J Med. 2014; 371:2200-2206; Yang X, et al. J Lipid Res. 2016;57:706-713.
Slide18Known Mutations in FCS
Stroes E, et al. Atheroscler Suppl. 2017;23:1-7; Rodrigues R, et al. J Clin Lipidol. 2016;10:394-409; Brahm AJ, et al. Nat Rev Endocrinol. 2015;11:352-362.GeneFunction% of monogenic-causing mutationsLPLHydrolysis of TGs
and peripheral uptake of FFA95%APOC2Required cofactor of LPL2.0%
GPIHBP1
Stabilizes the binding of chylomicrons near LPL
2.0%
APOA5
Enhances
LPL activity
0.6%
LMF1
Chaperone
molecule
necessary for LPL folding
0.4%
Slide19Recognition and Diagnosis of
FCS
Slide20What are the Signs and Symptoms of FCS?
Stroes E, et al. Atheroscler Suppl. 2017;23:1-7;Kota SK, et al. Indian J Gastroenterol. 2012;31:277-279. Eruptive XanthomasShouldersExtremitiesButtocksLipemia RetinalisWhitened retinal vessels upon fundoscopyVision unimpairedHepatosplenomegalyDue to macrophage infiltrationAbdominal PainPancreatitis(recurrent acute and chronic)Most severe clinical manifestation
Slide21Clinical Manifestations of FCS:
Eruptive Xanthomas
Slide22Clinical Manifestations of FCS:
Lipemia Retinalis
Slide23Pancreatitis: Life-threatening Complication of FCS
Pancreatitis is a life threatening complication of FCSFCS accounts for ~7% of all pancreatitis cases (or more)FCS pancreatitis is often misdiagnosed as being alcohol-related Recurrent pancreatitis often leads to chronic pancreatitisAssociated with severe pain and reduced quality of lifeCan lead to steatosis, malabsorption and other complicationsSymptoms similar to pancreatitis of any cause Can manifest at any ageAcute pancreatitis should be treated with standard of care supportive treatment, pain management, plasmapheresis Al Azkawi H, et al. Case Rep Med. 2010;2010:807434; Sisman G, et al. Hepatobiliary Pancreat Dis Int. 2014;13:209-214; Gardner TB, et al. Pancreas. 2010;39:498-501; Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
Slide24Diagnosing the Presence of Chylomicrons
Hallmark is abnormal persistence of circulating chylomicrons following a fasting period from 12 – 14 hours“Refrigerator Test”Confirms the presence of chylomicronsBlood samples stand in refrigerator overnight Chylomicrons float to the top, forming a creamy layer Stroes E, et al. Atheroscler Suppl. 2017;23:1-7. Kota SK, et al. Indian J Gastroenterol. 2012;31:277-279.
Slide25When Should FCS be Suspected?
Severe HTG presenting in childhood or infancySecondary causes (eg, uncontrolled diabetes, alcohol abuse) have been ruled outTG levels >1000 mg/dL (fasting) or 2000 mg/dL (non-fasting)Low or normal LDL, normal HDLNormal BMI Recurrent episodes of abdominal pain, with or without recurrent pancreatitisPresence of other symptoms such as fatigue, malaise, and cognitive impairment Family history of FCSAhmad Z, et al. Exp Rev Clin Pharm. 2017;10:1-3; Al Azkawi H, et al. Case Rep Med. 2010;2010:807434; Brunzell JD. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2011 Dec 15]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/
Slide26Differential Diagnosis: If it is Not FCS, Then What Might it Be?
ObesityDiabetes mellitusAlcohol abuseNephrotic syndromeHypothyroidismMedicationsApoCII deficiencyLMF1 deficiencyGPIHBP1 deficiency Familial ApoAV deficiencyParaproteinemic disordersPolygenic combined hyperlipidemia (pCH)Stroes E, et al. Atheroscler Suppl. 2017;23:1-7; Sisman G, et al. Hepatobiliary Pancreat Dis Int. 2014;13:209-214; Brunzell JD. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2011 Dec 15]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/
Slide27Diagnostic Algorithm
Stroes E, et al. Atheroscler Suppl. 2017;23:1-7. Patient in non-acute settingTG > 10 mmol/L (885 mg/dL) for 3 consecutive blood analysesOnset of symptoms at age <40 yearsHistory
of pancreatitis No secondary lifestyle factors (except pregnancy and
estrogen use
)
No history of
familial combined hyperlipidemia
Suspect
TG/TC ratio >
2.2 (
mmol
/L/
mmol
/L)
or >5 (mg/dL/mg/dL)
Normal/low
ApoB
level
(<
100 mg/
dL
)
, if performed
No
positive effect of fibrate therapy
Patient in acute
setting
(pancreatitis
event)
Refer to
specialist
(
e
ndocrinologist,
gastroenterologist, and/or
lipidologist
)
Slide28Diagnostic Algorithm (cont’d)
Stroes E, et al. Atheroscler Suppl. 2017;23:1-7. Homozygous mutationIdentification of 2 mutationsDescribed pathogenic variant
Novel variant
To confirm compound heterozygosity:
Family screening OR
PCR cloning-based analysis
In-silico analysis OR post-heparin
LPL activity, if performed
LPLD diagnosis
ApoE
and LPL
> ApoA5
> GPIHBP1 > ApoC2 > LMF1
Low
post-heparin LPL activity, if performed
Positive FCS Diagnosis
Slide29Management of FCS
Slide30What is the Goal of Therapy for FCS Patients?
Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488. <500 mg/dL – Goal of therapyTriglyceride Levels4000 mg/dL – Increased risk of lipemia retinalis, hepatomegaly, splenomegaly2000 mg/dL – Appearance of eruptive xanthomasPancreatitis can occur at any of these levels
Slide31Challenges of Treating FCS
Standard triglyceride-lowering agents (niacin, fish oils, fibrates) are generally not effective. Currently, there is a lack of FDA-approved agents to lower TGs in FCS patients. Severe dietary restriction is currently the most effective form of therapy but is difficult to maintain.Alcohol intake and certain medications that increase TGs should be avoided.Al Azkawi H, et al. Case Rep Med. 2010;2010:807434; Williams L, et al. J Clin Lipidol. 2016;10:462-465;Leaf DA. Am J Med. 2008;121:10-12.
Slide32Dietary Restrictions
Sugar and carbohydrate restrictionFat restriction (less than 20 to 25 g per day)Complete avoidance of alcohol Monitored intake of fat-soluble vitamins (A, D, E, K)Leaf DA. Am J Med. 2008;121:10-12.
Slide33How Should Patients Manage Fat Intake?
Williams L, et al. J Clin Lipidol. 2016;10:462-465.Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Recommended sources of dietary fat intake for patients with FCSTotal fat intake should comprise from 10% to 15% of daily caloric needs.
Slide34Dietary Recommendations – Infants
Avoid breast milkAvoid standard formulaUtilize formula low in fat and high in medium chain triglycerides and micronutrientsWilliams L, et al. J Clin Lipidol. 2016;10:462-465.Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
Slide35Avoid Medications Known to Increase Triglyceride Levels
Thiazides Beta blockers EstrogenTamoxifenIsotretinoin Protease inhibitors 2nd generation antipsychotics GlucocorticoidsSertralineLeaf DA. Am J Med. 2008;121:10-12.
Slide36How Does FCS Affect the Patient’s Quality of Life?
Stroes E, et al. Atheroscler Suppl. 2017;23:1-7; Brunzell JD. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2011 Dec 15]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/; Brown A, et al. Presented at: the 2016 Congress on Atherosclerotic Cardiovascular Disease Prevention, Sept. 16–18,2016, Boca Raton, Florida Abstract 131; Davidson M, et al. Expert Rev Cardiovasc Ther. 2017;1-9. [Epub ahead of print].Severe dietary restrictionsPregnancy Emotional burden
Social isolationAnxietyDepression Neurological symptomsFatigueCognitive impairmentLack of concentration
Physical complications
Fatty liver disease
Diabetes
Cholecystectomy
Financial burden
Frequent hospitalizations
Missed work and school days
Stress on caregivers
Slide37Burden of FCS: New Insights from IN-FOCUS Study
Survey to evaluate patient-reported burden of FCSPatients reported seeing a mean of 5 physicians for FCS-related symptoms before being diagnosed Patients report various types of FCS symptoms (physical, psychosocial, emotional, and cognitive) Daily abdominal pain Extreme fatigue Brain fog, impaired judgement Multiple days of work/school missed due to symptoms Dietary lifestyle restrictions and fatigue limit social life and employment IN-FOCUS = Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients. Davidson M, et al. Expert Rev Cardiovasc Ther. 2017;1-9.
Slide38Emerging Therapies for FCS
Slide39Emerging Therapies for FCS
Meyers CD, et al. Lipids Health Dis. 2015;14:8; Gaudet D, et al. N Engl J Med. 2015;373:438-447; Gaudet D, et al. N Engl J Med. 2014; 371:2200-2206; Gaudet D, et al. Hum Gene Ther. 2016;27:916-925; Gaudet D, et al. Gene Ther. 2013;20:361-369.
Slide40Apolipoprotein C-IIIKey Regulator of Serum Triglyceride Levels
ApoC-III is a 79 amino acid glycoprotein synthesized principally in the liverMultiple ApoC-III particles on VLDLPlays a key role in determining serum TG levelsPotent inhibitor of LPL-catalyzed lipolysis of TGRL Also inhibits hepatic lipase which also plays an important role in the conversion of dense VLDL to IDL to LDLPlays a key role as a mediator of atherosclerosis and insulin resistancePromotes pancreatic B cell death in type 1 diabetesPlays a role in endothelial dysfunction and atherogenesisImpairs insulin signaling, decreasing NO productionTGRL = triglyceride-rich lipoproteins; NO = nitric oxide. Sacks FM, et al. J Lipid Res. 2011;52:1067-1070; Avall K, et al. Proc Natl Acad Sci U S A. 2015;112:E2611-2619; Holmberg R, et al. Proc Natl Acad Sci USA. 2011;108:10685–10689.
Slide41Volanesorsen
Antisense agent designed to reduce the production of ApoC-III Reduces TG levels by increasing TG clearance Subcutaneous injection, 300 mg/week Positive results in phase 2 and 3 trials Substantial reductions in triglyceridesDecreased incidence of pancreatitis attacksGraham MJ, et al. Circ Res. 2013;112:1479-1490; Gaudet D, et al. N Engl J Med. 2015;373:438-447; Gaudet D, et al. N Engl J Med. 2014; 371:2200-2206;Gaudet D, et al. Presented at EAS 2017 Late Breaking Session. Prague, Czech Republic. April 25, 2017.
Slide42Phase 3 APPROACH Study of Volanesorsen: Primary Endpoint
Gaudet D, et al. Presented at EAS 2017 Late Breaking Session. Prague, Czech Republic. April 25, 2017.Placebo(n = 33)Volanesorsen(n = 33)P
<.0001
Slide43Phase 3 APPROACH Study of Volanesorsen:
Effects on Pancreatitis EventsPlacebo n = 33Volanesorsen n = 33PatientsEventsPatientsEventsPatients with multiple adjudicated events in past 5 years417724Events during study3400
P-valueP=.02Gaudet D, et al. Presented at EAS 2017 Late Breaking Session. Prague, Czech Republic. April 25, 2017.
Slide44Gene Replacement Therapy for LPL Deficiency
Alipogene tiparvovecAAV1-based gene therapy containing the LPL S447X gene Administered by intramuscular injectionShown to improve chylomicron clearance Designed for patients with LPL deficiency caused by loss-of-function mutations in the LPL gene Not for diseases caused by apoA5, apoC2, GPIHBP1, LMF-1 gene mutationsRequires genotyping (genetic test) Carpentier AC, et al. J Clin Endocrinol Metab. 2012;97:1635-1644; Gaudet D, et al Gene Ther. 2013;20:361-369; Gaudet D, et al. Curr Opin Lipidol. 2012;23:310-320; Wierzbicki AS, et al. Expert Opin Biol Ther. 2013;13:7-10;
Ferreira V, et al. Hum Gene Ther. 2014;25:180-188; Alipogene tiparvovec. Assessment Report 2012. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002145/WC500135476.pdf.
Slide45Multidisciplinary
Management of FCS
Slide46Multidisciplinary Management of FCS
Pancreatitis ManagementLipid and CVD risk reductionFamily and Social NetworkAssessment, Education, and TrainingRecord Consolidation, Care TransitionMedical Nutrition TherapyMedication Therapy ManagementT3cDM ManagementGastroenterologist, PancreatologistAdministrative Staff
Cardiologist, Lipidologist
Slide47Summary
FCS is a genetic disease characterized by extremely high levels of triglycerides.FCS causes recurrent pancreatitis and other serious manifestations.Currently, there are no FDA-approved therapies for FCS; research and development is ongoing. FCS requires lifelong dietary restriction and very low fat diet.Debilitating symptoms of FCS reduce quality of life.