Familial Chylomicronemia Syndrome (FCS): - PowerPoint Presentation

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Familial 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.

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What 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.

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Epidemiology

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/.

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Pathophysiology of FCS

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What 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/.

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What 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

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What 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.

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Chylomicron 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

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Lipoprotein Biology

Lusis AJ, et al. Nat Genet. 2008;40:129-130.

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Pathway 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

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LMF1 and LPL Maturation

LMF1 = Lipase maturation factor-1.Doolittle MH, et al. Curr Opin Lipidol. 2010;21:198-203.

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Sequence 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

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Physiologic 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.

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Known 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%

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Recognition and Diagnosis of

FCS

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What 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

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Clinical Manifestations of FCS:

Eruptive Xanthomas

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Clinical Manifestations of FCS:

Lipemia Retinalis

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Pancreatitis: 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.

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Diagnosing 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. 

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When 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/

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Differential 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/

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Diagnostic 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

)

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Diagnostic 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

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Management of FCS

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What 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

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Challenges 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.

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Dietary 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.

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How 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.

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Dietary 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.

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Avoid Medications Known to Increase Triglyceride Levels

Thiazides Beta blockers EstrogenTamoxifenIsotretinoin Protease inhibitors 2nd generation antipsychotics GlucocorticoidsSertralineLeaf DA. Am J Med. 2008;121:10-12.

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How 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

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Burden 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.

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Emerging Therapies for FCS

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Emerging 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.

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Apolipoprotein 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.

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Volanesorsen

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.

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Phase 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

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Phase 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.

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Gene 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.

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Multidisciplinary

Management of FCS

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Multidisciplinary 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

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Summary

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.