FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS)

Transcription

1 FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS) Dr. Joseph L. Witztum Distinguished Professor of Medicine, Department of Medicine & Director, Atherosclerosis Research Group, University of California, San Diego Dr. Daniel Gaudet Head, Community Genomic Medicine Center & Lipidology and Rare Lipid Disorders Unit, Dept of Medicine, University of Montreal, Chicoutimi, Qc, Canada 1

2 2 Objectives for Today s Call Gain a better understanding of FCS A severe, rare genetic disease with constant day to day symptoms punctuated by acute pancreatitis attacks FCS patients experience highly variable platelet counts High and low platelet counts Platelet counts as low as 42K/uL Platelet counts appear to be associated with triglyceride-rich chylomicrons

3 3 Familial Chylomicronemia Syndrome (FCS) is a Severe, Rare Genetic Disease FCS Can be monogenic: LPL, APOC2, APOA5, LMF1, GPIHBP1 and GPD Nonfasting plasma triglycerides, mg/dl Mild-to-moderate TG elevation Severe TG elevation Chylomicronemia Hegele et al Diabetes Endo 2014

4 4 FCS: A Severe, Rare Genetic Disease Severe hypertriglyceridemia (often TG >2,000 mg/dl) causing extreme risk for acute pancreatitis events and other serious manifestations beginning in childhood Daily, often crippling abdominal pain Type 2 diabetes Fatty liver Brain fog No currently available therapy can adequately treat patients with FCS Life-long restriction of only eating foods with no or severely low fat

5 5 Chylomicrons and VLDL Two Types of TG-rich Lipoproteins Chylomicron from intestine TG:Chol = 50 VLDL From Liver TG:Chol = 5

6 6 Simplified View: Triglyceride Entry and Clearance from Plasma Liver (VLDL) Intestines - Diet (Chylomicrons) Plasma compartment Lipoprotein Lipase (LPL) ApoC-III LPL-dependent Clearance Plasma TG Fatty Acids (Fuel) Normal TG 150 mg/dl ApoC-III LPL-independent Clearance Liver Adipose tissue Muscle

7 7 Lipoprotein Lipase (LPL) Breaks Down TGs in the Circulation Allowing Fatty Acids to Enter Tissues VLDL Chylomicron Capillary endothelium LPL: hydrolyzes fatty acids from glycerol backbone Capillary endothelium Glycerol Fatty Acids Tissue (muscle, fat cell, etc) Wang & Eckel, 2009

8 Absence of LPL Activity is Unique to FCS Patients Null loss-of-function mutations in LPL, GPIHPB1, APOC2, APOA5, or LMF1 genes 8 Liver (VLDL) Intestines - Diet (Chylomicrons) TG >> 750 mg/dl LPL-dependent Clearance Plasma TG a TG Fatty Acids (Fuel) Normal TG 150 mg/dl ApoC-III LPL-independent Clearance Liver Adipose tissue Muscle

9 Drug Therapy for FCS is Ineffective Today Standard TG-Lowering Therapies Primarily Work Through Modulating Hepatic TG Synthesis or LPL Activity 9 Standard TG- Lowering Drugs Fibrates Fish Oils Niacin Liver (VLDL) LPL-dependent Clearance Plasma TG a TG Fatty Acids (Fuel) Intestines - Diet (Chylomicrons) TG >> 750 mg/dl Normal TG 150 mg/dl ApoC-III LPL-independent Clearance Liver Adipose tissue Muscle

10 Extreme Diet Restriction is Currently the Only Way to Reduce the Severe Manifestations of FCS 10 Avoid Increasing Liver TG Input Alcohol Estrogens Certain Drugs Pregnancy Stress Liver (VLDL) Intestines - Diet (Chylomicrons) 0-10% Fat Diet Every single meal for lifetime! TG = mg/dl LPL-dependent Clearance Plasma TG a TG Fatty Acids (Fuel) Normal ApoC-III LPL-independent Clearance Liver Adipose tissue Muscle

11 11 Postprandial Triglyceride Levels Spike Substantially in Patients with FCS 3000 Plasma Triglycerides (mg/dl) ~500 mg/dl increase in TGs after a single meal placing patient at higher risk for acute pancreatitis 150 Normal TG Level Hours

12 12 Strict Diet Required to Manage FCS Does Not Resolve Symptoms and Causes Profound Psychosocial Issues Patient s With FCS Must Maintain <20g of Daily Total Fat < 2 tablespoons of olive oil A 0-10% fat restriction is difficult to maintain everyday, for every meal, for a lifetime A normal, healthy diet consists of 35% fat This fat restricted diet does not bring triglyceride levels to normal; it just reduces the risk of pancreatitis. However, other symptoms of FCS still dramatically impact their quality of life. When abdominal symptoms present because there are no other options patients learn to stop eating, often for days at a time

13 What are Chylomicrons? 13 Chylomicron Structure % TG --Very light and buoyant --Will separate out of water Chylomicron VLDL LDL HDL

14 Extreme Triglyceride Accumulation Forms Fat Layer in Blood That Separates Immediately After Draw 14 Chylomicron accumulation increases blood viscosity resulting in multiple clinical complications

15 15 Multiple Clinical Complications of FCS Lipemia (Milky) Retinitis Milky Plasma Eruptive Xanthoma (TG deposits in skin)

16 16 Multiple Clinical Manifestations of FCS Lipemia (Milky) Retinitis Milky Plasma Erruptive Xanthoma (TG deposits in skin)

17 17 Multiple Clinical Manifestations of FCS Lipemia (Milky) Retinitis Milky Plasma Erruptive Xanthoma (TG deposits in skin)

18 18 Multiple Clinical Manifestations of FCS Cognitive Impairment Emotional Burden

19 19 The Neurocognitive Burden of FCS is Underappreciated Neurocognitive manifestations and fatigue significantly impact patients daily work life, relationships, and employment opportunities Neurocognitive manifestations of excess chylomicronemia include: Difficulty understanding what others are staying Impaired judgement Brain fog Forgetfulness Memory loss Difficulty concentrating Daily fatigue disrupts work days and can cause difficulty maintaining social relationships

20 20 Multiple Clinical Manifestations of FCS Pancreatitis Crippling Abdominal Pain Diabetes Fatty Liver Enlarged Spleen/Liver GI Disturbances

21 FCS Patients Experience a Daily Burden of Disease Daily abdominal pain ranges from discomfort to debilitating pain Can rapidly escalate to incapacitating pain May represent sub-clinical pancreatitis Negatively impacts patient s work and life Constant reminder of disease Patients also suffer from frequent nausea, diarrhea, constipation, and bloating further affecting their quality of life 21

22 22 Pancreatitis is a Life-Threatening Complication of FCS Acute Pancreatitis: Occurs when Chylo-TG are digested by pancreatic lipases leading to tissue damage Manifests as crippling pain often requiring a trip to the emergency room and stay in the intensive care unit Pancreatitis can cause life-threatening complications such as sepsis, renal failure, ARDS (Acute Respiratory Distress Syndrome) and shock Recurring attacks cause chronic pancreatitis Insulin dependent diabetes Exocrine pancreatic insufficiency leading to malabsorption Chronic pain leading to opioid dependency Un-needed abdominal surgery

23 Triglyceride Levels Correlate with Number of Episodes of Acute Pancreatitis Attacks Per Patient 23 Number of pancreatitis episodes/patient Mean Triglycerides (mg/dl) r s =0.55 p<0.0001

24 24 FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS) Dr. Joseph L. Witztum Distinguished Professor of Medicine, Department of Medicine & Director, Atherosclerosis Research Group, University of California, San Diego Dr. Daniel Gaudet Head, Community Genomic Medicine Center & Lipidology and Rare Lipid Disorders Unit, Dept of Medicine, University of Montreal, Chicoutimi, Qc, Canada

25 FCS Natural History Program : The SMASH Initiative Set up to understand the natural history and burden of FCS Systematic review of medical files and hospitalizations (since birth) of LPL patients (many records go back up to 20 years) Extensive questionnaires (family history, medical history, symptoms, clinical signs, life habits, prescriptions, quality of life) Fine clinical phenotyping, endophenotyping and post-prandial investigation Omics: exome sequencing (or GWAS), epigenomics, microbiomics, lipidomics, gene expression profiling 25 Ref: EAS June 1, 2016 Plenary session 4: Future therapeutic challengesspecific talk title: Lessons Learned from Emerging Therapies for Severe HTG, Daniel Gaudet

26 FCS Natural History Program: The Approach Differential Dx: -Cluster analyses -ROC curves, etc 445 Patients with Chylomicronemia 104 FCS 341 Multifactorial Chylomicronemia 87 -Natural History -Clinical burden -Epidemiology -Omics Replication in other populations

27 Clinical Burden of Disease of FCS Patients 27 Clinical Manifestation of FCS SMASH LPLD (N=57) Lipemia retinalis (%) 54 Eruptive xanthomata (%) 27 Recurrent abdominal pain without hospitalization (%) 50 History of acute pancreatitis (%) 83 History of recurrent acute pancreatitis (%) 52 Recurrent acute pancreatitis events (# of events/pt) Chronic pancreatitis (%) 7

28 The Burden of FCS Patients from a Patient s Perspective Daily abdominal pain and GI disturbances Multiple days spent in the hospital due to FCS symptoms and/or acute pancreatitis events Multiple days of school/work missed due to FCS symptoms affecting their performance Dissatisfaction with managing through diet and viewed as extremely burdensome Fatigue and dietary lifestyle considerations limit employment opportunities and social life 28

29 The Burden of FCS Patients from a Patient s Perspective Anxiety due to the stress and isolation caused from daily symptoms and constant fear of pancreatitis and of dying (sword of Damocles) Interfere with the quality of life of relatives Insurability, health resources consumption, etc. Family issues/concerns; Important restrictions (eating, alcohol, leisure, traveling); 29

30 30 New Understandings of Platelet Variations in the Natural History of FCS

31 Patients with FCS Experience Dramatic Variability in Platelet Levels 31 Platelet count (x 10 3 /µl) Thrombocytosis Thrombocytopenia Patients

32 The FCS Natural History Database Consists of Patients with a Variety of FCS Causing Mutations 32 Characteristic All (n=87) History of thrombocytopenia (n=48) History of thrombocytosis (n=11) Males, n (%) Age, years (sd) 44.7 (16.9) 45.5 (15.6) 49.9 (12.9) Body mass index, kg/m 2 (sd) 23.1 (4.1) 22.6 (3.5) 23.4 (4.4) History of acute pancreatitis (%) History of cardiovascular disease (%) Genotype (LPL) (%) P207L Ho G188E Ho D250N Ho P207L/G188E compound He P207L/D250N compound He Others

33 The Range of Platelets in Patients in the FCS Natural History Database Ranged from Below < /µl to Above /µl 33 >55% have thrombocytopenia Thrombocytopenia (platelet count) A n (%) Thrombocytosis (platelet count) B n (%) /µl 31 (35.6) /L 6 (6.9) /µl 15 (17.2) /L 4 (4.6) < /µl 2 (2.4) /L 1 (1.1) Total 48 (55.2) Total 11 (12.6)

34 In the Majority of Cases, the Platelet Count Fluctuates Linearly and Positively with TG Values Example: Subject Platelet count (x 10 3 /µl) Triglycerides (mg/dl) 1000

35 In the Majority of Cases, the Platelet Count Fluctuates Linearly and Positively with TG Values Example: Subject Platelet count (x 10 3 /µl) Triglycerides (mg/dl) 1000

36 36 Platelet Counts in Patients with FCS: Conclusion Platelet counts vary substantially over time in patients with FCS More than 55% of FCS patients have presented at least one episode of thrombocytopenia There were no signs, symptoms or events of bleeding reported 12.9% have presented a history of thrombocytosis (no abnormal clotting) Fluctuations in platelet counts in FCS patients are most often correlated with fluctuations in TG values

37 Patient Case Studies 37

38 38 38 Patient Case Study #1 46 year old biotechnology executive presented to the ER with severe abdominal pain and shock admitted to the ICU Present Illness: Past History: Lab Data: Diagnosis: Resolution: Had been depressed, drinking modestly and not carefully following low-fat diet--was on fibrate Had episodes of abdominal pain since youth and prior pancreatitis (brother has similar history) TG were 15,600 mg/dl Life-threatening pancreatitis and hyperlipidemia NPO, Medical Rx, 2-weeks in hospital with ICU

39 39 39 Patient Case Study #2 21 year old female college student presented to the ER with severe abdominal pain Present Illness: Past History: Lab Data: Diagnosis: Had been at all night party at fraternity house day before History of recurrent episodes of pancreatitis since childhood TG level at 4,500 mg/dl Diagnosed as a child due to presentation of pancreatitis and hyperlipidemia

40 40 40 Patient Case Study #3 46 year old woman with a history of recurrent pancreatitis Diagnosis: Diagnosed with FCS at age 4 on a routine lab exam (pre-amygdalectomia) Past History: Recurrent medical visits for unexplained crying jag when she was an infant 22 episodes of acute pancreatitis since age 16 3 were extremely severe and required long ICU stay 1 occurred during pregnancy and lead to fetal death Does not respond to fibrates or other lipid lowering durgs Lab Data: TG values usually ranging between mg/dl

41 41 FCS A Severe, Rare Genetic Disease Patients with FCS have extremely high levels of triglycerides Daily symptoms punctuated with episodes of acute, potentially fatal pancreatitis Extreme variations in platelet levels observed; correlation with triglyceride levels No adequate treatment currently available