inherited triglyceride disorders - lipid · • “familial” implies genetic cause but actual...
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Inherited Triglyceride Disorders
Anne Carol Goldberg, MD, FNLAProfessor of Medicine
Washington University School of MedicineMay 20, 2016
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Disclosures– Board and committee membership—National Lipid
Association, Foundation of National Lipid Association– Statement/Guideline development—AHA Triglyceride
Scientific Statement, ACC/AHA 2013 Cholesterol Guideline, Endocrine Society Triglyceride Clinical Practice Guideline, National Lipid Association Familial Hypercholesterolemia Recommendations
– Research contracts— Merck, Genzyme/ISIS, Genzyme/Sanofi-Aventis, Glaxo-Smith-Kline, Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, Genentech/Roche, Regeneron, IONIS (all grants to medical school)
– Consulting/Advisory Board—Sanofi-Aventis, OptumRx, uniQure
– Editorial—Merck
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Outline
• Case• General approach to hypertriglyceridemia• Inheritance patterns• Specific disorders• Secondary causes and contributors to
hypertriglyceridemia• Some practical aspects to treatment
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Case• 27 year old man with severe hyperlipidemia• Presents with rash, triglycerides 8910 mg/dL• Drinks ½ gallon of Gatorade daily and soda and juices• Father-hyperlipidemia; mother-high cholesterol• Power plant worker, no tobacco, rare alcohol• Exam: BMI 30.6, central obesity• Diffuse eruptive xanthomas in clusters and singly over
back, upper arms, legs, feet• Referring labs: triglycerides 8910, cholesterol 1156• Repeat labs: triglycerides 6540 cholesterol 1150
glucose 426 mg/dL, hemoglobin A1c 14.4%
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Approach to evaluation of lipid disorders
• What lipoproteins are elevated?• Likely genetic disorder?
– Age, symptoms, physical exam, lipids– Family history– Dominant or recessive pattern
• Contributing conditions?– Factors affecting production and clearance
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Lipoprotein Subclasses
1.20
1.101.06
1.02
1.006
0.95
5 10 20 40 60 80 1000Diameter (nm)
Den
sity
(g/m
L)
6
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Composition of Plasma Lipoproteins
Chylomicrons VLDL IDL LDL HDLDensity (g/mL)
< 0.95 0.95-1.006 1.006-1.109 1.019-1.063
1.063-1.21
Apo B48, CII, CIII, E Apo B100, CII, CIII, E
Apo B100,CIII, E
Apo B100 Apo AI,AII, CI, II,
III, E
TriglycerideCholesterol
Phospholipid
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Classification of Lipoprotein Disorders(Frederickson / Levy / Lees)
III V
TG N
Xanthomas none palmartubero-eruptive
none eruptive
Clinical CHD CHD pancreatitis
Etiology unknown apoE2+ unknown unknown
Name Mixed Dyslip
FamilialDyslip
Fam EndogHTG
I
eruptive
pancreatitis
Def. LPLapoC-II
FamilialChylo Synd
Lipoprotein LDL+VLDL
Remnants VLDL CM+VLDL
Chylomicron
IIa IIb IV
LDL
tendon
CHD CHD
DefLDLR+
FamilialHyperchol
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Classification of Serum TG Levels
Miller, M et al. Circulation. 2011;123:2292-33,
Berglund, L et al. J Clin Endocrinol Metab 2012; 97: 2969.
2011 AHA Scientific Statement
2012 Endocrine Society
Triglyceride Designation
mg/dL Triglyceride Designation
mg/dL
Normal < 150 Normal < 150Borderline- high 150 – 199 Mild HTG 150 – 199
High 200 – 499 Moderate HTG 200 – 999
Very high > 500 Severe HTG 1000 –1999
Very severe HTG > 2000
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Very-High and Severe HTG are Usually Genetic
• 150 to 500 mg/dL--mild to moderate triglyceride elevations associated with increased cardiovascular risk—possibly polygenic
• Over 500 mg/dL—possibly polygenic• Over 885 mg/dL (10 mmol/L)—more likely
monogenic, associated with risk of pancreatitis
Hegele et al. Lancet Diabetes & Endocrinology 2014; 2: 655.
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Causes of severe hypertriglyceridemia
• Gene mutations of lipoprotein lipase, apoC2, apoA5, apoE and others—homozygous and heterozygous
• Polygenic less severe mutations• Combination of genetic and secondary
factors• Congenital and acquired lipoatrophic
disordersBerglund L et al, J Clin Endo Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Hereditary Dyslipidemias
• Monogenic– Less common or rare– Large effect mutations
• Polygenic– Common small effect mutations– Combination of mutations and secondary
factors– Combination of multiple variants (SNPs)
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Hereditary Hypertriglyceridemia• Monogenic Hyperchylomicronemia
• Lipoprotein lipase deficiency• ApoCII deficiency • Also mutations in apo A5, GPIHBP1
(glycosylphosphatidylinositol-anchored HDL-binding protein 1), LMF1 (lipase maturation factor 1 and others)
• Dysbetalipoproteinemia• ApoE mutations
• Polygenic hypertriglyceridemia• Familial hypertriglyceridemia• Familial combined hyperlipidemia: overproduction
of apoBBerglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Hyperchylomicronemia—monogenic or polygenic/secondary
• Monogenic– Very high chylomicrons (absent or very decreased
lipoprotein lipase function →delayed chylo clearance)– Acute/recurrent pancreatitis– Eruptive xanthomas/lipemia retinalis– Neuropathy, memory loss– Fatty liver
• Polygenic– Increased VLDL (hepatic overproduction + delayed
VLDL clearance)– Adult onset– Obesity-related– Diabetes-related– Multifactorial and variable LPL and other mutations
Miller M et al. Circulation. 2011;123:2292-2333.
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Secondary hypertriglyceridemia• Dietary: high calorie, fat, sugar• Alcohol• Obesity • Metabolic syndrome• Drugs including: thiazides, beta-blockers, oral estrogens,
isotretinoin, corticosteroids, bile acid-binding resins, protease inhibitors, cyclophosphamide, asparaginase, antipsychotics
• Untreated diabetes mellitus• Endocrine diseases: hypothyroidism• Renal disease (nephrotic syndrome, uremia)• Pregnancy (especially third trimester)• Autoimmune disorders—SLE• Paraproteinemia
Berglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Familial hyperchylomicronemia• Mutations of lipoprotein lipase or apo CII (and other rare
gene mutations)• Autosomal recessive inheritance• Frequency 1:1,000,000 or higher with founder effect,
heterozygotes 0.04-22% • Impaired intravascular lipolysis • Severely elevated triglycerides and chylomicrons, LDL-C
low, HDL-C low, severe post-prandial lipemia• Abdominal pain, eruptive xanthomas,
hepatosplenomegaly, lipemia retinalis, acute pancreatitis, neuropathy, onset in childhood
• Treat with very low fat diet
Berglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Eruptive xanthomas
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Familial dysbetalipoproteinemia• Autosomal recessive, mutations of ApoE (rare
mutation causes autosomal dominant form)• Impaired hepatic uptake of VLDL and
chylomicron remnants• E2/E2 genotype plus a second genetic or
acquired defect• High cholesterol and triglyceride levels-300 to
1000 mg/dL and roughly equal• Increased vascular disease• Palmar and tuberoeruptive xanthomas• May be very sensitive to lifestyle change
Berglund L et al, J Clin Endo Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Tuberous Xanthomas
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Tuberous Xanthoma
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Familial combined hyperlipidemia• Common; 1 to 2% of population• Classically, autosomal dominant• “Familial” implies genetic cause but actual
molecular basis is unclear• Likely a number of genetic causes
Multiple genes, heterozygosity for defects in lipoprotein lipase
• Variable phenotype—high cholesterol or high triglycerides or both
• Overproduction of apoB, increased VLDL particles, small dense LDL
• Increased risk of CHDBerglund L et al, J Clin Endo Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Familial hypertriglyceridemia• Common (1% of population), possibly autosomal
dominant• Increased triglyceride synthesis, large VLDL
particles• Triglycerides 250 to 1000 mg/dL• No clear risk of CHD but risk of chylomicronemia
with obesity, high carbohydrate diet, estrogen, alcohol, diabetes
• Likely polygenic• No typical physical findings: but findings of
chylomicronemia syndrome if triglycerides are higher enough Berglund L et al, J Clin Endo Metab 97: 2969–2989, 2012
Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014
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Endocrine Society Clinical Practice Guidelines on the Evaluation of Hypertriglyceridemia
From Berglund et al. J Clin Endocrinol Metab 2012; 97: 2969
• Recommend screening adults for hypertriglyceridemia as part of a lipid panel at least every 5 years
• The diagnosis should be based on fasting triglyceride levels
• Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia
• Patients with primary hypertriglyceridemia should be assessed for other CV risk factors and for a family history of dyslipidemia and CV disease to assess genetic causes and future CV risk
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Causes of hypertriglyceridemia—dietary factors
Increased chylomicronsFat
Increased VLDL production• Excess calories• Alcohol• Obesity • Sugar, simple carbohydrates• Fats• Weight gain
Berglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014Miller et al. Circulation 2011; 123: 2292.
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Causes of hypertriglyceridemia—disorders and conditions
• Metabolic syndrome• Untreated diabetes mellitus• Insulin resistance• Endocrine diseases: hypothyroidism• Renal disease (nephrotic syndrome, chronici kidney
disease)• HIV infection• Pregnancy (especially third trimester)• Polycystic ovary syndrome• Autoimmune disorders—SLE• Paraproteinemia
Berglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014Miller et al. Circulation 2011; 123: 2292.
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Drugs that raise triglycerides• Oral estrogens, tamoxifen, raloxifene• Retinoids• Immunosuppressive drugs (cyclosporine, sirolimus)• Interferon• Beta-blockers (especially non-beta 1-selective)• Atypical antipsychotic drugs (clozapine, olanzapine)• Protease inhibitors• Thiazide diuretics• Glucocorticoids• Bile acid sequestrants• L-asparaginase• Cyclophosphamide
Berglund L et al, J Clin Endocrinol Metab 97: 2969–2989, 2012Hegele RA et al, The Lancet Diabetes and Endocrinology 2:655-666, 2014Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488.
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Treatment of hypertriglyceridemia
• Moderately high (150 to 880 mg/dL—1.7 to 10 mmol/L)– Prevent cardiovascular disease– Treat secondary factors (i.e. diabetes)– Reduce body weight, reduce alcohol, reduce
simple sugars and total carbohydrate, increase dietary omega-3 fatty acids
– Statins if high risk or high LDL-C– Fibrates, omega-3, niacin for triglycerides that
remain above 500 mg/dL
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Treatment of hypertriglyceridemia• High (500 mg/dL and above, especially >880
mg/dL--10 mmol/L)– Prevent pancreatits– Treat secondary factors (i.e. diabetes)– No oral intake if having pancreatitis– Post pancreatitis fat intake <20% of calories– Reduce body weight, reduce alcohol, reduce simple
sugars and total carbohydrate, increase dietary omega-3 fatty acids; increased physical activity
– Fibrates, omega-3, niacin for triglycerides that remain above 500 mg/dL
– Statins once triglycerides are down
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Dietary Measures to Lower TG Levels
Change TG LoweringWeight loss 10% – 20%(5-10% ↓body weight : 1 kg↓→2%TG↓)
“Mediterranean” diet (fiber, fish, fruits/veg) 10% – 15%(vs. high-carb/low-fiber diet)
Marine-derived omega-3 (EPA/DHA)/gram 5% – 10%(herring≈salmon>trout>tuna)
↓Carbohydratesby 5-10% of energy (1-2% ↓ 5% – 20%per 1% energy replacement w/MUFA or PUFA)
Eliminate trans fats (1% ↓ per 1% energy 1% – 3%replacement with MUFA/PUFA)
MUFA = monounsaturated FA; PUFA = polyunsaturated FA. Miller M et al. Circulation. 2011;123:2292-333.
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Physical Exercise Lowers TG• ↓TG is usually the first/strongest lipid effect of
↑physical activity• % ↓TG is directly proportional to:
– Baseline TG– Amount of exercise (no minimum threshold)
• Aerobic activity better • Frequency and intensity important• Exercise can block CHO-induced ↑TG• ↓VLDL production and ↑VLDL clearance
Bays HE et al. J Clin Lipidol. 2013;7:304-83.Bellou, E. Med Sci Sports Exerc. 2013;45(3)455-461.Couillard C et al. Arterioscler Thromb Vasc Biol. 2001;21:1226-32.Jensen MD et al. J Am Coll Cardiol. 2013;Nov 7 [Epub ahead of print]King AC, et al. Circulation. 1995;91:2596-2604.Miller M et al. Circulation. 2011;123:2292-333.
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Case• 27 year old man with severe hyperlipidemia• Presents with rash, triglycerides 8910 mg/dL• Drinks ½ gallon of Gatorade daily and soda and juices• Father-hyperlipidemia; mother-high cholesterol• Power plant worker, no tobacco, rare alcohol• Exam: BMI 30.6, central obesity• Diffuse eruptive xanthomas in clusters and singly over
back, upper arms, legs, feet• Referring labs: triglycerides 8910, cholesterol 1156• Repeat labs: triglycerides 6540 cholesterol 1150
glucose 426 mg/dL, hemoglobin A1c 14.4%
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Initial approach to the patient with triglycerides over 2000
• History– Past history of lipid disorders, pancreatitis,
rash– Medications– Detailed family history
• Assess diet– Food records or recall– Ask about beverages: alcohol, soda, juice,
sweetened drinks
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Initial approach to the patient with triglycerides over 2000
• Physical exam– Fundoscopic: lipemia retinalis (trig >4000)– Skin--eruptive xanthomas, palmar xanthomas,
tuberous xanthomas• Laboratory
– Measure blood glucose, TSH, creatinine– Urine dipstick for protein– Fasting lipid profile– CBC, ANA
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Diabetes and lipids• Increased triglycerides, low HDL-C, small dense
LDL• Increased free fatty acids to the liver increase
VLDL production• Decreased insulin affects lipoprotein lipase
function• Saturation of lipoprotein lipase at trig > 400• Triglycerides can spiral up quickly, especially
with underlying lipid disorder
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Lowering triglycerides
• Glycemic control & lifestyle modification including diet and exercise
• Statins provide some lowering• Fibrates, omega 3 fatty acids and niacin better
triglyceride lowering medications• Niacin second line therapy• Fish oil with statin or added to combination drug
therapy• Fenofibrate preferred in combination with statins
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Hypertriglyceridemia: diet and diabetes
• Diet can be critical—calories, fat, sugar, alcohol
• Have the patient bring in food records and blood sugar logs
• Assess beverage intake• Give specific diet recommendations and
refer to dietitian and diabetes educator• Diabetes and pre-diabetes: metformin
helps lower triglycerides
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Hypertriglyceridemia practical issues
• Bedtime insulin can be very useful• LDL cholesterol will often increase when
you lower triglycerides• Always check the medication list• Acute illness can raise triglycerides• Assess cardiovascular risk and use statins
when applicable
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Take home points
• Hereditary triglyceride disorders may be monogenic or polygenic
• Diet, other conditions and medications can contribute to high triglyceride levels.
• Treatment needs to address secondary issues as well as the hereditary
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Thank [email protected]