Dyslipidaemia (hypercholesterolaemia & hypertriglyceridaemia) Flashcards
Define hypertriglyceridaemia.
fasting plasma triglyceride level ≥2.3 mmol/L
When does triglyceridaemia cause chylomicronaemia? What condition may arise as a result of trigycerides >20mmol/L?
When triglyceride level is >11.3mmol/L
Pancreatitis occurs at levels >20mmol/L
How common is triglyceridaemia?
- Related to insulin resistance and linked to being obese/overweight so prevalence is rising
What are the causes of hypertriglyceridaemia?
Primary/genetic causes:
- monogenic chylomicronaemia
- polygenic HTG
- dysbetalipoproteinaemia
- combined hyperlipoproteinaemia
Secondary causes:
- obesity, DM
- lipodystrophies e.g. metabolic syndrome (high triglycerides, low HDL), hypothyroidism,
- renal disease, nephrotic syndrome, dialysis
- liver disease, NASH, viral hepatitis
- cystic fibrosis, HIV infection
- genetics - apo A-V, apo CIII and angiopoietic-like proteins 3 and 4
- anorexia nervosa
- excess alcohol (acute and chronic)
- Cushing’s
- organ transplant, sarcoidosis, SLE, myeloma
Medications
- glucocorticoids
- oestrogens, tamoxifen
- Accutane, retiinoid (bexarotene)
- antihypertensive meds like hydrochlorothiazide and non-selective beta blockers
- antiretroviral therapy
- interferons
- propofol
What is the pathophysiology of hypertriglyceridaemia (triglyceride metabolis
- TG arise from exogenous and endogenous sources
- Exogenous = dietary fats + TG-rich chylomicron particles from blood that are cleared by liver → absorbed in GI tract
- Liver secretes VLDLs into blood → peripheral tissues → metabolised by lipoprotein lipases for energy for muscle or storage by adipose tissue.
- Chylomicrons and VLDLs are cleared by tissue lipase pathways.
- When lipoprotein lipase activity is decreased the clearance VLDL/chylomicrons is impaired → accumulation of triglycerides in blood
What are the risk factors for hypertriglyceridaemia?
- FH
- overweight/obese
- high saturated fat, carb/glycaemic index diet, excess alcohol intake
- insulin resistance
- liver disease, renal disease
- hypothyroidism
- Cushing’s
- anorexia nervosa
- HIV
- CF
- medications
- acute spinal cord injury
- inflammatory/immune disorders
- organ transplant
What might you see on examination in a patient with hypertriglyceridaemia?
Lipaemia retinalis = retina is pale and retinal vessels are white
Eruptive xanthoma = small yellow papules surrounded by erythematous base (appear on buttocks, elbows, pressure sensitive spots) - below
Both uncommon. Patients typically asymptomatic
What investigation would you do for suspected hypertriglyceridaemia?
- TG level - after 12-14hr fasting
Other:
- TFTs - for hypothyroidism
- Fasting plasma glucose
- Urea, Cr, albumin - raised with low albumin in nephrOtic syndrome
- LFTs
- Serum protein electrophoresis - if suspicious of multiple myeloma/SLE
- CT - if signs of acute pancreatitis
- Apolipoprotein B
- CRP
How is hypertriglyceridaemia managed?
Conservative -
Lifestyle modification - e.g. smoking, HDLs. Recommended for 3-6month before medication is started.
Treat underlying conditions
Medical:
Statins - 40-80mg OD. Dose based on ASCVD score.
+/- non-statin LDL-lowering medications - ezetimibe, PCSK9i (e.g. evolocumab, alirocumab) or bempedoic acid
+/- isosapent ethyl or omega3acid ethyl esters - if persistent TG >1.7mmol/L
+/- fibrate e.g. gemfibrozil- do NOT give with a statin
How is acute chylomicronaemia managed?
Chylomicronaemia/acute pancreatitis - hospital admission and supportive care
- IV hydration and NBM for 48-72hrs - until TGs <5mmol/L
- Start statins once TGs <5mmol/L
- +/- IV insulin - may help lower TGs in poorly controlled DM.
What are the complications of hypertriglyceridaemia? What is the prognosis?
- Coronary events
- Acute pancreatitis
What is the prognosis with HTG?
Improves significantly with lowering of TG levels.
Once plasma lipid levels are stable they can be monitored with LFTs every 6-12 months.
Define hypercholesterolaemia.
Elevation of total cholesterol and/or LDL or non-HDL cholesterol in the blood = dyslipidaemia
Briefly describe what is meant by dyslipidaemia.
Dyslipidaemia = serum TC, LDL-C, TGs , apolipoprotein B, or lipoprotein(a) concentrations above the 90th percentile, or HDL-C or apolipoprotein A-I concentrations below the 10th percentile for the general population.
However, these classic percentile cut-off points should not be used too rigidly - evidence suggests that lipoprotein(a) ≥80th percentile is abnormal and linked to elevated CVD risk.
How common is hypercholesterolaemia?
- Depends on definition
- Approx 12% of US pop has TCs over 6.2mmol/L
- In those with CHD, dyslipidaemia presence is 80-88%
What is the aetiology of hypercholesterolaemia?
Primary causes:
- Gene mutations → disturbance in LDL or TG production/clearance
- e.g. familial hypercholesterolaemia
Secondary causes:
- Combination of polygenes and unhealthy lifestyle
- Sedentary lifestyle
- Excess consumption of saturated fats/trans-fatty acids
- Abdominal obesity
- Chronic renal insufficiency
- DM
- Hypothyroidism
- Cholestatic liver disease
- Alcohol dependency
- Drugs - high dose thiazide diuretics, oral oestrogens, glucocorticoids, anabolic steroids, anti-HIV agents, atypical antipsychotics (olanzapine, clozapine), beta blockers without intrinsic sympathomimetic or alpha blocking activity.
What is the pathophysiology of hypercholesterolaemia?
- Usually from abnormal lipoprotein metabolism e.g. less LDL-R expression or activity → less hepatic LDL clearance → atherosclerosis
What are the risk factors for hypercholesterolaemia?
- Insulin resistance and T2DM
- Overweight
- Hypothyroidism
- Cholestatic liver disease
- Smoking
- NephOtic syndrome
- Medications e.g. atypical antipsychotics
What signs might be present on physical examination in hypercholesterolaemia?
- Obesity
- Xanthelasmas
- Tendinous xanthomas
- Tuberous xanthomas - firm, painless, red-yellow nodules
- Yellow palmar striae (should be red) - found in type III familial dys-beta-lipoproteinaemia
- Corneal arcus with onset before age 45yrs
What investigations would you do for hypercholesterolaemia?
Lipid profile - consists of TC, TGs, LDL, HDL and non-HDLs -
- TC - >5.18mmol/L
- LDL - >2.59mmol/L
- non-HDL - <3.4mmol/L
- HDL - <1.04mmol/L (M), <1.29mmol/L (F)
- TGs - >1.7mmol/L
TSH - elevated in primary hypothyroidism (but may be low in secondary hypothyroidism)
Lipoprotein(a) - covalently bound to apolipoprotein B of LDL - values >50 mg/dL or >125 nmol/L are considered high
+/- Genetic testing - if suspecting familial hypercholesterolaemia
What is the management of hypercholesterolaemia?
- Lifestyle modification - cholesterol intake should be <300mg/day, aerobic exercise, complex carbohydrates and unsaturated fat.
- High intensity statin - atorvastatin 40-80mg OD; check HDL-C and non-HDL-C at 3 months
- +/- Ezetimibe - impairs dietary and biliary cholesterol absorption; ezetimibe may be added to maximally tolerated statin
- +/- PCSK9 inhibitor - alirocumab - inhibits PCSK9 binding to LDL-R which causes degradation
- +/- Bile acid sequestrants - prevent bile reabsorption; e.g. colestyramine and colesevelam for severe hypercholesterolaemia
How do statins work?
They work by reducing the liver’s production of cholesterol. They block an enzyme called HMG CoA reductase that the liver uses to convert acetate to MVA and then cholesterol.
Which risk calculator is used to calculate 10 year risk of heart disease or stroke and provides statin recommendation?
ASCVD risk algorithm - similar to QRISK
What are the complications of hypercholesterolaemia? What is the prognosis on statins?
- IHD
- peripheral vascular disease
- ACS
- stroke
- erectile dysfunction (due to endothelial dysfunction)
Prognosis:
- Rates of adverse outcomes have been reduced since statin treatment. Vast majority do well on statins.
How long should you fast for accurate lipid levels measurement?
12 hours - because TGs change with meals and by then the chylomicrons (transporting TGs) will be cleared
Name 2 medications which can cause hypercholesterolaemia.
Ciclosporin
Thiazide diuretics
Name 3 side effects of statins.
- Asthenia (weakness)
- GI disturbance
- Headache
- Myositis (rare)
BNF also lists T2DM as a SE in those who are at risk although incidence unknown.
What abx should be avoided with statins?
Clarithromycin - will increase exposure and predispose to rhabdomyolysis
Which juice should be avoided with statins?
Grapefruit - increases exposure
What are the BHS 1-2-3-4 cholesterol targets?
HDL - >1
LDL - <2
Non-HDL <3
Total cholesterol <4
Where is HLD made?
Liver and gut
What are the types of lipoproteins from largest to smallest?
- Chylomicrons
- VLDLs - main carrier of TRIGLYCERIDES
- LDLs - main carriers of CHOLESTEROL
- HDLs
Where is bile absorbed?
Terminal ileum
How common is familial homozygous hypercholesterolaemia?
1 in a million - presents as corneal arcus in children or cholesterol levels >30mmol/L from birth.
NB: heterozygous hypercholesterolaemia is more common at 1 in 500 and will manifest around age 40yrs
Which drug causes the largest:
- decrease in LDL
- increase in HDL
- decrease in TG
- atorvastatin (-51%)
- nicotinic acid (not used) → gemfibrozil is next (+12%)
- gemfibrozil (-40%)
