Dyslipidaemia. Dr NM Oosthuizen Dept of Chemical Pathology SA

Transcription

1 Dyslipidaemia Dr NM Oosthuizen Dept of Chemical Pathology SA

2 Endogenous and exogenous pathways Endogenous Exogenous

3 Reverse cholesterol transport

4 Dyslipidaemias Causes can be primary or secondary Secondary dyslipidaemias Take a full drug history and measure: fasting plasma glucose serum creatinine urinary protein (dipstick) LFTs TFTs creatine kinase (CK) Treat secondary causes before risk assessment Lipogram may demonstrate predominant cholesterol, TG or mixed pattern Inverse relationship between TG and HDL

5 Overview of hyperlipidaemias Predominantly increased cholesterol Primary Familial hypercholesterolaemia LDL Familial defective apo-b-100 FH due to PCSK9 activating mutations Familial combined hyperlipidaemia Polygenic hypercholesterolaemia LDL LDL LDL LDL Secondary Diet high in SFA /cholesterol LDL Hypothyroidism Cholestasis Progestogens (HDL often ), cyclosporin, AIP LDL Lipoprotein X (LpX) and HDL LDL Predominantly increased triglycerides Primary Familial hypertriglyceridaemia VLDL and CM Familial hyperchylomicronaemia Familial combined hyperlipidaemia VLDL and CM VLDL Secondary Obesity, CHO-rich diet, DM, CRF, β-blockers VLDL (HDL often ) Alcohol abuse, pregnancy, E2, glucocorticoids VLDL (HDL ) Increased cholesterol and triglycerides Primary Familial combined hyperlipidaemia VLDL and LDL Familial dysbetalipoproteinaemia IDL and CM remnants Secondary DM, metabolic sd, hypothyroidism, nephrotic sd VLDL and sdldl (HDL often ) References 1 and 2 Androgens, retinoids, ART, SLE, diuretics VLDL and LDL (HDL may be )

6 Case: primary hypothyroidism 33-year-old man with 2-year history of tiredness, depression and weight gain of 10 kg Stopped playing soccer, because his muscles ached on exertion TC (<5) TGL (<1.7) HDLC (>1.0) LDLC TSH ( ) FT4 (10 27) CK (30 200) 10.2 mmol/l 1.1 mmol/l 1.0 mmol/l 8.7 mmol/l >100 mu/l <6 pmol/l 1330 U/L After Tx with Eltroxin, TC came down to 4.6 mmol/l

7 Familial hypercholesterolaemia 2 Gene mutations affecting LDL receptor Reference 1

8 FH (cntd) Homozygous/compound heterozygous No or very little LDL receptor activity TC mmol/l Symptomatic CVD in teens Tx: high dose statins and plasmapheresis Heterozygous 1:500 (SA 1:80 in Afrikaners) 50% LDL receptor activity Autosomal dominant inheritance TC 8 15 mmol/l Symptomatic CVD in 20 s-50 s Tx: HMG-CoA reductase inhibitors Founder effect in SA Tendon xanthomas, xanthelasma and arcus juvenilis

9 Case: familial hypercholesterolaemia 28-year-old man whose father and grandfather died of myocardial infarction in their early forties Tendon xanthomas on knuckles and Achilles tendons Non-smoker, normotensive, took plenty of exercise and was not overweight Plasma TC (<5) TGL (<1.7) HDLC (>1.0) LDLC 10.6 mmol/l 1.4 mmol/l 1.9 mmol/l 8.1 mmol/l Risk calculation not applicable in genetic dyslipidaemias Treatment with lipid-lowering drugs indicated

10 Other causes of FH Familial defective apo-b Mutation in binding domain of apo-b-100 Autosomal dominant inheritance No founder effect in SA Similar to FH, but tendon xanthomas less common and hypercholesterolaemia less severe FH due to PCSK9 activating mutation Proprotein convertase subtilisin/kexin 9 binds to LDLR complex endocytosed and degraded in lysosomes (LDLR not recycled to surface) PCKSK9 is a new target for LDL-lowering Tx

11 Int J Biol Sci 2012; 8(3): doi: /ijbs.3524 Diagnostic criteria for familial hypercholesterolaemia (Simon Broome criteria) Definitive diagnosis of FH Serum cholesterol >7.5 mmol/l (>6.7 mmol/l in children <16 yrs) or LDL cholesterol >4.9 mmol/l in adults Tendon xanthomas present in pt or 1 st or 2 nd degree relative Possible diagnosis of FH Serum cholesterol >7.5 mmol/l (>6.7 mmol/l in children <16 yrs) or LDL cholesterol >4.9 mmol/l in adults A family history of myocardial infarction before the age of 60 in 1 st or 2 nd degree relative or serum cholesterol >7.5 mmol/l in 1 st or 2 nd degree relative

12 Familial combined hyperlipidaemia 2 FCH is most common disorder in CVD patients Hyperapobetalipoproteinaemia Usually manifests in adulthood Autosomal dominant Obesity and insulin resistance common in FCH Increased LDL, VLDL or both; HDL decreased Atherogenic lipid profile = TG, HDL and small, dense LDL particles

13 Familial hypertriglyceridaemia 2 Rarely manifests before adulthood Mutations in APOA5 gene Apo AV augments LPL-mediated hydrolysis of TG in CM and VLDL Autosomal dominant Plasma TG usually not >5 mmol/l, but may be higher with DM, obesity or excess alcohol Chylomicronaemia, eruptive xanthomas, retinal lipaemia and risk of pancreatitis in severe cases Uncertain whether CVD risk is increased

14 Familial hyperchylomicronaemia 2 Chylomicronaemia syndrome: eruptive xanthomas, retinal lipaemia, recurrent abdominal pain (pancreatitis) and hepatosplenomegaly Plasma TG>10 mmol/l, fasting CM s, HDL Lipoprotein lipase or Apo-CII deficiency Autosomal recessive Manifests in childhood (apo-cii deficiency later, milder) Tx: low-fat diet, medium chain fatty acids and fibrates

15 Case: familial hyperchylomicronaemia A 20-year-old girl with history of recurrent pancreatitis with severe abdominal pain Her plasma was grossly lipaemic and developed a creamy layer on standing in the fridge overnight She had eruptive xanthomas, retinal lipaemia and hepatosplenomegaly Plasma TC (<5) TGL (<1.7) HDLC (>1.0) Amylase (<300) 7.0 mmol/l 31.0 mmol/l 0.6 mmol/l 525 U/L Postheparin plasma lipoprotein lipase activity was reduced, and did not normalise after addition of apo CII Diagnosis: lipoprotein lipase deficiency

16 Familial dysbetalipoproteinaemia 2 Remnant hyperlipoproteinaemia Autosomal recessive Most have apo-e2/e-2 polymorphism High prevalence of AD inherited mutant apo-e2 (Arg145 Cys) amongst SA Blacks Superimposed genetic/environmental factor for condition to manifest e.g., obesity, DM, genetic hyperlipidaemia, or hypothyroidism Binding of apo-e-2 is defective leading to impaired uptake of IDL and CM remnants Presents in adulthood with palmar and tuberoeruptive xanthomas, and increased risk of CAD, PVD, and cerebral VD

17 Case: familial dysbetalipoproteinaemia A 45-year-old obese man was referred from a dermatologist with fatty streaks in the palmar creases and tuboeruptive xanthomas on the elbows and buttocks Plasma TC (<5) TGL (<1.7) HDLC (>1.0) Lipoprotein electrophoresis 8.1 mmol/l 7.6 mmol/l 0.6 mmol/l Broad β band Apo E genotyping revealed homozygosity for E 2

18 Metabolic syndrome Features Abdominal obesity ( visceral fat) Dyslipidaemia ( TG, HDL, number sdldl) Hypertension Insulin resistance Hyperuricaemia Non-alcoholic steatohepatitis or fatty liver disease (NASH and NAFLD respectively) CAD risk due to: Atherogenic dyslipidaemia Prothrombotic effect (PAI-1) Proinflammatory effect (TNFα and IL-6) TC and LDL may not accurately reflect risk use Apo B and non-hdl-c

19 Management of dyslipidaemia 4,5 Official SA guidelines adopted from European Societies of Cardiology (ESC) and Atherosclerosis (EAS) guidelines published in June 2011 High-risk individuals existing CAD, DM (type 2; type 1 with microalbuminuria), genetic dyslipidaemia, CKD, severe hypertension, metabolic syndrome Risk-scoring not required (underestimates risk) Non-high-risk individuals Risk-scoring using new Framingham system with lipogram at least once as young adult (>20 yrs)

20 Indications for doing a lipogram Hypertension Smoking Obesity (BMI 30 or waist >94 cm M >80 cm F) Family hx of premature CAD Stigmata of dyslipidaemia Autoimmune chronic inflammatory disease HIV-positive patients on ART

21 The lipogram Fasting for accurate TG particularly if LDL calculated Calc LDL (Friedewald)= TC [HDL + TG/2.2] Inaccurate when TG >4.5 mmol/l Many labs measure LDL directly Average of two values 1 week apart Lipogram includes TC, TG, HDL and LDL Normal lifestyle for previous fortnight Collection after overnight fast Venous stasis should be minimal Novel biomarkers to refine risk assessment in those at moderate risk; Lp(a) in high risk/or family hx of premature CVD (cutoff >50 mg/dl)

22 Targets 4, 5 TC and LDL are the primary targets for therapy Non-HDL provides better risk estimation in DM, metabolic syndrome or CKD, because it includes all the atherogenic particles [VLDL, IDL, LDL, Lp(a)] Non-HDL = TC HDL Non-HDL target is 0.8 mmol/l higher than LDL target Optimal HDL >1 in men; >1.3 mmol/l in women Optimal fasting TG <1.7 mmol/l

23 Risk levels and treatment targets for LDL-C 4,5 VERY HIGH risk Existing CAD, ischaemic stroke or peripheral artery disease Type 2 DM and type 1 DM with targetorgan damage Genetic dyslipidaemia Moderate to severe CKD (GFR <60 ml/min/m 2 ) Framingham score 30% LDL-C treatment target LDL-C < 1.8 mmol/l Or 50% reduction in LDL-C if target unattainable Or Apo B <80 mg/dl Non-HDL-C <2.6 mmol/l HIGH risk Markedly elevated single risk factor e.g., severe hypertension Framingham score 15 <30% LDL-C < 2.5 mmol/l Or Apo B <100 mg/dl Non-HDL-C <3.3 mmol/l MODERATE risk Framingham score 3 <15% modulated by family history, abdominal obesity, physical inactivity, social deprivation, low HDL/Apo A1, high TG, Apo B, hs-crp, Lp(a), homocysteine, fibrinogen LDL-C < 3.0 mmol/l Or Apo B <120 mg/dl Non-HDL-C <3.8 mmol/l LOW risk Framingham score <3%

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25 Statin toxicity 5 Check ALT and CK prior to starting statin Raised ALT does not exclude statin Tx investigate cause ALT <3x ULN: continue Tx and recheck 4-6 wks ALT >3x ULN: stop Tx and recheck 4-6 wks Don t commence statin if CK >5x ULN Routine CK monitoring unnecessary only check if pt develops myalgia on Tx CK <5x ULN with or without muscle Sx: continue Tx, monitor Sx and monitor CK CK >5x ULN: stop Tx, monitor CK every 2 wks Statin intolerance: potent statin on alternate days or combine with e.g., ezetimibe

26 References 1. Marshall WJ, Bangert SK. Clinical Chemistry, 5 th Edition, Marshall WJ, Bangert SK. Clinical Biochemistry, Metabolic and Clinical Aspects, 2 nd Edition, Gaw A, Murphy MJ, Cowan RA et al. Clinical Biochemistry an Illustrated Colour Text, 3 rd Edition, 2004, Reiner Z et al. ESC/EAS guidelines for the management of dyslipidaemias. European Heart Journal 2011;32: SA Heart and LASSA. South African Dyslipidaemia Guideline Consensus Statement. SAMJ 2012; 102(3):