Dyslipidaemia

Dr NM Oosthuizen

Dept of Chemical Pathology

SA13 2014

Endogenous and exogenous pathways

Endogenous

Exogenous

Reverse cholesterol transport

Dyslipidaemias

� Causes can be primary or secondary

� Secondary dyslipidaemiasTake 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

Overview of hyperlipidaemias

Predominantly increased cholesterol

Primary Familial hypercholesterolaemia LDL

Familial defective apo-B-100 LDL

FH due to PCSK9 activating mutations LDL

Familial combined hyperlipidaemia LDL

Polygenic hypercholesterolaemia LDL

Secondary Diet high in SFA /cholesterol LDL

Hypothyroidism LDL

Cholestasis Lipoprotein X (LpX) and HDL ↑

Progestogens (HDL often ↓), cyclosporin, AIP LDL

Predominantly increased triglycerides

Primary Familial hypertriglyceridaemia VLDL and CM

Familial hyperchylomicronaemia VLDL and CM

Familial combined hyperlipidaemia 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 ↓)

Androgens, retinoids, ART, SLE, diuretics VLDL and LDL (HDL may be ↓)

References 1 and 2

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

� After Tx with Eltroxin, TC came down to 4.6 mmol/L

TC (<5) 10.2 mmol/L �

TGL (<1.7) 1.1 mmol/L

HDLC (>1.0) 1.0 mmol/L

LDLC 8.7 mmol/L �

TSH (0.15 – 3.5) >100 mU/L �

FT4 (10 – 27) <6 pmol/L �

CK (30 – 200) 1330 U/L �

Familial hypercholesterolaemia2

� Gene mutations affecting LDL receptor

Reference 1

FH (cntd)

� Homozygous/compound heterozygous � No or very little LDL receptor activity� TC 20 – 26 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

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

� Risk calculation not applicable in genetic dyslipidaemias� Treatment with lipid-lowering drugs indicated

Plasma

TC (<5) 10.6 mmol/L �

TGL (<1.7) 1.4 mmol/L

HDLC (>1.0) 1.9 mmol/L

LDLC 8.1 mmol/L �

Other causes of FH

� Familial defective apo-B-1002

� 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

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 1st or 2nd 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 1st or 2nd degree

relative or serum cholesterol >7.5 mmol/L in 1st or 2nd degree relative

Int J Biol Sci 2012; 8(3):310-327. doi:10.7150/ijbs.3524

Familial combined hyperlipidaemia2

� 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

Familial hypertriglyceridaemia2

� 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

Familial hyperchylomicronaemia2

� 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

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

� Postheparin plasma lipoprotein lipase activity was reduced, and did not normalise after addition of apo CII

� Diagnosis: lipoprotein lipase deficiency

Plasma

TC (<5) 7.0 mmol/L �

TGL (<1.7) 31.0 mmol/L �

HDLC (>1.0) 0.6 mmol/L �

Amylase (<300) 525 U/L �

Familial dysbetalipoproteinaemia2

� 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

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

� Apo E genotyping revealed homozygosity for E2

Plasma

TC (<5) 8.1 mmol/L �

TGL (<1.7) 7.6 mmol/L �

HDLC (>1.0) 0.6 mmol/L �

Lipoprotein electrophoresis “Broad β band”

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

Management of dyslipidaemia4,5

� 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)

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

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)

Targets4, 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

Risk levels and treatment targets for LDL-C4,5

VERY HIGH risk LDL-C treatment target

�Existing CAD, ischaemic stroke or peripheral artery disease

�Type 2 DM and type 1 DM with target-organ damage

�Genetic dyslipidaemia

�Moderate to severe CKD (GFR <60 ml/min/m2)

�Framingham score ≥30%

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%

Statin toxicity5

� 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

References

1. Marshall WJ, Bangert SK. Clinical Chemistry, 5th

Edition, 2004.

2. Marshall WJ, Bangert SK. Clinical Biochemistry, Metabolic and Clinical Aspects, 2nd Edition, 2008.

3. Gaw A, Murphy MJ, Cowan RA et al. Clinical Biochemistry – an Illustrated Colour Text, 3rd Edition, 2004, 128-129.

4. Reiner Z et al. ESC/EAS guidelines for the management of dyslipidaemias. European Heart Journal 2011;32:1769-1818.

5. SA Heart and LASSA. South African Dyslipidaemia Guideline Consensus Statement. SAMJ 2012; 102(3):177-188.