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Lecture 24 - Plasma Ins 2 - 2006

1. Elevated levels of blood lipids and lipoproteins like total cholesterol, triglycerides, LDL, and apolipoproteins have been associated with increased risk of cardiovascular disease. 2. Various factors can influence plasma lipid levels including age, sex, diet, exercise, alcohol consumption, medications, and medical conditions. 3. Different types of hyperlipidemias are classified based on which lipoproteins are predominantly elevated, including hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemias, with genetic and secondary causes identified.

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55 views

Lecture 24 - Plasma Ins 2 - 2006

1. Elevated levels of blood lipids and lipoproteins like total cholesterol, triglycerides, LDL, and apolipoproteins have been associated with increased risk of cardiovascular disease. 2. Various factors can influence plasma lipid levels including age, sex, diet, exercise, alcohol consumption, medications, and medical conditions. 3. Different types of hyperlipidemias are classified based on which lipoproteins are predominantly elevated, including hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemias, with genetic and secondary causes identified.

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Blood Lipids and Lipoproteins

and Cardiovascular Disease


Risk - II

Prof. Abayomi Akanji


Clinical Chemistry Unit
Department of Pathology
Faculty of Medicine
Investigation of Lipid Disorders
• Inspection – immediately/after overnight standing
• Plasma lipid estimation
– TC, TG, HDL, apo A1, apo B
– Calculate LDL according to formula;
• LDL = TC – (HDL + TG/2.2) mmol/L
Assuming that TG < 4.5 mmol/L
• Ultracentrifugation
– Not routine
– More detailed lipid analyses
• Lipoprotein electrophoresis
• Others: LDL and HDL subtypes
• Classification
– Primary vs secondary hyperlipidaemia
– WHO/Friederickson types
Indications for plasma lipid investigation

• Clinical: xanthomas, xanthelasmas, corneal


arcus, premature vascular disease, diabetes
• Laboratory lipaemic plasma: ensure that
sample is fasting
• Screening – for the population at high risk:
– vascular disease of early onset – premature
CHD
– Major risk factors for CHD: DM, hypertension
– Family history of hyperlipidaemia or premature
heart disease
– Clinical features of hyperlipidaemia
Sampling blood for plasma lipid investigation

Affected by eating, smoking, alcohol intake,


changes in posture and stress
Sampling Precautions to include:
– After 12hr fasting; not on lipid infusion
– On normal diet with maintained body weight
– Avoid venous stasis or changes in posture as
this affects proteins
– Note treatment, if any, that patient is on
– Avoid lipid typing for at least 3 mo after major
illness: MI, surgery, severe stress
– Avoid heparinised samples and separate
serum/plasma from cells as soon as possible
Preanalytical factors that influence plasma lipids

• Biological variation: day to day, major illness, stress


• Posture: higher in ambulant patients
• Age: increases with age
• Sex: different trends for males vs. pre-menopausal
females
• Geography/environmental: racial
• Fasting vs. feeding: particularly for TG
• Time of specimens: diurnal variations up to 10%
• Haemolysis: negligible effect
• Menstruation: levels increase before menstruation,
peak at ovulation, then decline
• Reference intervals: rather use decision limits
Influences on plasma
lipoproteins
variable HDL LDL TG
sex F>M M=F F<M
age slight ↑ in F ↑ ↑
high P/S ratio - or ↓ ↓ - or ↓
Exercise ↑ ↓ ↓
alcohol ↑ - ↑
Exogenous
↑ ↓ ↑
estrogens
Inspection: 4ml plasma/serum from fasting patient;
allow to stand vertically in tube in fridge at 4oC
for18hr. Inspect against a dark background.

Appearance Abnormality
Normal
Clear raised LDL (β-lipoproteins)
raised HDL (α-lipoproteins)
Clear subnate with Chylomicronaemia (exogenous
creamy layer on top hypertriglyceridaemia)
Pre-β (VLDL) hyperlipidaemia,
Even turbidity through remnant hyperlipidaemia
specimen
Mixed hyperlipidaemia
Turbid with creamy Increased Pre-β (VLDL) lipoproteins
layer at top + chylomicrons
WHO Classification of Hyperlipidaemias

Type CM VLDL LDL Chol TG


I ↑ N N N ↑↑
IIa - N ↑↑ ↑↑ N
IIb - ↑ ↑ ↑ ↑
III - Broad β band ↑ ↑
IV - ↑ N N↑ ↑
V ↑ ↑ N N↑ ↑↑
Consequences of Hyperlipoproteinaemias
Lp Plasma TC TG LDL HDL Apo EP Pheno Clinical
band

CM Creamy N ↑↑↑ N N or ↓ ↑B-48 origin Type I Acute


top, pancrea
clear
bottom
LDL Clear, ↑↑ N ↑↑ N or ↓ ↑B-100 β- Type IIA ↑ CHD
yellow region risk
tint
LDL, Clear to ↑ ↑ ↑ N or ↓ ↑B-100 β& Type IIB ↑ CHD
VLDL turbid pre-β risk

IDL Turbid to ↑ ↑ N or ↓ N or ↓ ↑E2 broad β Type III ↑ CHD


opaque ↓ risk

VLDL Turbid to N or ↑ ↑↑ N N or ↓ ↑B-100 pre-β Type IV ↑ CHD


opaque risk

VLDL, Creamy Slight ↑↑ N N or ↓ ↑B-48, origin & Type V ↑ CHD


CM top, ↑ B-100 pre-β risk +
turbid pancrea
bottom
HDL clear N to N N ↑ ↑A-1 α- Hyper- ↓ CHD
mod ↑ region alpha risk
Clinical Classification of Hyperlipidaemias –
predominant hypercholesterolemia or
hypertriglyceridaemia or mixed hyperlipidaemia

Primary:
Hypercholesterolemia: familial, polygenic
Hypertriglyceridaemia: familial LPL deficiency, familial apo C-II
deficiency, familial hypertriglyceridaemia
Mixed hypercholesterolemia and hypertriglyceridaemia: familial
combined hyperlipidaemia, familial type 3 hyperlipidaemia
Secondary:
Hypercholesterolemia: hypothyroidism, obstructive jaundice, steroid Rx
Hypertriglyceridaemia: thiazide diuretics, diabetes, alcoholism, renal failure,
estrogens (pregnancy, OCs), severe stress
Mixed hypercholesterolemia and hypertriglyceridaemia: nephrotic
syndrome, multiple myeloma
Genetic Hyperlipidaemias
Disease Genetic defect Fredrickson/WHO Risk
Familial Hyper- ↓ functional LDL IIa or IIb CHD
cholesterolemia receptors
Familial Hyper- ? Single gene IV or V pancreatitis
triglyceridaemia defect
Famil combined ? Single gene IIb, IV, V CHD
hyperlipidaemia defect
LPL deficiency ↓ functional LPL I pancreatitis
Apo C-II reduced Apo C-II I pancreatitis
deficiency synthesis
abetalipoprotein reduced Apo B Normal Vitamin def;
aemia synthesis neurologic
Tangier disease reduced Apo A Normal Neurologic;
synthesis storage dis
Predominant Hypercholesterolemia
Familial Hypercholesterolaemia: prevalence 0.2%
• Heterozygotes: total chol: 7-13 mM
 elevated LDL, phenotype IIa,
 usually develop xanthomas in adulthood and CHD by age 30-50 yr.
• Homozygotes: total chol: TC >13 mM
 grossly elevated LDL, phenotype IIa
 usually develop xanthomas and CHD in childhood
 Death by age 30yr if untreated
Cause: Single mutant gene causing deficiency or functional abnormality
of the cellular LDL receptors
 Inheritance is autosomal dominant
 Plasma LDL is increased due to:
 Reduced clearance by peripheral tissues
 Increased production due to reduced hepatic uptake
Consequences:
 Premature CHD
 Tendon xanthomas
Predominant Hypercholesterolemia 2
Familial Defective Apo B100:
 heterozygotes: total chol: 7-13 mM
 elevated LDL
 phenotype IIa,
 usually develop xanthomas in adulthood and CHD by
age 30-50 yr.

Polygenic Hypercholesterolaemia:
 total chol: 6.5-9 mM;
 elevated LDL
 phenotype IIa
 usually asymptomatic until CHD develops in mid to late
adulthood
 no xanthomas
Predominant Hypertriglyceridaemia
Familial Hypertriglyceridaemia
 Quite common – affects 0.2% of the population
 Inheritance: autosomal dominance, weak penetrance
 TG: 2.8-12 mM
 elevated VLDL (increased production, reduced catabolism)
 Lp phenotype IV
 usually asymptomatic, manifest by age 40yr
 plasma may be cloudy
 Consequences:
 may be associated with increased CHD risk in adulthood
 pancreatitis
 Other characteristically associated disorders:
 Obesity
 Hyperuricaemia
 Mild diabetes and glucose intolerance
 Eruptive xanthomas and lipaemia retinalis
Predominant Hypertriglyceridaemia 2
Familial LPL Deficiency: (familial exogenous hypertriglyceridaemia)
 Very rare,
 Inheritance: Autosomal recessive
 TG > 8.5 mM;
 milky plasma from grossly elevated chylomicrons
 Lp phenotype I, V
 may be asymptomatic or present in infancy with pancreatitis,
abdominal pain, hepatosplenomegaly
 Eruptive xanthomas

Familial Apo CII Deficiency:


 Also very rare, Inheritance: Autosomal recessive
 deficiency of Apo CII – a co-factor for LPL activity
 Clinically and biochemically similar to LPL deficiency with:
 TG > 8.5 mM;
 milky plasma; elevated chylomicrons, phenotype I, V
Combined Hypertriglyceridaemia &
Hypercholesterolaemia
Combined Hyperlipidaemia
 TG: 2.8-8.5 mM; total chol 6.5-13.0 mM
 elevated VLDL, LDL; phenotype IIb
 usually asymptomatic until CHD develops in mid to late adulthood;
no xanthomas;
 familial forms occasionally present as isolated high TG or LDL

Familial Dysbetalipoproteinaemia
 TG: 2.8-5.6 mM; total chol 6.5-13.0 mM
 elevated VLDL, IDL, normal LDL
 phenotype III
 usually asymptomatic until CHD develops in mid to late adulthood
 May have palmar or tuboeruptive xanthomas
Normal Arterial Wall

Tunica adventitia

Tunica media

Tunica intima
Endothelium

Subendothelial connective
tissue

Internal elastic membrane

Smooth muscle cells

Elastic/collagen fibers

External elastic membrane


Development of Atherosclerotic
Plaques
Fatty streak
Normal

Lipid-rich plaque

Foam cells

Fibrous cap

Lipid core
Thrombus
Schematic Time Course of Human
Atherogenesis
Ischemic
Heart
Disease

Cerebrovascular
Disease

Peripheral
Vascular
Disease

Transition from chronic to acute


atheroma
Categories of Risk Factors
• Major, independent risk factors
• Life-habit risk factors
– Obesity (BMI ≥ 30)
– Physical inactivity
– Atherogenic diet
• Emerging risk factors
– Lipoprotein (a)
– Homocysteine
– Prothrombotic factors
– Proinflammatory factors
– Impaired fasting glucose
– Subclinical atherosclerosis
Major Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals
• Cigarette smoking
• Hypertension (BP ≥140/90 mmHg or on antiBP treatment
• Low HDL cholesterol (<40 mg/dL)†
• Family history of premature CHD
– CHD in male first degree relative <55 years
– CHD in female first degree relative <65 years
• Age (men ≥45 years; women ≥55 years)

Focus on Multiple Risk Factors

• Diabetes: CHD risk equivalent


• Multiple metabolic risk factors (metabolic syndrome)

†
HDL cholesterol ≥60 mg/dL counts as a “negative” risk factor; its
presence removes one risk factor from the total count.

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