Dyslipidaemia

Question 1

Physiological Importance of Lipids

Answer 1

Highest energy yielding metabolic fuel
Fat soluble vitamins absorption 
Heat insulating and shock protection
Cell membrane constituent
Steroid biosynthesis
Nerve conduction

Question 2

Normal lipid and lipoprotein metabolism

Answer 2

Exogenous cycle

• diet to liver/peripheral tissues
• by chylomicrons and chylomicron remnants

Endogenous cycle

• liver to peripheral tissues
• by VLDL – IDL – LDL

Reverse cholesterol transport

• peripheral tissues/ CM/ VLDL/ IDK to liver
• by HDL

Low solubility of lipids = need carrier for transport in blood

• lipoproteins, hormone binding proteins
• apolipoproteins attached to lipoproteins acting as receptor to divert and regulate circulation of lipoproteins in body

Question 3

Major apolipoproteins

Answer 3

ApoA-I: HDL –> activates LCAT, structural

Apo(a): Lp(a) –> structural (also arthrogenic)

ApoB-100: VLDL, IDL, LDL, Lp(a) –> ligand for binding to LDL receptor

ApoC-II: Chylomicrons –> cofactor for LPL (lipoprotein lipase for metabolism of TG)

ApoE: CMR, IDL, HDL –> ligand for binding to LDL receptor and other receptor

Question 4

Classification of lipoproteins

Answer 4

Chemical content, density and charge

CM - TRIGLYCERIDES (86%)
VLDL - TG 55%, cholesterol 12%
LDL - CHOLESTEROL (42%)
HDL - cholesterol 13%, TG 3%

Question 5

Why are lipids important?

Answer 5

RISK FACTOR FOR ATHEROSCLEROSIS! (especially LDL)

–> stroke, AMI, secondary HT (kidney), claudication

Question 6

**Clinical approach to dyslipidaemia

Answer 6

1. Test validity (any acute stress, concurrent drug use, paraproteins?, LITHIUM HEPARIN TUBE (GREEN))
2. Pattern recognition
   - hyper/hypo
   - cholesterol or TG? which lipoprotein? (LDLC, Non HDLC)
3. CVS risk factors and risk calculation
4. Look for secondary causes (Hx and Ix)
5. If primary defect: Fam hypercholesterolaemia scoring systems, Fam cascade screening
6. Consider acute Tx (risk of acute pancreatitis)
7. Chronic Tx (underlying cause, lipid control, control CVS risk)
8. Monitor response and complications

Question 7

Hypercholesterolaemia DDx

Answer 7

First consider secondary causes:

• DM
• Hypothyroidism
• Nephrotic Syndrome
• Cholestasis
• Ig disorders
• Anorexia nervosa

Primary causes

• familial hypercholesterolaemia (FH) –> single gene defect of LDL receptor, ApoB-100 or PCSK9
• sitosterolaemia (rare)

Question 8

Hypertriglyceridaemia DDx

Answer 8

Secondary:

• post-prandial (but not necessarily in everyone; even if normal after fasting still suggests higher risk)
• DM
• renal failure
• (hypothyroidism)
• alcoholism
• nephrotic syndrome
• oestrogen/ steroid excess

Primary:
- familial hypertriglyceridaemia –> deficiency of LPL or ApoC-II (can’t metabolise exogenous TGs leading to increased risk of pancreatitis)

Question 9

Combined hypercholesterolaemia and hyperTG DDx

Answer 9

Familial dysbetalipoproteinaemia (broad beta band disease) –> diagnosis by electrophoresis and ApoE genotyping

Question 10

Lab investigations of Dyslipidaemia

Answer 10

1. Lipid profile
   - total cholesterol, HDL, TG, LDL (direct/calculated - Friedewald equation)
   - non-HDLC
2. Lipoprotein pattern
   - generally not needed unless strange/spurious lipoproteins
   - visual, overnight standing, electrophoresis, ultracentrifugation
3. Apolipoprotein measurements (apoB, apoA1 and Lp(a))
4. Secondary causes
   - Hx e.g. drug (OCP), alcohol, diet (other signs/ symptoms), and FHx of IHD
   - TFT, RLFT, fasting glucose, HbA1c, urinary protein
5. Genetic tests if [4] excluded
   - scoring system
6. Atherosclerosis risk assessment
7. Side effects of drug treatment

Question 11

Cut-off values

Answer 11

Fasting

• cholesterol <5
• TG <1.7
• HDL-C >1
• LDL-C <3.0
• Non-HDL-C <3.8

Treatment goals based on CVS risk
Very high risk e.g. CHD or CHD equivalent risk such as previous stoke, DM
- LDL-C <1.8; Non-HDL-C <2.6

High risk (>2 risk factors e.g. smoking, HT, FHx)
- LDL <2.5; HDL <3.3

Question 12

Caution in interpretation of LDL

Answer 12

LDL decreases in acute events e.g. AMI
–> take blood within 24hrs of acute onset or wait until 4-6 wks after patient recovered

Friedewald equation for LDL-C

• Total cholesterol - HDL- VLDL (or TG/2.2)
• ONLY VALID IF TG <4.5 mmol/L, no abnormal IDL present
• can use direct LDL measurement or non-HDL-C (cholesterol - HDl-C) if LDL-C invalid

Now acceptable to use non-fasting samples – proven to have no significant difference in lipid profiles (safer, more convenient, time-efficient, patient friendly)

Question 13

Lipoprotein analysis - visual, electrophoresis

Answer 13

Visual

• hazy when TG >2.3 mmol/L
• Turbid sample = excessive CM or VLDL – CM usually creamy top layer with uniform clear bottom; VLDL denser so expect even distribution throughout sample with turbid bottom plasma
• Clear sample – may be excessive LDL

Ultracentrifugation (obsolete now)
- physical separation by density

Electrophoresis

• indicated when lipid profile not correlated with lipoprotein profile e.g. high cholesterol but LDL normal
• CM > LDL > VLDL > HDL > Free fatty acids
• no chylomicrons normally (fasting)

Question 14

WHO-Fredrickson classification of lipid disorder (clinically not useful)

Answer 14

I: Chylomicron -- TG
IIa: LDL -- Cholesterol
IIb: LDL + VLDL -- mixed
III: IDL -- mixed
IV: VLDL -- TG
V: CM and VLDL -- TG and some cholesterol

Need to Ix whether VLDL or CM are causing hyperTG (appearance and VLDL would also cause elevated cholesterol)

Cholesterol – RISK OF CHD
Chylomicrons – RISK OF PANCREATITIS

Question 15

Secondary hyperlipidaemia (lipid profiles)

Answer 15

DM – cholesterol and TG
Nephrotic syndrome – cholesterol and TG

Hypothyroidism, biliary obstruction, acute porphyria – cholesterol

Pancreatitis, renal failure, alcoholism, OCP, glycogen storage disease – TG

Further investigations:

• DM (glucose, HbA1c)
• Nephrotic (oedema, RFT, LFT, urine protein)
• **Hypothyroid (TFT) - most common cause after high cholesterol diet (reduced LDL-R and lipoprotein lipase activity)
• Cholestasis (LFT)

Question 16

Primary and Secondary prevention of CHD, treatment targets, risk factors for CVD

Answer 16

Primary = without previous hx of atherosclerotic vascular event

Secondary = already had event before

LDL-C as treatment target
- if >2.6 mmol/L –> calculate baseline CVS risk and TREAT THOSE WITH >10% 10 year risk

• exercise, diet, lose weight for all whose LDL-C is high

Risk calculators e.g. framingham, ACC/AHA, SCORE, QRISK

Major Risk factors for CVD (>2 = high 10 year risk of CVD)

• age (M>45, F>55)
• male sex
• high total cholesterol
• low HDL
• HT or on anti-HT medications
• smoker
• DM/ CKD (CHD-equivalent with >20% of 10 year risk!)
• others e.g. obesity, sedentary, FHx, Lp(a), CRP, hyperhomocysteinaemia

Question 17

Treatment guidelines

Answer 17

Different for different guidelines

ACC/AHA 2013
- 40-75 with no CVD, LDL-C 1.81-4.90 and >7.5% 10 yr risk ==> moderate dose of statin

• LDL-C >4.92 ==> higher dose of statin
  AND CONSIDER PRIMARY CAUSE!

UK NICE
- treat if >10% risk

SCORE 2016

• 2.6 treatment target
• SCORE >5 = 10% risk

Question 18

Primary hyperlipidaemia features, causes

Answer 18

No apparent disease to explain lipid abnormality

Early onset, severe hyperlipidaemia

• -> prominent features e.g. xanthoma
• -> high risk of vascular diseases or complications (premature)

Hypercholesterolaemia

• FH –> LDL-R, ApoB-100, PCSK9 defects, ARH adaptor protein mutations
• Sitosterolaemia

HyperTG
- familial hyperchylomicronaemia (AR) –> LPL deficiency or ApoC-II deficiency ==> recurrent pancreatitis!

Hypercholestrol and HyperTG
- familial dysbetalipoproteinaemia (ApoE) – IDL clearance defect

Question 19

Familial Hypercholesterolaemia: diagnostic criteria, characteristics, LDL-C levels, treatment

Answer 19

Autosomal Dominant

Criteria for diagnosis
- Simon Broome
–> TC >7.5 mmol/L
AND
–> xanthomata in index or first degree relatives or positive DNA test (common mutations) = definitive
OR
–> FHx of premature CVD or TC >7.5 in first-degree relative = probable

Characteristics:

• 1/500 in Chinese (heterozygous FH) – LDL-R defect most common affecting LDL uptake
• 15x risk of CVD (<45 yrs old)
• homozygous very rare (LDL-C 15-24, CHD <12.5 yrs old)
• LDL-C typically 5-11
• Early and lifelong treatment with statins, lifestyle modification (+family cascade screening)

Question 20

Sitosterolaemia: TC and LDL-C levels, clinical features, treatment

Answer 20

Low to high plasma TC (<10) and LDL-C
Clinically mimic FH but neg FHx (AR)
ABCG5/8 mutations = dysfunctional transporters

Childhood onset

• recurrent joint arthritis
• splenomegaly
• haemolytic anaemia, stomatocytes
• tendon xanthomata
• premature atherosclerosis and CVD

Test plant sterols for diagnosis

Treatment

• elimination of non-cholesterol sterol sources
• bile acid sequestrants