Lipid disorder

Question 1

Learning outcomes

Answer 1

• Describe the ways in which lipid disorders come to a doctor’s attention
• Outline the normal transport of LDL-cholesterol and how abnormalities in this system can result in familial hypercholesterolaemia (FH)
• Discuss when FH should be suspected and explain how to test for it
• Appreciate the importance of treatment of patients with FH and describe cascade screening
• Describe dysbetalipoproteinaemia-clinical features, diagnosis and treatment
• Have a broad understanding of other common and rare lipid disorders
• Describe how to predict cardiovascular risk and outline some shortcomings of existing prediction tools

Question 2

How might a lipid disorder come to a doctor’s attention?

Answer 2

1. After a CV event- e.g MI, Stroke
2. Patient has physical signs of a lipid disorder
   - Xanthelasma- yellow coloured patches around eye
   - Corneal arcus
   - Tendon xanthoma- enlarged tendons e.g achilles
   - Eruptive xanthoma- pink coloured spots on inside of forearm
   - Palmar xanthoma- yellow patches on hands
   - Lipaemia retinalis
3. Patient has acute pancreatitis-may be caused by high triglycerides
4. Blood looks abnormal
5. Patient chosen for testing
   Who to test?–GPs should estimate cardiovascular risk from risk factors recorded in electronic medical records–If estimated risk is above or equal to 10%, perform a formal assessment which will include measurement of lipids–Review regularly when over 40 years old
6. Patients with a family history-of a lipid disorder-of ‘premature’ cardiovascular disease-as part of ‘cascade screening’

Question 3

Lipoproteins- components

Answer 3

Hydrophobic core- triglycerides, cholestryl esters
Amphipathic phospholipid shell and free cholesterol
Amphipathic proteins on shell= apolipoprotein

Question 4

Endogenous lipid pathway

Answer 4

• VLDL secreted from liver
• Apo C-II interacts with lipoprotein lipase
• Hydrolyses triglyceride to free fatty acids
• Free fatty acids enter cells for energy or storage
• Become smaller remnants
• 50% cleared by liver; 50% hydrolysed to form LDL

LDL particle, with Apo B100 lipoprotein binds to LDL receptor on liver cell (with PCSK9 enzyme)-
Enters cell where the enzyme signals to not recycle the receptor- the cholesterol is used by cell

Question 5

Mechanism of FH

Answer 5

•Mechanisms of FH
–Faulty LDL-receptor (majority)
–Faulty Apo-B100
–Gain of function of PCSK9
•Net result–Less LDL taken into cells >blood LDL level rises
–Less cholesterol in cells >cells make cholesterol >blood LDL level rises
•Blood LDL level rises >atherosclerosis

Question 6

FH (familial hypercholestrolaemia)

Answer 6

• Heterozygous FH–1 in 250-500 of the population
• Homozygous FH–1 in 1,000,000
• A disorder of low density lipoprotein (LDL) cholesterol that increases the risk of premature cardiovascular disease

Question 7

When to suspect heterozygous FH

Answer 7

• Total cholesterol > 7.5 mmol/L +/or
• Personal or family history of premature coronary heart disease
• Exclude a secondary cause of high cholesterol first
• Use defined criteria to assess a person’s risk

Question 8

Testing for FH

Answer 8

Clinical assessment
•Lipid profile- measure cholestrol
•Genetic testing

Question 9

Dysbetalipoproteinaemia

Answer 9

•1 in 5,000 to 10,000 are affected
•AKA –Type 3 hyperlipidaemia
–Remanthyperlipidaemia
–Broad beta disease
•Caused by mutations in APO-E gene–2 copies of APO-E2 predispose to the condition
–Autosomal recessive inheritance
•<10% of people with APO-E2/E2 develop the features of this condition
•Needs a trigger, e.g.:
–Obesity
–Diabetes
–Hypothyroidism
–Low oestrogen states in women

•Features–Markedly raised cholesterol and triglycerides
–Cutaneous lipid deposition e.g palmar xanthoma
–Premature cardiovascular disease

Question 10

Familial Chylomicronaemia syndrome

Answer 10

• Lipoprotein lipase deficiency
• Large amount of chylomicrons in blood
• Very high circulating triglyceride levels
• Recurrent acute pancreatitis

Question 11

Lipid breakdown in the body

Answer 11

Eat meal containing fat >Fat broken down by enzymes in upper GI tract> Forms free cholesterol, monoglycerides, free fatty acids, glycerol>Solubilized by bile acids to form micelles> Enter enterocytes and esterify into cholesteryl esters and triglycerides>Form chylomicrons> Released into lymphatics >Transported via thoracic duct >Enters the circulation >Acquires Apo C-II >Apo C-II interacts with lipoprotein lipase > Hydrolyses triglyceride to free fatty acids >Free fatty acids enter cells for energy or storage >Chylomicrons gradually reduce in size >Become chylomicron remnants >lRemnants enter liver

Question 12

Other rare lipid disorders

Answer 12

Tangier’s disease
Fish eye syndrome
Polygenic hypercholestrolaemia