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YEAR 5: Chemical Pathology PM > ChemPath: Brief Lipid Update > Flashcards

ChemPath: Brief Lipid Update Flashcards

1
Q

What is the optimal medical therapy for people with coronary heart disease?

A
  • Intensive lifestyle modification
  • Aspirin
  • High-dose statin (atorvastatin 40-80mg OD)
  • Optimal blood glucose control
  • Thiazides
  • Assessment for probable T2DM
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2
Q

What is the statistical mortality benefit of adding a thiazide diuretic to outstanding BP medications, following an MI?

A

Worth it, as 2 in 100 will be prevented from a further MI in the next 5 years

20% relative risk reduction

2% absolute risk reduction

Shown by the SPRINT Study

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3
Q

List some options for people with statin intolerance.

A
  • Ezetemibe
  • Plasma exchange
  • PCSK9 inhibitors

NOTE: niacin is no longer available

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4
Q

Describe the function of PCSK9

A
  • PCSK9 targets the LDL receptors leading to endocytosis and their degradation
  • This reduces the ability of the liver to take up cholesterol from the blood
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5
Q

Name a PCSK9 inhibitor.

A

Evolocumab

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6
Q

Which patient group may benefit from PCSK9 inhibitors?

A

Patients who are at very high risk (e.g. familial hypercholesterolaemia)

Statin-intolerant patients

NOTE: PCSK9 inhibitors reduce the incidence of cardiovascular events but has no effect on mortality, and has a high NNT (Fourier study)

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7
Q

How long does it take to see benefit from good glucose control?

A

15 years to see a reduction in complications

Shown by the UKPDS study

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8
Q

What is the legacy effect?

A

A period of good glycaemic control will have a beneficial effect on mortality for up to 10 years even if the patient reverts to poor glycaemic control after a certain period of time.

Shown by the UKPDS study

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9
Q

What did the DCCT show?

A

Good control in type 1 diabetes improves outcomes

*Legacy effect was shown here too*

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10
Q

What did the Advance study show?

A

Targeting HbA1c of less than 6.5% reduces microvascular events

Intensive glucose control was associated with an increased risk of severe hypoglycaemia and hospitalisation BUT no increased risk of mortality (unlike Accord study)

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11
Q

What are the effects of sudden aggressive blood glucose control in patients with long-standing poor glycemic control and cardiovascular complications?

A
  • Reduced the incidence of complications
  • Increased mortality (likely due to precipitating tachycardia and arrhythmias)

Really important to consider whether the patient has atheromas to begin with before suddenly tightening glucose control

This was found by the ACCORD trial

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12
Q

Describe how SGLT2 inhibitors can reduce blood glucose.

A

Increases urinary excretion of glucose causing a reduction in blood glucose and blood pressure.

NOTE: this can also be used in heart failure because of its diuretic effect

Main side-effects: UTIs due to glycosuria, rarely DKA

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13
Q

Name an SGLT2 inhibitor

A

Empagliflozin

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14
Q

What were the key findings of the EMPA-REG study?

A

Significant reduction in mortality after just 4 years

Reduces HbA1c

Treats heart failure due to diuresis

Prevents nephropathy as it reduces albuminuria by letting glucose pass into the tubules instead - protects the kidneys (initial sharp reduction in GFR but then recovers)

*Albumin is poisonous to the kidneys so these SGLT2 inhibitors are renal-protective*

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15
Q

What is the physiological role of GLP1?

A
  • Produced by the gut and signals to the pancreas to produce more insulin (incretin effect)
  • Also has a direct effect on satiety and gastric emptying
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16
Q

What breaks down GLP1?

A

DPP4

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17
Q

Which class of drugs inhibits the breakdown of GLP1?

A

Gliptins (by inhibiting DPP4 and, thereby, preventing the breakdown of GLP1)

Likely to be phased out as GLP-1 analogues work better

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18
Q

List three examples of GLP1 analogues.

A
  • Exanatide (synthetic version of exendin 4)
  • Liraglutide (saxenda)
  • Semaglutide

All injections at the moment so SGLT2 inhibitors are preferred in combination with metformin

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19
Q

Summarise the steps in the pharmacological management of type 2 diabetes mellitus.

A
  1. Metformin
  2. if non-insulin monotherapy at maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months add either:
    • Second oral agent OR
    • GLP1 agonist OR
    • Basal insulin

In patients with long-standing suboptimally controlled T2DM and established cardiovascular disease, empagliflozin (SGLT2 inhibitor) or liraglutide (GLP1 analogue) should be considered.

20
Q

What are the two sources of cholesterol arriving in the small intestine

A

Bile. Dietary.

21
Q

What is the main carrier protein which determines cholesterol absorption?

A

NPC1L1

22
Q

What are the two protein channels which allow cholesterol to move back into the intestinal lumen?

A

ABC G5

ABC G8

23
Q

What are the two fates of cholesterol once they are absorbed in the liver? (name the enzymes responsible)

A

Hydrolysed by 7-alpha-hydroxylase into bile acids.

Esterification by ACAT and incorporation with ApoB + triglycerides to form VLDL

24
Q

What is the enzyme responsible for packing cholesterol ester, triglycerides and ApoB into VLDLs

A

MTP

25
Q

What is the enzyme which mediates the transfer of free cholesterol from peripheral cells to HDL

A

ABC A1

26
Q

What is the protein which transfers triglycerides from HDL to VLDL and cholesterol ester from VLDL to HDL?

A

CETP (cholesterol ester transfer protein)

27
Q

Which receptor in the liver facilitates the uptake of HDL?

A

SR-B1

28
Q

What are the major transporters of:

a. cholesterol
b. triglycerides

in the fasting state?

A

a. LDL
b. VLDL

29
Q

Outline the route of triglyceride absorption from the intestine to the its 2 final destinations. (5-steps)

A
  1. Hydrolysis into fatty acids in the intestinal lumen and absorption
  2. Re-synthesis into triglycerides - incorporation into chylomicrons
  3. Hydrolysis of chylomicrons by LPL into free fatty acids
  4. FFAs taken up by the liver and adipose cells
  5. The liver resynthesises FFAs into TGs - package into VLDLs
30
Q

What are the 4 main categories of primary dyslipidaemia?

A

Primary hypercholesterolaemia

Primary hypertriglyceridaemia

Primary mixed hyperlipidaemia

Hypolipidaemia

31
Q

What are the 4 subtypes of primary hypercholesterolaemia?

A

Familial hypercholesterolaemia (type II)

Polygenic hypercholesterolaemia

Familial hyper-alpha-lipoproteinaemia (high HDL)

Phytosterolaemia

32
Q

What are the main genes involved in familial hypercholesterolaemia and what is their mode of inheritance?

A

PCKS9 gain of function (autosomal dominant)

LDLR (autosomal dominant)

apoB (autosomal dominant)

LDLRAP1 (autosomal recessive)

33
Q

What is the genetic basis of hyper-alpha-cholesterolaemia?

A

CETP deficiency. Reduction in the transfer of cholesterol ester and triglycerides with VLDL

34
Q

What is the genetic basis of phytosterolaemia?

A

ABC G5 and G8 mutations. Failure to prevent absorption of plant sterols.

Highly atherogenic.

35
Q

What are the clinical signs of familial hypercholesterolaemia (type II) and main pathological consequence?

A

Corneal arcus.

Xanthelasma.

Tendon xanthoma.

Atheroma formation.

36
Q

What is the function of PCSK9?

A

LDL receptor binding to promote LDL receptor endocytosis and degradation.

37
Q

What are the 3 subtypes of primary hypertriglyceridaemia and their genetic basis?

A

Familial type I (lipoprotein lipase / apoC deficiency a LPL cofactor)

Familial type IV (increase in triglyceride synthesis)

Familial type V (apoA deficiency)

38
Q

Which carrier molecule is raised in the following hypertriglyceridaemias:

a. Familial type I
b. Familial type V
c. Familial type IV

A

a. chylomicrons
b. VLDL
c. VLDL

39
Q

What are the 3 types of primary mixed hyperlipidaemia?

A

Familial combined hyperlipidaemia (unknown)

Familial dys-beta-lipoproteinaemia (type III)

Familial hepatic lipase deficiency

40
Q

What is the genetic basis of familial dys-beta-lipoproteinaemia

A

ApoE 2/2 mutation (very uncommon)

41
Q

What are the 4 types of hypolipidaemia and their genetic basis?

A

A-beta-lipoproteinaemia (MTP deficiency).

Hypo-beta-lipoproteinaemia (apoB truncated).

Tangier disease (ABC A1 deficiency).

Hypo-alpha-lipoproteinaemia (apoA-I deficiency)

42
Q

What are the hormonal factors which may cause secondary hyperlipidaemia?

A

Pregnancy.

Exogenous sex-hormone (mainly oestradiol).

Hypothyroidism.

43
Q

What are the metabolic causes of secondary hyperlipidaemia

A

Diabetes.

Gout.

Obesity.

Storage disorders.

44
Q

How does nephrotic syndrome cause hyperlipidaemia?

A

Protein loss leads to upregulation of LDL and VLDL production.

45
Q

How does atherosclerosis form?

A
  1. transport of LDL across endothelial wall.
  2. oxidation of LDL and uptake into macrophages
  3. cholesterol is esterified
  4. formation of foam cells and atherosclerotic cap
46
Q

How is obesity treated?

A

Lifestyle measure (hypocaloric diet and exercise).

Orlistat.

Bariatric surgery (BMI>40).

YEAR 5: Chemical Pathology PM (27 decks)

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