Chempath - Lipids

Question 1

Plasma lipoproteins from big to small

Answer 1

Chylomicrons, FFA, VLDL, IDL, LDL, HDL

Question 2

Cholesterol transport in fasting plasma

Answer 2

Chylomicrons - 5%
VLDL - 13%
LDL - 70%
HDL - 17%

Question 3

Cholesterol Metabolism (might be good to look at this with diagram from lec)

Answer 3

Cholesterol in gut from diet and bile – solubleised in mixed micelles (major component of bile acids)

Cholesterol transported across the brush border by NPC1L1 into the lymphatics and liver.

Balance between this and ABC G5/ABC G8 (causes it to go back into lumen) which determines net amount of cholesterol that is absorbed.

Bile acids reabsorbed in terminal ileum

When cholesterol gets to the liver, it downregulates the activity of HMG-CoA reductase (main enzyme involved in cholesterol synthesis from acetate and MVA) – efficient absorbers of cholesterol will have low rates of cholesterol synthesis and vice versa

Cholesterol (from gut or liver) – hydrolysed by 7a hydroxylase into bile acids OR becomes esterified by ACAT to become cholesterol ester

Cholesterol ester + triglyceride + apoB –> incorporated into VLDL (transfer protein MTP important in this packaging process)

VLDL is main precursor of LDL. LDL then circulates in plasma for 3-4 days before being taken up by receptors on the liver surface (LDL-R).

LDL transports lipids from liver to periphery –> deliver it to cells that have LDL receptors other than the liver

HDL – transports excess lipids from the periphery (ABCA1 important in this process: mediates the movement of free cholesterol from the peripheral cells to the HDL)

CETP (cholesterol ester transfer protein) – mediates movement of cholesterol ester from HDL to VLDL, and of triglyceride from VLDL to HDL

Once this is completed, some of the HDL cholesterol ester is taken up by the SR-B1 receptor on the liver

Question 4

Triglyceride transport in fasting plasma

Answer 4

Chylomicrons - <5%
VLDL - 55%
LDL - 29%
HDL - 11%

Question 5

Triglyceride Transport and Metabolism (look at diagram)

Answer 5

Chylomicrons have short HL in plasma
VLDL main transporter of cholesterol in the fasted state

Trigs absorbed in the small intestine
Get hydrolysed into FFAs then resynthesized into trigylcerides and transported via chylomicorns into the plasma
Chylomicrons hydrolysed by lipoprotein lipase (in capillaries, particularly in muscles) into FFAs
These FFAs are partly taken up by the liver and resynthesized into trigs and exports them as VLDL (or go to adipose tissue)
VLDL acted on my lipoprotein lipase and hydrolysed  IDL /FFA

Question 6

Primary hypercholesterolaemia

Answer 6

Familial hypercholesterolaemia (type II): dominant mutations of LDL receptor, apoB or PCSK9 genes. Rarely, autosomal recessive inheritance (LDLRAP1).

Polygenic hypercholesterolaemia: Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms

Familial hyperαlipoproteinaemia: sometimes CETP deficiency

Phytosterolaemia: mutations of ABC G5 & G8 (photo = plant sterols, usually these are returned to the lumen in the small intestine)

Question 7

Normal uptake of LDL

Answer 7

LDL binds to receptors in coated pits (1) and subsequently undergoes endocytosis (2). Taken up in lysosomes for further processing.

Question 8

Homozygous Familial Hypercholesterolaemia

Answer 8

Rare - 1 in a million
Corneal arcus in young children
LDL 10x normal
Untreated - death before 20 due to atherosclerosis of the aortic root –> acute coronary insufficiency

Question 9

Heterozygous Familial Hypercholesterolaemia

Answer 9

Much more common - 1 in 500
Corneal arcus
Xanthelasma
Tendon xanthoma - achilles

Question 10

Proprotein convertase subtilisin/kexin type 9 (PCSK9) mutation as a cause of familial hypercholesterolaemia

Answer 10

Function is to bind to LDL receptor and promote its degradation.

Rarely FH is caused by dominantly-inherited gain of function mutations of PCSK9, which increase rate of degradation of LDL receptors. –> fewer on surface of the liver therefore less LDL being bound and degraded

Loss of function mutations of PCSK9 are associated with low LDL levels.

Question 11

Primary Hypertrigylceridaemia

Answer 11

Familial type I: lipoprotein lipase or apoC II deficiency. Can see chylomicrons in plasma if you leave it to sit - creamy layer. Eruptive xanthomas.

Familial type IV: Increased synthesis of TG? Cause. Can see VLDL in plasma.

Familial type V: sometimes due to apoA V deficiency. More severe version of 4. Can see both chylomicron and VLDL layers in fridge test.

Question 12

Primary Mixed Hyperlidiaemia

Answer 12

Familial combined hyperlipidaemia: ? cause - in a family some people will have high cholesterol and some will have high triglycerides

Familial hepatic lipase deficiency

Familial dysβlipoproteinaemia (type III) - quite uncommon, aberrant form of ApoeE (2/2) - homozygous. If you have ApoeE4/4 - increased risk of alzheimer's x10. ApoE3/3 is normal. 
Palmar striae (lipid deposits in palmar crease) - diagnostic of type 3. Can also get eruptive xanthomas.

Question 13

Nephrotic Syndrome

Answer 13

Loss of albumin increases cholesterol synthesis

Question 14

Primary biliary cirrhosis can present with

Answer 14

Gross xanthelasma

Question 15

Hypolipidaemia

Answer 15

Aβ-lipoproteinaemia: MTP deficiency (recessive)

Hypoβ-lipoproteinaemia: truncated apoB (dominant)

Tangier disease: HDL deficiency caused by ABC AI mutations

Hypoα-lipoproteinaemia: sometimes due to apoA-I mutations

Question 16

Aim for LDL:HDL

Answer 16

<3

Question 17

Medical Management of Hyperlipidaemia - Statins & Others

Answer 17

Statin therapy e.g. atorvastatin

• HMG-CoA reductase inhibitor –> Reduces intrinsic synthesis of cholesterol in the liver
• Side effects – myopathy/rhabdomyolysis, fatigue
• Total & coronary mortality decreased 12% & 19% and major vascular events including strokes decreased by 25% for each 1 mmol/l decrease in LDL cholesterol (26%)

Others (more rarely used):

• Fibrates – gemfibrozil
• Ezetimibe- cholesterol absorption blocker
• Colestyramine- anion exchange resin which binds bile acids so they can’t be reabsorbed
• (Plasma exchange where available)

Question 18

Lipoprotein A

Answer 18

Measure in those at intermediate/high CVD/CHD risk inc including familial hypercholesterolaemia, or with premature or statin-resistant CVD.

Should be <500mg/L.

Rx: nicotinic acid. In refractory cases, weekly LDL-apheresis is effective in removing Lp(a).

Question 19

Medical Management of Hyperlipidaemia - Novel forms of LDL lowering therapy

Answer 19

• Microsomal Triglyceride Transfer Protein (MTP) inhibitor (lomitapide)
• Anti-PCSK9 monoclonal antibody (REGN727) - Evolocumab. No effect on mortality. Relative RR is 20% but absolute risk reduction is v small and it is very expensive. Reserved for high risk pts - statin intolerant, uncontrolled lipids.
• Anti-sense apoB oligonucleotide (mipomersen)

Question 20

Medical Management of Hyperlipidaemia - Novel HDL based therapies

Answer 20

Apolipoprotein A-I or A-1 mimetic infusion therapy

Cholesterol ester transfer protein (CETP) inhibitors

Question 21

Obesity- Rx

Answer 21

Hypocaloric diet and exercise

Iatrogenic malabsorption: Orlistat 120 – 360 mg daily

Bariatric surgery if BMI > 40 (Kg/m2)

Question 22

Thiazide diuretics in CVD

Answer 22

Using thiazides in 100 people with CAD will save 2 lives over 5 years.
Cheap

Question 23

Study that concluded that good glucose control increases mortality

Answer 23

Accord

Question 24

Studies of effects of glucose control on CVD outcomes

Answer 24

DCCT: type 1 diabetes, good control improves outcome
UKPDS: New type 2 diabetes put onto good control
Low mortality in both groups for 15 years, but then good control improved outcome, LEGACY EFFECT
ACCORD: take older people who had poor control for a long time, and suddenly massively tighten control (A1c=6%): they already had coronary artery disease, so increased unexpected death
ADVANCE: (A1c=6.5%, reduced death)

Question 25

SGLT2 inhibitors (EMPA-REG OUTCOME TRIAL)

Answer 25

Empagliflozin
Reduces renal glucose reabsorption

Trial critique:
Relative risk reduction ~14% overall.
Substantial effect on CV mortality (30% reduction)
Absolute reductions in CV mortality 1% pa
NNT is 100 = £48,000 to prevent one death
Additional benefits on renal function and heart failure

Question 26

GLP1 analogues

Answer 26

GLP-1 = endogenous
(Exendin 4)- glia monster saliva, longer half life
Exanatide - synthetic exendin 4 (also liraglutide e.g. victoza/sandexa, semaglutide)

Increases hypothalamic satiety:

• Incretin - GLP-1 is secreted from the gut, and signals the pancreas to make even more insulin.
• It also has a direct effect on appetite and gastric emptying

“In patient with long-standing sub optimally controlled T2DM and established atherosclerotic CVD, empagliflozin or liraglutide should be considered as they have been shown to reduce CV and all cause mortality when added to standard care”

Question 27

The van den Bergh reaction

Answer 27

The van den Bergh reaction measures serum bilirubin via fractionation. A direct reaction measures conjugated bilirubin. The addition of methanol causes a complete reaction, which measures total bilirubin (conjugated plus unconjugated); the difference measures unconjugated bilirubin (an indirect reaction).

Question 28

Gilbert’s

Answer 28

Common
Don't biopsy - if all other enzymes normal 
Recessive inheritance 
50% of people carry the gene 
5-6% of the population have the disease
1 in 20
Worsened by fasting 

UDP glucuronyl transferase activity reduced to 30%
Unconjugated bilirubin tightly albumin bound and does NOT enter urine.

Question 29

Causes of fatty liver disease

Answer 29

Alcohol
Being overweight
Malnourishment - kwashiorkor

Question 30

Rx - Alcholic Hepatitis

Answer 30

Supportive.
Stop alcohol.
Nutrition:
Vitamins (esp B1, thiamine)

Occasionally steroids.

Question 31

Thiamine (B1) deficiency causes

Answer 31

Beri- Beri

niacin is B3 def

Question 32

Signs of portal HTN

Answer 32

Visible veins (on abdo)
Splenomegaly
Ascites

(portal HTN caused by cirrhosis)

Question 33

Flapping tremor suggests

Answer 33

Liver failure. Poisoning of the brain that the body can’t get rid of.

Question 34

Liver failure

Answer 34

Failed synthetic function
Failed clotting factor and albumin
Failed clearance of bilirubin
Failed clearance of ammonia (encephalopathy)

Question 35

Porto-systemic anastomoses

Answer 35

Oesophageal varices
Rectal varices
Umbilical vein recanalising
Spleno-renal shunt

Question 36

Itchiness caused by

Answer 36

obstruction of the bile ducts