Chemical Pathology Flashcards
1
Q
What are the 5 plasma lipoproteins?
A
Chylomicrons VLDL LDL HDL 2 HDL 3
2
Q
What are chylomicrons and VLDLs rich in?
A
Triglyceride
3
Q
Which lipoprotein is the main carrier of cholesterol?
A
LDL
4
Q
describe the lipid transport in fasting plasma
A
no cholesterol in chylomicrons
70% of cholesterol is transported by LDL
17% of cholesterol is transported by HDL
5
Q
Where does cholesterol in the intestines come from?
A
diet and bile
6
Q
Where does majority of cholesterol coming in to the upper small intestine come from?
A
bile duct
7
Q
What is the name of the protein used to transport cholesterol across the intestinal bush border?
A
NPC1L1
8
Q
What does NPC1L1 do?
A
It is the main determinant of cholesterol transport going into the lymphatics and then to the liver
9
Q
Name 2 other transporters that are involved with transport of cholesterol from the upper small intestine
A
ABC G5
ABC G8
10
Q
Where do ABC G5 and ABC G8 transport cholesterol?
A
Opposite direction to NPC1L1, into the lumen
11
Q
What determines the amount of cholesterol that is absorbed?
A
The balance between NPC1L1 and ABC G5 and ABC G8
12
Q
Where are bile acids reabsorbed?
A
Terminal ileum
13
Q
What is the main enzyme involved in production of cholesterol?
A
HMG-CoA reductase
14
Q
What does HMG-CoA reducatse do?
A
Converts acetate and mavelonic acid into cholesterol
acetate–> mva–>cholesterol
15
Q
What effect does cholesterol being absorbed into the liver have?
A
Downregulates the activity of HMG-CoA reductase
The amount of cholesterol produced by the liver is determined by the amount absorbed from the small intestine.
16
Q
What are the two fates of cholesterol absorbed from the gut or synthesised in the liver?
A
1) esterification
2) hydroxylation
17
Q
what happens when cholesterol undergoes esterification in the liver?
A
Cholesterol undergoes esterification by ACAT to form a cholesterol ester, this is then incorporated into VLDL particles along with triglycerides and apoB.
18
Q
what happens when cholesterol undergoes hydroxylation in the liver?
A
cholesterol is hydroxylated by7alpha-hydroxylase into bile acids–> this is then excreted via the bile ducts.
19
Q
What is VLDL
A
main precursor of LDL
20
Q
What does LDL do?
A
transports cholesterol from the liver into the peripheries
21
Q
What does HDL do?
A
Goes in the opposite direction to LDL, picking up excess cholesterol from the periphery
22
Q
What does ABC A1 do?
A
helps mediate the movement of free cholesterol from the periphery into HDLs
23
Q
What does CETP stand for?
A
Cholesteryl Ester Transferase Protein
24
Q
What does CETP do?
A
It mediates the movement of
- Cholesterol from HDL to VLDL
- Triglyceride from VLDL to HDL
25
What does SR-B1 do?
Take up some of the HDL cholesterol ester back into the liver
26
Describe the transport and metabolism of triglycerides?
1. Fats from the diet are broken down into fatty acids in the small intestine and converted into triglycerides (TG).
2. TG is transported by chyloicrons into the plasma
3. The chylomicrons are hydrolysed in the capilleries by lipoprotein lipase (LPL)
4. This forms free fatty acids (FFA) which is then absorbed by adipose tissue or into the liver
5. In the liver the FFA is resynthesised into TG and exports then as VLDL
6. VLDLs will also be acted upon by LPL to liberate FFAs.
27
What are the 4 different types of primary hypercholesterolaemia called?
1. Familial hypercholesterolaemia type II
2. Polygenic hypercholesterolaemia
3. Familial hyperlipoproteinaemia
4. Phytosterolaemia
28
What causes familial hypercholesterolaemia type II
autosomal dominant mutations of LDLR, ApoB and PCSK9 genes
| rarely, autosomal recessive inheritance (LDLRAP1)
29
What causes polygenic hypercholesterolaemia?
Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms
| - Combined can have a modest increase in cholesterol
30
What causes familial lipoproteinaemia
Inherited increase in HDL
Sometimes causes by CETP deficiency
Benign connotation- associated with longevity
31
What causes phytosterolaemia
Mutations of ABC G5 and ABC G8
| - This means plant sterols can be absorbed freely
32
Mutations in which protein can cause FH
LDLR
33
What are the clinical features of LDL
corneal arcus
xanthelasma
tendon xanthomas- achilles tendone
34
What does PCSK9 do?
Proprotein Convertase Subtilisin/Kexin type 9 (PCKS9) is a chaperone protein that binds to LDRL and promote degeneration
35
what type of mutation to PCSK9 can cause FH and what is the impact of this?
gain of function mutation- this increases the degeneration of LDLR
This leads to LDLs not being degraded as much as they should be resulting in high plasma LDL levels
36
What are the three different types of hypertriglyceridaemia?
Type I--> LPL or ApoC deficiency
Type IV--> increased synthesis of triglyceride
Type V- sometimes due to ApoA deficiency
37
How would you test for primary hypetriglycerideaemia?
Fridge test: chylomicrons should float to the top
38
What is familial dyslipoproteinaemia (type III)
- It is caused by an aberrant form of ApoE
- Apo E 2/2 is diagnostic of type III, (ApoE 3/3 is normal)
- ApoE 4/4 is associated with alzheimer's disease
39
What is a clinical feature of familial dyslipoproteinaemia?
yellowing of palmar crease (palmar striae)
40
What are the four types of hypolipidaemia?
1. A-lipoproteinaemia- MTP deficiency, autosomal recessive
2. Hypo-lipoproteinaemia- ApoB truncation- autosomal dominant
3. Tangier disease- HDL deficiency caused by ABC A1 deficiency
4. Hypo- lipoproteinaemia- ApoA1 mutation
41
Describe the process of plaque fissuring
1. Increase in LDL
2. LDL becomes oxidised as soon as it penetrates the vascular wall
3. Once oxidised, it gets taken up by macrophages
4. The cholesterol within the LDL gets esterified
5. This produces FOAM CELLS
42
Name 4 lipid regulating drugs
Statins
Fibrates
Ezetimibe
Cholestyramine
43
What do statins do?
Reduce LDL, increase HDL slightly and triglycerides
44
What do fibrates such as Gemfibrozil do?
very good at reducing triglycerides and may increase HDL
45
What does Ezetimibe do?
reduces LDL (blocks cholesterol absorption by inhibiting NPC1L1
46
What does cholestyramine do?
reduce LDL
- binds to bile acids and reduces their absorption
- this results in increased cholesterol catabolism as there is an increased synthesis of bile acids by the liver
47
How would you treat obesity?
1. Hypocaloric diet and exercise
2. Orlistat 120-360 mg daily
3. Bariatric surgery
48
When do you give bariatric surgery?
BMI >40Kg/m2
49
What are three types of bariatric surgeries?
1. Gastric banding
2. Roux-en-Y gastric bypass
3. Biliopancreatic diversion
50
What are some benefits and risks of bariatric surgery?
* Success= ≥ 50% reduction in excess weight (i.e. actual minus ideal)
* Reduces Diabetes risk (by 72%)
* Reduces Serum triglycerides (by 50-60%)
* Increases HDL cholesterol (by 13-47%)
* Reduces Fatty liver
* Reduces HTN
* Post-operative mortality= 0.1-2%
* HbA1c reduces even more compared with medical therapy
51
What are the features of an atherosclerotic lesion?
Fibrous cap
Foam cells
Necrotic core
52
76 year old patient with previous MI has a BP of 140/80 on atenalol, LDL is 3.0mmol on artovastatin 80 mg, if there evidence to lower BP further by adding a thiazide diuretic to 120/80, or should you leave the patient?
Add a thiazide diuretic
53
Which drug class is encourages as the first-line agent in reducing cardiovascular outcomes in HTN?
Thiazide-type-diuretics
54
Which drug class would you prescribe to reduce CVD events in HTN patients with CKD?
Loop-diuretics
55
Which drug class would you prescribe to HTN patients with coronary artery disease?
Beta-adrenergic blockers
56
Which drug is encouraged as the primary thiazide-type-diuretic?
Chlorthalidone
57
Which drug is encouraged as the preferred calcium-channel blocker?
Amlodipine
58
What is optimum management in patients with coronary artery disease?
1. Intensive lifestile modification
2. Aspirin
3. High dose statin (atorvastatin 40-80mg od)
4. Optimal blood pressure control
5. Thiazides
6. Assessment for probable T2D check HbA1c
59
What are the options available for patients with statin intolerance?
Ezetemibe
Plasma exchange where available
Evolocumab (PCSK9 monoclonal antibody)
(none of these have had evidence for prevention of ASCVD).
60
What does PCSK9 do?
Regulate the levels of the LDL receptor
61
What do gain of function mutations in PCSK9 do?
Reduce LDL receptor levels in the liver
Resulting in high levels of LDL cholesterol
Increased risk of coronary heart disease
62
What do loss of function mutations in PCSK9 do?
Results in higher levels of LDLR
lower LDL cholesterol levels
protection from coronary heart disease
63
Name a PCSK9 inhibitor
Evolocumab
64
Should Evolocumab be used in clinical practise
reserve for high risk patients
pts who are statin intolerant
have uncontrolled lipids like in FH
High net value patients
65
Name 4 studies involved in tight versus conservative glucose control
DCCT: type 1 diabetes, good control improves outcome
UKPDS: new type 2 diabetes put onto good control, after 15 years, good control improved outcome
ACCORD: took older pts with poor control and suddenly tightened control, they already had CHD so increased rate of unexplained death
ADVANCE: (A1c=6.5%, reduced death)
66
Which study suggested that tight glucose control increases mortality?
Accord
67
What is SGLT2?
Protein that makes you resorb glucose in the renal tubules
68
Name an SGLT2 inhibitor
Empagliflozin
69
Name 3 GLP-1 analogues
Exanatide
Liraglutide
Semaglutide
70
Define hyponatraemia
Serum Na+ < 135mmol/L
71
What is the underlying pathogenesis of hyponatraemia?
Increased extracellular water
72
How does ADH control water balance?
Acts on V2 receptors in the collecting duct
leads to insertion of aquaporin-2
This increases the amount of water reabsorbed by the collecting duct
73
What effect does ADH have on V1 receptors?
V1 receptors are found on vascular smooth muscle
causes vasoconstriction
aka vasopressin
74
What are the two main stimuli for ADH secretion?
Increased osmolality which triggers hypothalamic osmoreceptors
Decreased blood volume/pressure which acts on baroreceptors in the carotids (atria and aorta).
75
What is the first step in managing a patient with hyponatraemia?
Assess VOLUME STATUS
76
What are the clinical features of hypovolaemia?
```
Tachycardia
postural hypotension
dry mucous membranes
reduced skin turgor
confusion/drowsiness
reduced urine output
KEY SYMPTOM: low urine Na+ (<20)
- Most reliable clinical sign of hypovolaemia
```
77
What causes a pt to have high urine na regardless of volume status?
diuretics
78
What are clinical features of hypervolaemia?
Raised JVP
bibasal crackles
peripheral oedema
79
What are the causes of hyponatraemia in hypovolaemic patients?
Diarrhoea
vomiting
diuretics
salt losing nephropathy
80
What are the causes of hyponatraemia in euvolaemic patients?
Hypothyroidism
adrenal insufficiency
SIADH
81
What are the causes of hyponatraemia in hypervolaemic patients?
Cardiac failure
cirrhosis
nephrotic syndrome
82
How does hypovolaemia cause hyponatraemia?
Hypovolaemia patients still have excess water
d and v causes loss of salt and water
--> low perfusion pressure --> increase in ADH release
--> more water reabsorbed at the CD than Na+
83
How does cirrhosis cause hyponatraemia?
leads to release of vasodilaters
| leads to drop in perfusion pressure
84
What are the causes of SIADH?
```
CNS pathology
Lung pathology
Drugs (SSRI, TCA, opiates, PPIs, carbamazepine
Tumours
Surgery
```
85
How do you diagnose SIADH?
```
Diagnosis by exclusion
No hypovolaemia
no hypothyroidism
no adrenal insufficiency
REDUCED PLASMA OSMOLALITY
INCREASED URINE OSMOLALITY
```
86
investigation of hypovolaemic hyponatraemia?
are they clinically hypovolaemic?
87
investigation for euvolaemic hyponatraemia
TFTs--> hypothyroidism
Short synachthen test --> adrenal insufficiency
SIADH--> plasma and urine osmolality
88
Investigation for hypervolaemic hynopatraemia?
check for fluid overload?
89
What happens in euvolaemic hyponatraemia?
Initial increased in adh---> WATER RETENTION
| Then the atrial expansion caused by the increased circulating volume will lead to natriuetic peptide release
90
What is treatment for hypovalaemic hyponatreamia
volume replacement with 0.9% saline
91
What is the treatment for Hypervolaemic hyponatraemia
fluid restriction
| treat underlying cause
92
What is the treatment for euvolaemic hyponatraemia?
fluid restriction
| treat underlying cause
93
What are signs of severe hyponatraemia?
Reduced GCS
Seizures
Seek expert help (treat with 3% hypertonic saline)
94
What is an important complication of note in treating hyponatraemia?
Serum sodium must not be corrected faster than 8-10mmol.L in the first 24 hrs
95
What happens if serum sodium is corrected too fast in hyponatraemia?
osmotic demyelination resulting in CENTRAL PONTINE MYELINOLYSIS
96
What are the symptoms of central pontine myelinolysis?
```
quadraplegia
dysarthria
dysphagia
seizures
coma-->death
```
97
Which drugs can you use to treat SIADH if fluid restriction is insufficient?
Demeclocycline
- reduces the responsiveness of collecting tubules to ADH
Tolvaptan
- V2 receptor anatgonist
Alternatively: fluir restriction, salt tablets, frusemide
98
Define hypernatraemia
serum Na+ concnetration >145mmol/L
99
What are the causes of hypernatraemia?
GI losses
Sweat losses
Renal losses: osmotic diuresis, diabetes insipidus
100
Which group of people does hypernatreamia typically present in?
Elderly or children who do not drink water when dehydrated
101
What investigations would you perform for patients with diabetes insipidus
```
Serum glucose (exclude DM)
Serum K+ (exclude hypokalaemia)
Serum Ca2+ (exclude hypercalcaemia)
plasma and urine osmolality
water deprivation test
```
102
What is treatment of hypernatraemia?
Fluid replacement- DEXTROSE
| Treat underlying cause
103
How do you treat someone who is hypovolaemic and hyponatraemic?
saline for hypovolaemia , then dextrose for hypernatraemia
104
```
A 70 yr old man
3 day hx of diarrhoea
altered mental status
dry mucous membranes
Serum N+ is 168mmol/L
```
How would you treat?
Correct water deficit
- 5% dextros
Correct extracellular fluid depletion
- 09% saline
Serial Na+ measurements every 4-6 hrs
105
What effect can DM have on serum Na+?
Hyperglycaemia--> draw water out of cells leading to hyponatraemia
Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
106
What is the most abundant intracellular cation?
Potassium
107
What is the normal serum concentration of k+
3.5-5.0mmol/L
108
Which two hormones are involved in the regulation of potassium?
Aldosterone
| Angiotensin II
109
Describe the renin-angiotensin system
reduced perfusion/low na+ will stimulate production of renin from juxta-glomerular cells (next to the glomerulus)
Renin converts angiotensinogen (liver) to angiotensin 1
ACE converts angiotensin I to angiotensin II in the lungs
Angiotensin II stimulates the adrenal glands to produce aldosterone
Aldosterone will stimulate Na+ reabsorption into the cells and k+ excretion into the tubules, into urine
110
What are the stimulants for aldosterone production?
angiotensin II
| K+
111
What is the compensatory mechanism for hyperkalaemia?
Increased serum k+--> increased aldosterone production--> increased k+ excretion
112
Which cells in the collecting duct does aldosterone work on?
Principle cells
113
What effect does aldosterone have on the principle cells int he cortical collecting tubule?
Leads to absorption of Na+
Na moves into the cell and subequently into the blood
K+ moves out
114
What is the mechanism of action of aldosterone?
Aldosterone binds to mineralocorticoid receptors and stimulates transcription of ENaC (Epithelial Sodium Channels)
As you reabsorb more Na+, the lumen becoes more negative
Consequently, K+ moves DOWN THE ELECTRICAL GRADIENT through ROMK channels
115
What is the role of Nedd4?
ubiquinate sodium channels and degrade them
116
What effect does aldosterone have on Nedd4 and consequently K+?
Aldosterone binding to MR increases expression of Sgk1
This leads to increased inhibition of nedd4
This leads to reduced degradation of na+ channels
Increased na+ absorption makes the lumen more negative and k+ moves down the electrochemical gradient via ROMK channels
117
How does hypokalaemia cause nephrogenic diabetes?
hypokalaemia causes polyuraemia which causes nephrogenic diabetes i.e. in conn's syndrome
