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Pathology Year 5 > Chemical Pathology > Flashcards

Chemical Pathology Flashcards

1
Q

What are the 5 plasma lipoproteins?

A 
Chylomicrons 
VLDL 
LDL 
HDL 2
HDL 3
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2
Q

What are chylomicrons and VLDLs rich in?

A

Triglyceride

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3
Q

Which lipoprotein is the main carrier of cholesterol?

A

LDL

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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

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5
Q

Where does cholesterol in the intestines come from?

A

diet and bile

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6
Q

Where does majority of cholesterol coming in to the upper small intestine come from?

A

bile duct

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7
Q

What is the name of the protein used to transport cholesterol across the intestinal bush border?

A

NPC1L1

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8
Q

What does NPC1L1 do?

A

It is the main determinant of cholesterol transport going into the lymphatics and then to the liver

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9
Q

Name 2 other transporters that are involved with transport of cholesterol from the upper small intestine

A

ABC G5

ABC G8

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10
Q

Where do ABC G5 and ABC G8 transport cholesterol?

A

Opposite direction to NPC1L1, into the lumen

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11
Q

What determines the amount of cholesterol that is absorbed?

A

The balance between NPC1L1 and ABC G5 and ABC G8

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12
Q

Where are bile acids reabsorbed?

A

Terminal ileum

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13
Q

What is the main enzyme involved in production of cholesterol?

A

HMG-CoA reductase

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14
Q

What does HMG-CoA reducatse do?

A

Converts acetate and mavelonic acid into cholesterol

acetate–> mva–>cholesterol

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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.

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16
Q

What are the two fates of cholesterol absorbed from the gut or synthesised in the liver?

A

1) esterification

2) hydroxylation

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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.

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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.

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19
Q

What is VLDL

A

main precursor of LDL

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20
Q

What does LDL do?

A

transports cholesterol from the liver into the peripheries

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21
Q

What does HDL do?

A

Goes in the opposite direction to LDL, picking up excess cholesterol from the periphery

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22
Q

What does ABC A1 do?

A

helps mediate the movement of free cholesterol from the periphery into HDLs

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23
Q

What does CETP stand for?

A

Cholesteryl Ester Transferase Protein

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24
Q

What does CETP do?

A

It mediates the movement of

  • Cholesterol from HDL to VLDL
  • Triglyceride from VLDL to HDL
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25
Q

What does SR-B1 do?

A

Take up some of the HDL cholesterol ester back into the liver

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26
Q

Describe the transport and metabolism of triglycerides?

A
  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.
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27
Q

What are the 4 different types of primary hypercholesterolaemia called?

A
  1. Familial hypercholesterolaemia type II
  2. Polygenic hypercholesterolaemia
  3. Familial hyperlipoproteinaemia
  4. Phytosterolaemia
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28
Q

What causes familial hypercholesterolaemia type II

A

autosomal dominant mutations of LDLR, ApoB and PCSK9 genes

rarely, autosomal recessive inheritance (LDLRAP1)

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29
Q

What causes polygenic hypercholesterolaemia?

A

Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms

- Combined can have a modest increase in cholesterol

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30
Q

What causes familial lipoproteinaemia

A

Inherited increase in HDL
Sometimes causes by CETP deficiency
Benign connotation- associated with longevity

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31
Q

What causes phytosterolaemia

A

Mutations of ABC G5 and ABC G8

- This means plant sterols can be absorbed freely

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32
Q

Mutations in which protein can cause FH

A

LDLR

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33
Q

What are the clinical features of LDL

A

corneal arcus
xanthelasma
tendon xanthomas- achilles tendone

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34
Q

What does PCSK9 do?

A

Proprotein Convertase Subtilisin/Kexin type 9 (PCKS9) is a chaperone protein that binds to LDRL and promote degeneration

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35
Q

what type of mutation to PCSK9 can cause FH and what is the impact of this?

A

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

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36
Q

What are the three different types of hypertriglyceridaemia?

A

Type I–> LPL or ApoC deficiency
Type IV–> increased synthesis of triglyceride
Type V- sometimes due to ApoA deficiency

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37
Q

How would you test for primary hypetriglycerideaemia?

A

Fridge test: chylomicrons should float to the top

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38
Q

What is familial dyslipoproteinaemia (type III)

A
  • 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
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39
Q

What is a clinical feature of familial dyslipoproteinaemia?

A

yellowing of palmar crease (palmar striae)

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40
Q

What are the four types of hypolipidaemia?

A
  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
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41
Q

Describe the process of plaque fissuring

A
  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
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42
Q

Name 4 lipid regulating drugs

A

Statins
Fibrates
Ezetimibe
Cholestyramine

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43
Q

What do statins do?

A

Reduce LDL, increase HDL slightly and triglycerides

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44
Q

What do fibrates such as Gemfibrozil do?

A

very good at reducing triglycerides and may increase HDL

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45
Q

What does Ezetimibe do?

A

reduces LDL (blocks cholesterol absorption by inhibiting NPC1L1

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46
Q

What does cholestyramine do?

A

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
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47
Q

How would you treat obesity?

A
  1. Hypocaloric diet and exercise
  2. Orlistat 120-360 mg daily
  3. Bariatric surgery
48
Q

When do you give bariatric surgery?

A

BMI >40Kg/m2

49
Q

What are three types of bariatric surgeries?

A
  1. Gastric banding
  2. Roux-en-Y gastric bypass
  3. Biliopancreatic diversion
50
Q

What are some benefits and risks of bariatric surgery?

A
  • 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
Q

What are the features of an atherosclerotic lesion?

A

Fibrous cap
Foam cells
Necrotic core

52
Q

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?

A

Add a thiazide diuretic

53
Q

Which drug class is encourages as the first-line agent in reducing cardiovascular outcomes in HTN?

A

Thiazide-type-diuretics

54
Q

Which drug class would you prescribe to reduce CVD events in HTN patients with CKD?

A

Loop-diuretics

55
Q

Which drug class would you prescribe to HTN patients with coronary artery disease?

A

Beta-adrenergic blockers

56
Q

Which drug is encouraged as the primary thiazide-type-diuretic?

A

Chlorthalidone

57
Q

Which drug is encouraged as the preferred calcium-channel blocker?

A

Amlodipine

58
Q

What is optimum management in patients with coronary artery disease?

A
  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
Q

What are the options available for patients with statin intolerance?

A

Ezetemibe
Plasma exchange where available
Evolocumab (PCSK9 monoclonal antibody)
(none of these have had evidence for prevention of ASCVD).

60
Q

What does PCSK9 do?

A

Regulate the levels of the LDL receptor

61
Q

What do gain of function mutations in PCSK9 do?

A

Reduce LDL receptor levels in the liver
Resulting in high levels of LDL cholesterol
Increased risk of coronary heart disease

62
Q

What do loss of function mutations in PCSK9 do?

A

Results in higher levels of LDLR
lower LDL cholesterol levels
protection from coronary heart disease

63
Q

Name a PCSK9 inhibitor

A

Evolocumab

64
Q

Should Evolocumab be used in clinical practise

A

reserve for high risk patients
pts who are statin intolerant
have uncontrolled lipids like in FH
High net value patients

65
Q

Name 4 studies involved in tight versus conservative glucose control

A

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
Q

Which study suggested that tight glucose control increases mortality?

A

Accord

67
Q

What is SGLT2?

A

Protein that makes you resorb glucose in the renal tubules

68
Q

Name an SGLT2 inhibitor

A

Empagliflozin

69
Q

Name 3 GLP-1 analogues

A

Exanatide
Liraglutide
Semaglutide

70
Q

Define hyponatraemia

A

Serum Na+ < 135mmol/L

71
Q

What is the underlying pathogenesis of hyponatraemia?

A

Increased extracellular water

72
Q

How does ADH control water balance?

A

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
Q

What effect does ADH have on V1 receptors?

A

V1 receptors are found on vascular smooth muscle
causes vasoconstriction
aka vasopressin

74
Q

What are the two main stimuli for ADH secretion?

A

Increased osmolality which triggers hypothalamic osmoreceptors
Decreased blood volume/pressure which acts on baroreceptors in the carotids (atria and aorta).

75
Q

What is the first step in managing a patient with hyponatraemia?

A

Assess VOLUME STATUS

76
Q

What are the clinical features of hypovolaemia?

A 
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
Q

What causes a pt to have high urine na regardless of volume status?

A

diuretics

78
Q

What are clinical features of hypervolaemia?

A

Raised JVP
bibasal crackles
peripheral oedema

79
Q

What are the causes of hyponatraemia in hypovolaemic patients?

A

Diarrhoea
vomiting
diuretics
salt losing nephropathy

80
Q

What are the causes of hyponatraemia in euvolaemic patients?

A

Hypothyroidism
adrenal insufficiency
SIADH

81
Q

What are the causes of hyponatraemia in hypervolaemic patients?

A

Cardiac failure
cirrhosis
nephrotic syndrome

82
Q

How does hypovolaemia cause hyponatraemia?

A

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
Q

How does cirrhosis cause hyponatraemia?

A

leads to release of vasodilaters

leads to drop in perfusion pressure

84
Q

What are the causes of SIADH?

A 
CNS pathology 
Lung pathology 
Drugs (SSRI, TCA, opiates, PPIs, carbamazepine 
Tumours 
Surgery
85
Q

How do you diagnose SIADH?

A 
Diagnosis by exclusion 
No hypovolaemia 
no hypothyroidism 
no adrenal insufficiency 
REDUCED PLASMA OSMOLALITY 
INCREASED URINE OSMOLALITY
86
Q

investigation of hypovolaemic hyponatraemia?

A

are they clinically hypovolaemic?

87
Q

investigation for euvolaemic hyponatraemia

A

TFTs–> hypothyroidism
Short synachthen test –> adrenal insufficiency
SIADH–> plasma and urine osmolality

88
Q

Investigation for hypervolaemic hynopatraemia?

A

check for fluid overload?

89
Q

What happens in euvolaemic hyponatraemia?

A

Initial increased in adh—> WATER RETENTION

Then the atrial expansion caused by the increased circulating volume will lead to natriuetic peptide release

90
Q

What is treatment for hypovalaemic hyponatreamia

A

volume replacement with 0.9% saline

91
Q

What is the treatment for Hypervolaemic hyponatraemia

A

fluid restriction

treat underlying cause

92
Q

What is the treatment for euvolaemic hyponatraemia?

A

fluid restriction

treat underlying cause

93
Q

What are signs of severe hyponatraemia?

A

Reduced GCS
Seizures
Seek expert help (treat with 3% hypertonic saline)

94
Q

What is an important complication of note in treating hyponatraemia?

A

Serum sodium must not be corrected faster than 8-10mmol.L in the first 24 hrs

95
Q

What happens if serum sodium is corrected too fast in hyponatraemia?

A

osmotic demyelination resulting in CENTRAL PONTINE MYELINOLYSIS

96
Q

What are the symptoms of central pontine myelinolysis?

A 
quadraplegia 
dysarthria 
dysphagia 
seizures 
coma-->death
97
Q

Which drugs can you use to treat SIADH if fluid restriction is insufficient?

A

Demeclocycline
- reduces the responsiveness of collecting tubules to ADH
Tolvaptan
- V2 receptor anatgonist
Alternatively: fluir restriction, salt tablets, frusemide

98
Q

Define hypernatraemia

A

serum Na+ concnetration >145mmol/L

99
Q

What are the causes of hypernatraemia?

A

GI losses
Sweat losses
Renal losses: osmotic diuresis, diabetes insipidus

100
Q

Which group of people does hypernatreamia typically present in?

A

Elderly or children who do not drink water when dehydrated

101
Q

What investigations would you perform for patients with diabetes insipidus

A 
Serum glucose (exclude DM) 
Serum K+ (exclude hypokalaemia) 
Serum Ca2+ (exclude hypercalcaemia) 
plasma and urine osmolality 
water deprivation test
102
Q

What is treatment of hypernatraemia?

A

Fluid replacement- DEXTROSE

Treat underlying cause

103
Q

How do you treat someone who is hypovolaemic and hyponatraemic?

A

saline for hypovolaemia , then dextrose for hypernatraemia

104
Q 
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?

A

Correct water deficit
- 5% dextros

Correct extracellular fluid depletion
- 09% saline

Serial Na+ measurements every 4-6 hrs

105
Q

What effect can DM have on serum Na+?

A

Hyperglycaemia–> draw water out of cells leading to hyponatraemia

Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia

106
Q

What is the most abundant intracellular cation?

A

Potassium

107
Q

What is the normal serum concentration of k+

A

3.5-5.0mmol/L

108
Q

Which two hormones are involved in the regulation of potassium?

A

Aldosterone

Angiotensin II

109
Q

Describe the renin-angiotensin system

A

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
Q

What are the stimulants for aldosterone production?

A

angiotensin II

K+

111
Q

What is the compensatory mechanism for hyperkalaemia?

A

Increased serum k+–> increased aldosterone production–> increased k+ excretion

112
Q

Which cells in the collecting duct does aldosterone work on?

A

Principle cells

113
Q

What effect does aldosterone have on the principle cells int he cortical collecting tubule?

A

Leads to absorption of Na+
Na moves into the cell and subequently into the blood
K+ moves out

114
Q

What is the mechanism of action of aldosterone?

A

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
Q

What is the role of Nedd4?

A

ubiquinate sodium channels and degrade them

116
Q

What effect does aldosterone have on Nedd4 and consequently K+?

A

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
Q

How does hypokalaemia cause nephrogenic diabetes?

A

hypokalaemia causes polyuraemia which causes nephrogenic diabetes i.e. in conn’s syndrome

Pathology Year 5 (3 decks)

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