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YEAR 5 PATHOLOGY SREYA > Chem Path > Flashcards

Chem Path Flashcards

1
Q

What is inosinic acid (IMP)?

A

An intermediate metabolite of AMP (adenylic acid) and GMP (guanylic acid)

Also a product of de novo purine synthesis

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2
Q

Describe the inhibitory and stimulatory controls on PAT enzyme.

A

AMP and GMP negatively regulate the activity of PAT.

PPRP positively regulates the activity of PAT.

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3
Q

What inborn error of purine metabolism is characterised by HPRT deficiency?

A

Lesch-Nyhan syndrome.

Very rare.

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4
Q

Describe the inheritance pattern of Lesch-Nyhan syndrome.

A

X-linked recessive

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5
Q

Outline the clinical features of Lesch-Nyhan syndrome.

A

Normal at birth Developmental delay at 6 months.

Hyperuricaemia.

Choreiform movements at 1 year.

Spasticity and mental retardation.

KEY FEATURE: Self-mutilation present in 85% (e.g. biting lips very hard)

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6
Q

Describe the biochemical basis of Lesch-Nyhan syndrome.

A

It is caused by absolute deficiency of HPRT (Hypoxanthine Phosphoribosyltransferase)

This reduces the production of IMP and GMP by the salvage pathway.

This reduces the inhibitory effect of IMP and GMP on PAT, thereby increasing the activity of the de novo pathway.

This leads to the production of vast amounts of IMP, which will be shunted down the catabolic pathway to produce urate (which accumulates).

Less conversion of guanine –> GMP leads to a build-up of PPRP (which stimulates PAT).

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7
Q

What are the two mechanisms of hyperuricaemia? List some examples.

A

Increased urate production (e.g. rapid cells turnover in myeloproliferative diseases and severe psoriasis)

Decreased urate excretion (e.g. saturnine gout (caused by lead poisoning) and diuretic use)

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8
Q

What is birefringence?

A

The ability of a crystal to rotate the axis of the polarised light

NEGATIVE – appear blue at 90 degrees to the axis of the red compensator

POSITIVE – appear blue in the axis of the red compensator

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9
Q

Describe the management of gout after the acute phase is over.

A

MANAGING HYPERURICAEMIA:

Encourage fluid intake

Reverse factors that may increase the concentration of uric acid (e.g. stopping diuretics)

Allopurinol – reduces synthesis of urate by inhibiting xanthine oxidase

Probenecid – increases renal excretion of urate (increases FEUA)

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10
Q

What are the three main purines?

A

Adenosine
Guanosine
Inosine

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11
Q

Three roles of purines.

A

Genetic code (A & G)

Second messengers for hormone action (e.g. cAMP) 

Energy transfer (e.g. ATP)

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12
Q

What is uricase?

A

Uricase breaks down urate into a highly soluble molecule called allantoin which is rapidly excreted in the urine.

In humans, the uricase gene is INACTIVE. 

This means that humans can end up with a build-up of urate 

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13
Q

Why is urate constantly at the brink of precipitating out and forming uric acid crystals?

A

Urate circulates at the limit of solubility.

Solubility is pH dependent - at lower pH, solubility will decrease.

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14
Q

Monosodium urate plasma concentrations in men and women.

A

Men: 0.12-0.42 mmol/L 

Women: 0.12-0.36 mmol/L 

NOTE: this is one reason why women get less gout than men .

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15
Q

What is the most commonly affected joint in gout?

A

The first metatarsophalangeal joint.

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16
Q

Why is the first metatarsophalangeal joint the most commonly affected joint in gout?

A

It is found at the periphery of the body which is likely to be cooler meaning that the uric acid crystals are more likely to precipitate. 

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17
Q

Where is uric acid reabsorbed and secreted?

A

The PCT.

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18
Q

Why is uric acid reabsorbed?

A

Urate may be an important antioxidant, so we’ve evolved this highly complicated system to keep our uric acid levels high to protect us against oxidative stress.

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19
Q

What is the FEUA?

A

Fractional Excretion of Uric Acid = 10%.

This is how much of the filtered urate is present in the urine.

The remaining 90% is reabsorbed.

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20
Q

What are the two main mechanisms of purine synthesis?

A

De novo purine synthesis.

The salvage pathway.

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21
Q

What is de novo purine metabolism?

A

Purine synthesis pathway.
Outputs: IMP, AMP and GMP.

Metabolically demanding and inefficient  so only used when there is a very high demand for purines (e.g. bone marrow).

IMPORTANT: the rate-limiting step of this pathway is catalysed by PAT.

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22
Q

What is the salvage pathway of purine metabolism?

A

Purine synthesis pathway.
This is a form of recycling. 
It is highly energy efficient. 

This is the PREDOMINANT pathway in purine synthesis. 

HPRT IS THE MAIN ENZYME OF THE SALVAGE PATHWAY

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23
Q

What is PAT?

A

Rate limiting step of de novo purine synthesis is catalysed by PAT enzyme.

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24
Q

What is the main enzyme of the salvage pathway?

A

HPRT aka HGPRT.

Hypoxanthine-guanine phosphoribosyltransferase.

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25
Q

What is the main function of HPRT?

A

HPRT is the main enzyme of the salvage pathway.

Scoops up partially catabolised purines and bring them back up the metabolic pathway to produce IMP and GMP .

Main reactions:
Hypoxanthine –> IMP 
Guanine –> GMP

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26
Q

What are the two mechanisms of hypouricaemia? List some examples.

A

Decreased urate production (e.g. xanthine oxidase deficiency, severe hepatic disease and allopurinol).

Increased urate excretion (e.g. Idiopathic, Fanconi syndrome, uricosuric drugs like probenecid).

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27
Q

What is gout?

A

Monosodium urate crystals.
These crystals are powerful inflammatory stimuli for inflammatory cells, which can trigger an intense inflammatory reaction in the synovium of the joint .

Tends to affect post-pubertal males and post-menopausal females .

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28
Q

Two types of gout.

A

Podagra (acute).

Tophaceous (chronic).

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29
Q

Where are tophi usually found?

A

Tend to be found on the fingers and on the pinna of the ear.

You can get some periosteal erosion due to the presence of a tophus.

30
Q

Clinical features of gout.

A

Rapid build-up of ‘exquisite’ pain 

Affected joint is red, hot and swollen 

1st MTP is the first site affected in 50% 

1st MTP is involved in 90% of cases 

31
Q

Diagnosis of gout.

A

Usually history, examination and uric acid levels is enough to diagnose gout .

If any doubt:
Tap effusion.
View under polarised light using a red filter/compensator.
Look at birefringence.

32
Q

What will monosodium urate look like under polarised light using a red filter/compensator?

A

Needle-shaped.

Negatively birefringent .

33
Q

What will calcium pyrophosphate look like under polarised light using a red filter/compensator?

A

Rhomboid-shaped.

Positively birefringent.

34
Q

What are the two branches in the treatment of gout?

A

Reducing inflammation 

Managing hyperuricaemia

35
Q

What is the mainstay of acute gout treatment?

A

REDUCING INFLAMMATION:
NSAIDs 
Colchicine 
Glucocorticoids 

IMPORTANT: the main focus is on reducing inflammation - you should NOT try to modify the plasma urate concentration at that stage, because it could actually lead to further urate deposition  .

36
Q

What is the mechanism of action of Colchicine?

A

Colchicine works by inhibiting the manufacture of tubulin.

Microtubule assembly is important for TWO reasons:

They are important for mitosis (so long-term, high-dose colchicine can suppress cell turnover).

Short-term administration of colchicine will inhibit microtubule assembly just enough to reduce the motility of neutrophils.

This means that neutrophils will not be able to get into the joints and react with the uric acid crystals to cause inflammation.

37
Q

Which drug should Allopurinol not be given with and why?

A

AZATHIOPRINE

Allopurinol interacts with azathioprine - a therapeutic dose can have toxic effects such as massively suppressing the bone marrow.

Azathioprine is a pro-drug that is metabolised to mercaptopurine and then to thioinosate, which is the active drug that actually interferes with purine metabolism.

Mercaptopurine is a purine, and so it is metabolised by the xanthine oxidase pathway.

If you are giving the patient allopurinol at the same time, the levels of mercaptopurine will build up, thereby increasing the exposure of the patient to azathioprine

38
Q

What is the mechanism of action of Allopurinol?

A

Inhibits xanthine oxidase and therefore inhibits urate production.

39
Q

What is pseudogout?

A

Calcium pyrophosphate crystals.

Occurs in patients with osteoarthritis.

Self-limiting and lasts 1-3 weeks .

40
Q

Describe the uptake of cholesterol by the intestinal epithelium.

A

Cholesterol entering the intestines will come from the diet and bile

Cholesterol will be solubilised in mixed micelles It is then transported across the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)

41
Q

Name two transporters that transport cholesterol back into the intestinal lumen.

A

ABC G5

ABC G8

ABC = ATP-binding cassette transporter

42
Q

What are the two fates of cholesterol that is either produced by or transported to the liver?

A

Hydroxylation by 7-alpha-hydroxylase to produce bile acids

Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides and ApoB

ACAT: Acyl-CoA cholesterol acyltransferase

43
Q

Which transfer protein is important in the packaging of VLDLs?

A

MTP (microsomal triglyceride transfer protein)

44
Q

Which transfer protein is important in the packaging of free cholesterol from the periphery into HDLs?

A

ABC A1

45
Q

Which receptor is responsible for the uptake of some HDLs by the liver?

A

SR-B1

46
Q

Describe the transport and metabolism of triglycerides.

A

Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma

Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids

Some free fatty acids are taken up by the liver, and some by adipose tissue

The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs

VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids

47
Q

List the three causes of familial hypercholesterolaemia (type II).

A

Caused by autosomal dominant gene mutations in:

LDL receptor

ApoB

PCSK9 (Proprotein convertase subtilisin/kexin type 9)

48
Q

List the key features of the following forms of familial hypertriglyceridaemia: a. Familial Type I b. Familial Type IV c. Familial Type V

A

a. Familial Type I Caused by deficiency of lipoprotein lipase and ApoC II NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase
b. Familial Type IV Characterised by increased synthesis of triglycerides
c. Familial Type V Characterised by deficiency of ApoA V NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate

49
Q

What are the three types of familial hypertriglyceridaemia?

A

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

50
Q

List the four causes of primary hypercholesterolaemia.

A

Familial hypercholesterolaemia (type II)

Polygenic hypercholesterolaemia

Familial hyperalphalipoproteinaemia

Phytosterolaemia

51
Q

What is polygenic hypercholesterolaemia caused by?

A

Multiple gene mutations including NPC1L1, HMGCR and CYP7A1 polymorphisms

52
Q

What is familial hyperalphalipoproteinaemia caused by?

A

Increase in HDL which is caused by deficiency of CETP - this is associated with longevity.

53
Q

What is phytosterolaemia caused by?

A

Plasma concentrations of plant sterols are increased due to mutations in ABC G5 and ABC G8.

The main function of ABC G5 and ABC G8 is to prevent the absorption of plant sterols.

Premature atherosclerosis is very common in this condition.

54
Q

What is the role of CETP?

A

CETP (cholesteryl ester transfer protein) mediates the movement of:

Cholesterol from HDL to VLDL

Triglyceride from VLDL to HDL

55
Q

What are the three types of primary mixed hyperlipidaemia?

A

Familial combined hyperlipidaemia

Familial hepatic lipase deficiency

Familial dysbetalipoproteinaemia (type III)

56
Q

What is familial dysbetalipoproteinaemia (type III)?

A

Due to aberrant form of ApoE (E2/2)
NOTE: normal form is ApoE (3/3) and ApoE4 is associated with Alzheimer’s disease.

A diagnostic clinical feature is yellowing of the palmar crease (palmar striae).
Patients also tend to get eruptive xanthomas on their elbows.

57
Q

What is an important renal cause of secondary hyperlipidaemia?

A

Nephrotic syndrome - the loss of protein in the urine and low serum albumin makes you switch on LDL (lipoprotein) synthesis to maintain the oncotic pressure.

58
Q

Describe LDL receptor function and its relation to familial hypercholesterolaemia.

A

LDL binds to receptors in coated pits (either in the periphery or on the surface of the liver).

They then undergo endocytosis.

There are thousands of mutations of the LDL receptor gene, which lead to familial hypercholesterolaemia.

The phenotype of the mutation will depend on which part of the LDL receptor is affected by the mutation (e.g. if there is a large mutation in the LDL binding region, then it will have a more severe phenotype).

59
Q

List the clinical features of familial hypercholesterolaemia.

A

Corneal arcus
Xanthelasma
Tendon xanthomas
Atheroma (of aortic root)

60
Q

Describe PCSK9 function and its relation to familial hypercholesterolaemia.

A

Proprotein convertase subtilisin/kexin type 9

This is the least common mutation that results in FH

This protein binds to the LDL receptor and promotes its degradation

Rarely, FH is caused by a dominantly-inherited gain of function mutation of PCSK9, resulting in increased breakdown of LDLR.

Gain of function mutations of PCSK9 are associated with high LDL levels.

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

61
Q

List four causes of hypolipidaemia and their underlying genetic defect. Abeta-lipoproteinaemia, Hypobeta-lipoproteinaemia, Tangier disease, Hypoalpha-lipoproteinaemia

A

Abeta-lipoproteinaemia

  • Autosomal recessive
  • Extremely low levels of cholesterol
  • Due to deficiency of MTP

Hypobeta-lipoproteinaemia

  • Autosomal dominant
  • Low LDL
  • Caused by mutations in ApoB leading to truncated versions of the protein

Tangier disease

  • Low HDL
  • Caused by mutation of ABC A1

Hypoalpha-lipoproteinaemia

• Sometimes caused by mutation of ApoA1

62
Q

What are the four causes of hypolipidaemia?

A

Abeta-lipoproteinaemia Hypobeta-lipoproteinaemia Tangier disease
Hypoalpha-lipoproteinaemia

63
Q

Describe the process of atherosclerosis.

A

This is particularly associated with increases in LDL

The LDL becomes oxidised once it has got through the vascular wall

Once oxidised, it gets taken up by macrophages

Within the macrophages, the LDLs become esterified and you develop foam cells.

These foam cells form atherosclerotic plaques which can fissure leading to thrombosis.

64
Q

List and describe the features of atherosclerotic lesions.

A

Fibrous cap

Foam cells
These are macrophages that are full of cholesteryl ester.
They are called foam cells because when you process them histologically, the organic solvent leaks out of the foam cells and leaves little holes.

Necrotic core
This will be full of cholesterol crystals.
They become deposited after the macrophages die and release enzymes that hydrolyse the cholesteryl ester and convert them into free cholesterol, which then crystallises.

65
Q

Describe the structure and function of the different types of lipoproteins.

A

They all have roughly the same shape but they come in different sizes.

Chylomicrons are the biggest.
Chylomicrons and VLDLs are high in triglycerides.
Chylomicrons are important in the transport of cholesterol after a meal, however, they are present in very small amounts in the fasted state.
VLDLs are the main carriers of triglycerides.

LDLs are smaller than VLDLs and they are the main carriers of cholesterol.

Want low LDLs and high HDLs.

66
Q

List some lipid-lowering drugs and their effect on lipid levels.

A

Statins – reduce LDLs, increase HDLs, slight increase in triglycerides

Fibrates (Gemfibrozil) – lower triglycerides, little effects on LDL/HDL

Ezetimibe – reduces cholesterol absorption (blocks NPC1L1)

Colestyramine – resin that binds to bile acids and reduces their absorption

Nicotinic acid – causes a significant rise in HDL, however, it has been removed from the market because of its side-effect profile

67
Q

List some NOVEL FORMS of lipid-lowering drugs and their effect on lipid levels.

A

Microsomal triglyceride transfer protein (MTP) inhibitor - LOMITAPIDE

Anti-PCSK9 monoclonal antibody - REGN727

Anti-sense ApoB oligonucleotide (MIPOMERSEN)
NOTE: this has not been licensed by the EMA

Novel HDL-based therapies:
Apolipoprotein A-1 mimetic infusion therapy.
Cholesteryl ester transfer protein (CETP) inhibitors.

68
Q

List three ways of treating obesity.

A

Hypocaloric diet and exercise

Iatrogenic malabsorption (Orlistat 120-360 mg daily) 
NOTE: this is a pancreatic lipase inhibitor

Bariatric surgery (if BMI > 40)

69
Q

Name the three types of bariatric surgery and how they work.

A

Gastric banding
The size of the stomach is reduced using a band so that you feel full even after a small meal.

Roux-en-Y gastric bypass
The distal part of the jejunum has been anastomosed to the stomach.
The stomach is reduced in size.
There is a lot of jejunum that is no longer doing anything OR DUODENUM NOT DOING ANYTHING??

Biliopancreatic diversion
A connection is made straight from the stomach to the terminal ileum.

70
Q

List the benefits and risks of bariatric surgery.

A

DEFINITION of Success = > 50% reduction in excess weight.
Excess weight is defined as the difference between the actual and the ideal

Reduces diabetes risk (by 72%)

Reduces serum triglycerides (by 50-60%)

Increases HDL levels (by 13-47%)

Reduces fatty liver

Reduces blood pressure

Post-operative mortality = 0.1-2%

NOTE: HbA1c reduces more with gastric banding than medical therapy. It decreases the most with biliopancreatic diversion.

YEAR 5 PATHOLOGY SREYA (1 decks)

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