Chemical Pathology Shohaib

Question 1

Name 3 purines

Answer 1

Adenosine, Guanosine, Inosine

Question 2

What enzyme converts hypoxanthine to xanthine

Answer 2

Xanthine Oxidase (also converts xanthine to urate)

Question 3

Name 2 factors that affect the plasma concentration of urate

Answer 3

1. Temperature (the extremities are colder, so this is why the foot is the site of acute gout presentation-> reach max solubility-> forms crystals)
2. pH

Question 4

What pathways is dominant in purine metabolism

Answer 4

Salvage pathway

the de novo pathway happens in bone marrow, and requires more energy

Question 5

what is the main enzyme of the salvage pathway in purine metabolism

Answer 5

HPRT/HGPRT

Question 6

what is the rate limiting step of purine synthesis

Answer 6

PPRP->IMP (enzyme PAT)

• Increase in end product inhibit PAT
• Increase of PPRP positive feedback on PAT

Question 7

What enzyme is deficient in Lesch Nyham Syndrome

Answer 7

complete HPRT deficency (X linked)

Question 8

Explain why Lesch Nyham syndrome leads to hyperuracaemia

Answer 8

There is a complete def of HPRT!
1. no recycling of guanine of hypoxanthine
2. decrease of IMP/GMP/AMP-> removes negative inhibition on PAT
3.This leads to an increase in de novo synthesis-> increasing IMP
4. IMP goes down the catabolic pathway (xanthine oxidase)
5. Increased urate
(Another reason: remember HPRT needs to be coupled with PPRP to work-> since deficient there is a build up of PPRP which acts as a feed forward for PAT)

Question 9

What symptoms/signs would you see at birth in Lesch Nyham syndrome

Answer 9

none-> normal at birth
see symptoms at 6/12 months
developmental delay, cholifrom movement, mental retardation, self mutilations, hyperuracemia.

Question 10

Causes of hyperuracemia

Answer 10

1) increased urate production
- primary: LNS, glycogen storage disorders,
- Secondary: Increwased cell turnover ( myeloprolif, psorasis, lumphoprolif)
2) decreased excretion
- primary: FJHN
- secondary: chronic kidney disease, diuretics (Thiazides), aspirin, Downs, lead poisoning

Question 11

What is formed in gout

Answer 11

monosodium urate crystals

Question 12

typical presentation of acute gout

Answer 12

rapid buildup of pain, red hot swollen joint

1st MTP-> 50% 1st site, 90% overall

Question 13

Management of acute gout

Answer 13

DECREASE INFLAM
1-> NSAIDs
2->Colchicine
3->steriods 
(dont modify plasma urate)

Question 14

how does colchinine work for acute gout

Answer 14

decreases tubulin formation-> inhibits microtubule assembly-> this decreases neutrophil motility-> unable to enter joints-> reduces inflam

Question 15

what is the management of hyperuricamia (non-acute gout)

Answer 15

1) drink water
2) reverse factors putting up urate (diuretics etc)
3) Drugs
- reduce synthesis: Allopurinol (XO inhibitor)
- Increase excretion:probenecid (uricosuric)

Question 16

which medication is a contraindication to prescribing allopurinol

Answer 16

AZOTHIOPRINE->leads to increased BM toxicity (neutropenia)

azothioprine->mercaptopurine (active drug)->thioisinate

mercaptopurine is catabolised by XO-> stopped with given allo> therefore increased-> increasing toxicity

Question 17

under polarized light urate crystals are…

Answer 17

-ve birefringent and needle shaped

Question 18

under polarized light pyrophsphate crystals are…

Answer 18

+ve birefringenet (pseudogout-> seen in pts with osteoarthritis)

Question 19

Which lipid makes up the majority of plasma lipids?

Answer 19

LDL-70%
HLD-17%
VLDL-13%
Chylomicrons-<5%

Question 20

Which is the largest circulating triglyceride?

Answer 20

VLDL-55%

Question 21

Which enzymes control cholesterol absorption in the jejunum?

Answer 21

NPC1-L1-> absorb cholesterol in the jejunum
ABC G5, ABC G8-> moves cholesterol into the jejunum

(BAT in the ileum absorbs bile acid)

Question 22

What is the main mutation that causes familial hypercholestalemia (type II)

Answer 22

LDL receptor mutation (AD)

Question 23

Name 3 AD mutations that can cause familial hypercholesterlemia (type II)

Answer 23

LDL receptor
apoB
PCSK9-> binds to LDLr (increased function, increased cholesterol)

Question 24

Causes of secondary hyperlipadamia

Answer 24

Hormonal->preg, hypothyrodism
Metabolic-> diabetes
Renal Dysfunction->CKD
Obstructive liver disease
Toxins->alcohol
Iatrogenic->HTN, immunosuppressive