Lec 18: Biochemistry: Urate, Calcium, Vitamin D

Question 1

Describe the biochemical pathogenesis of urate pt.1

Answer 1

-while pyramiding are easy for the body to breakdown and excrete, purine metabolism intermediates can be toxic and the final product is uric acid, which is barely soluble in blood and urine

So, urate comes from the breakdown of purine

Question 2

Describe the biochemical pathogenesis of urate pt.2
purine metabolism

Answer 2

There is de novo synthesis and the salvage pathway

** de novo synthesis**
- PRPP + glutamine = ATP and GTP. Catalyzed by amidophosphoribosyltransferase (irreversible!)
- activated by high levels of PRPP
- ++ de novo = ++ inc urate formation

salvage pathway
- dietary adenine and guanine = ATP and GTP, respectively. Catalyzed by HGPRT
- degradation converts purines into hypoxanthine catalyzed by hypoxanthine oxidase —> end product is uric acid
- basically recycles purines = - - dec urate formation
- ** ++ inc HGPRT activity = - - dec urate**

Question 3

How do the two pathways (de novo and salvage) interact?

Answer 3

Increased salvage = depletes PRPP —> less de novo

de novo generates MORE purine breakdown products = higher uric acid concentration —> salvage = lower plasma uric acid levels

Question 4

What is the result of increased plasma uric acid?

Answer 4

GOUT !

Question 5

Where does urate deposition take place?

Answer 5

Urate deposition occurs in renal tubules and gravity-dependent joints (Pollux, ankle, fingers, etc.)

Question 6

Causes for 2nd GOUT

Enzyme abnormalities a/w urate overproduction

Answer 6

Increased plasma uric acid = gout

secondary gout results from inc nucleic acid turnover (in leukemia, lymphoma, chemotherapy), inc ATP degradation (in glycogen storage dz and hypoxia), EtOH intake (inc ATP catabolism), renal dz, and dehydration/diuretic use

-saturnine gout occurs from lead exposure

Enzyme abnlties a/w urate overproduction

  -*decreased* **HGPRT** activity —> increased PRPP in ***Lesch-Nyhan*** syndrome (triad: self-mutilation, mental retardation, hyperuricemia)

-increased xanthine oxidase —> high levels of xanthine and low uric acid —> xanthine accumulates in kidneys and forms crystals and kidney stones that l/t kidney failure

-increased amidoPRT activity —> high PRPP

Question 7

When does calcium deposition occur and what is the end result called?

Answer 7

Calcium deposition occurs as a result of inflammation in the joint from excess PPi (pyrophosphate) forming insoluble calcium salt crystals in the synovial fluid.

end result of calcium deposition in pseudogout or chondrocalcinosis

And how does that excess pyrophosphate come about?

From extracellular ATP hydrolysis —>inflammation

Question 8

Is chondrocalcinosis AD or AR or sex-linked?

Is it a Loss or gain of function mutation?

What is the gene?

Answer 8

Chondrocalcinosis is inhereited AD

GOF mutation

In the ANKH gene

Question 9

In chondrocalcinosis, what increases production of pyrophosphate?

Answer 9

nucleotide triphosphate pyrophosphohydrolase increases production of pyrophosphate

Question 10

Compare/contrast CPPD to Calcium Hydroxyapatite Deposition disease?

Answer 10

Calcium Hydroxyapatite Deposition disease is analogous to CPPD, but with hyoxyapatite

AND in appearance

crystals are large and hexagonal (hexagonal planar arrangement in stacked layers)

AND in Biochemical composition

Calcium pyrophosphate =
2 phosphates bound by 2 Ca

Calcium Hydroxyapatite =
3 phosphates bound by 5 Ca

(This one is the physiological good stuff

Question 11

Compare/contrast
calcium hydroxyapatite crystal vs
uric acid crystal
vs
pyrophosphate crystal

Answer 11

calcium hydroxyapatite crystals are hexagonal planar and brown, yellow, or green

uric acid crystals are needle shaped and orange/brown/yellow

pyrophosphate crystals are rod/rhomboid and blue or yellow/orange

Question 12

Metabolism of Vitamin D

Answer 12

1. In liver —> cholesterol is converted to 7-dehydrocholesterol by cholesterol dehydrogenase
2. In skin —> storage of 7-dehydrocholesterol is converted to cholecalciferol by UVB radiation
3. In liver —> cholecalciferol is converted to calcidiol by 25-hydroxylase
4. In kidneys —> calcidiol is converted to calcitriol by 1a-hydroxylase

Question 13

Causes of Vitamin D deficiency and
Diseases from that

Answer 13

Lack of sun
CKD
Liver dz
Malnutrition/absorption or alcoholism
Preterm or exclusively breastfed infants w/o supplementation

rickets in children = bowing of the legs and impaired growth

osteomalacia in adults = bone pain, fractures, waddling gait, myopathy, spasms, cramps