Thread by @AdiG1993

1) I am a big fan of evolutionary medicine --> the study of human evolution and how it can be harnessed for the practice of medicine.

I recently went in for a deep dive into an important topic --> HYPERURICEMIA

Here is what I learnt!

2) Uric acid is the endproduct of purine metabolism in humans --> this is an exception among mammals!

Why does this happen?

1. Lack of uricase
2. Avid renal reabsorption of uric acid

3) Why happened to uricase?

This ancient enzyme, present since bacteria, accumulated a number of mutations approx 10-30 million years ago and gradually lost its function in humans, some higher primates and some New World monkeys.

pubmed.ncbi.nlm.nih.gov/11961098/

4) As you can see, the lack of uricase --> serum uric acid (SUA) levels in humans are ~ 6 mg/dL vs 0.5-1 mg/dL in other mammals!

5) This loss of uricase didn't happen overnight!

It would have cause extreme hyperuricemia and urate nephropathy +/- urolithiasis --> that is why the inactivation happened slowly over millions of years --> to allow adaptation!

6) This experiment attempted to disrupt the uricase enzyme in rats using recombination --> nearly half the rats died within a month.

This implies that sudden loss of uricase is most likey incompatible with life!
pnas.org/doi/abs/10.107…

7) Hypotheses as to why we needed high SUA!

First --> UA is a major antioxidant comprising nearly 50% of the blood antioxidant pool.

It also compensates for the mammalian inability to synthesize vitamin C --> another major antioxidant.

8) However, excess SUA does not contribute to longevity in humans --> in fact, patients with gout have excess cardiovascular mortality. Secondly, animals like elephants have comparable longevity wrt humans despite SUA as low as 0.2 mg/dL.

This theory is not 100% right!

9) Secondly, hominids of the Miocene epoch (24 to 6 million yrs ago) predominantly lived in subtropical forests and consumed fruits --> they had a very low sodium diet!

SUA probably helped maintain BP in this situation --> allowing an erect posture.

10) This study showed that in rats with a low salt diet, blocking of the uricase enzyme --> raised SUA --> afferent arteriolar smooth muscle proliferation --> renal hypoperfusion --> RAAS activation --> increased salt sensitivity!
ahajournals.org/doi/full/10.11…

11) Orowan, in 1955, postulated that UA has structural similarity to some neurostimulants like caffeine and theobromine --> the loss of uricase and rise of SUA --> jumpstarted the intellectual capacity of hominids in evolution.

12) Some studies have shown that hyperuricemia is a marker of cognitive ability and that highly gifted people have a higher risk of gout.

But this effect cannot be isolated and the rapid increase in brain size in hominids happened long after the loss of uricase.

13) The fourth theory --> increased SUA protects the brain which is highly metabolically active and has a larg amount of unsaturated fatty acids --> the huge 02 demand of the brain also leads to lipid peroxidation --> diseases like Alzheimers, multiple sclerosis etc.

14) In most of these diseases, cases have had much lower levels of SUA than controls --> in fact lower SUA has been linked to quicker progression and worse prognosis in these diseases --> AD, PD, ALS and MS.
Eg. No reported cases of MS with gout --> ?mutually exclusive?

15) Hyperuricemia and gout --> like biryani and aloo, chai and sutta and maach and bhaat --> it is a complex relationship!

Suffice to say --> hyperuricemia is a major risk factor of gout --> but most people with hyperuricemia never get gout!

16) I am no rheumatologist so I will not hold forth on gout here.

But if you wish to read more about this complex relationship --> I have provided a recent review!

ncbi.nlm.nih.gov/pmc/articles/P…

*What

17) I hope you liked this thread which is basically a summarization for what I have learned!

Feel free to add any extra tidbits that you know or correct me if Im wrong!

#MedTwitter
#Hyperuricemia
#gout
#rheumatology

18) Important takeaway --> if you find a SUA that is higher than the reference range --> don't reflexively start urate lowering therapy!

This is a much more complex issue spanning millions of years --> drug therapy for asymptomatic hyperuricemia is as controversial as they come!

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19) I was inspired by this lecture by @yousafali_md!

Absolutely amazing lecture --> strong recommendation!

@drdevrad is it true that your SUA is 25 mg/dL implying genius?

*caused