The Uric Acid Failure: Lessons Learned - Cure Parkinson's

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The Uric Acid Failure: Lessons Learned

park_bear profile image
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RR = relative risk

Lesson one: Association ≠ Causation!

Mistaking association for causation is a major source of medical misunderstanding. It comes with real consequences, as we shall see. Observational studies can only find associations. Proving causation requires interventional studies, which compare the effect of some intervention, usually a new drug, to placebo or an existing drug.

Depicted above is a table from an observational study showing the relative risks (RRs) of gout that are associated with different levels of uric acid. Reference: Epidemiology Of Gout In Women: Fifty-Two-Year Followup Of A Prospective Cohort, pubmed.ncbi.nlm.nih.gov/201...

Is there causation behind this association? Well, we know that gout occurs when uric acid crystallizes in a joint. Here we have an interventional trial showing a uric acid lowering drug alleviated gout far better than placebo: arthritis-research.biomedce... This proves high levels of uric acid cause gout. This knowledge tells us that the risks set forth in the observational study depicted above are real. Specifically, uric acid levels in excess of 5 milligrams per deciliter incur at least double or triple the risk of gout for women, and quadruple the risk for men. Gout is "a common and excruciatingly painful inflammatory arthritis" so it is not something to be trifled with.

What does this have to do with Parkinson's? It turns out there are countless studies showing Parkinson's is associated with relatively low uric acid. Does that mean that low uric acid is a cause of Parkinson's?

Let us consider the fact that many Parkinson's patients use levodopa, and the more severe the Parkinson's the more levodopa is used. Protein interferes with absorption of levodopa, so patients using levodopa tend to avoid ingesting protein at the same time. Patients with advanced Parkinson's take levodopa frequently, and so their ingestion of protein is typically the most limited. Protein foods are the main source of purines, which produce uric acid when metabolized. Less protein, lower uric acid. So for patients taking levodopa, we expect that worse Parkinson's results in lower uric acid.

The foregoing is merely my analysis. Here is an observational study that demonstrates this effect. Investigators compared uric acid levels of Parkinson's patients using levodopa (and dopamine agonists) to Parkinson's patients using only dopamine agonists: The relation of serum uric acid levels with L-Dopa treatment and progression in patients with Parkinson’s disease, pubmed.ncbi.nlm.nih.gov/267... "Serum UA[uric acid] levels were lower in the group under L-Dopa + dopamine agonist treatment and in patients at third and upper Hoehn and Yahr stages than the patients under only dopamine agonist treatment and in the patients at the first two stages"

So indeed, the worse the Parkinson's, the lower the uric acid, in patients taking levodopa. We have a known mechanism by which levodopa usage results in lower uric acid. So we can conclude that the low uric acid in Parkinson's patients is a result rather than a cause of the disease.

Also, the uric acid level in the dopamine agonist only arm of the study averaged 6.5, whereas the levodopa arm averaged 4.5 (this data in fulltext behind pay wall). In this case it was not so much a matter of uric acid being low in levodopa patients as it was being excessive in the other patients. It is typical for serum uric acid levels to be below 5 in Parkinson's patients and there is nothing wrong with that.

There is abundant reason to avoid raising uric acid levels. Besides causing gout, there is an interventional study that demonstrates lowering uric acid mitigates kidney disease, thus proving high uric acid is a cause of kidney disease. In addition there are studies showing associations of high uric acid and with stroke and heart disease. Those references can be found toward the end of my writing here: Association ≠ Causation. Do Not Be Led Astray By This Popular Health Guru tinyurl.com/ycsr4cfu

Despite the foregoing, some investigators embarked upon a phase 3 interventional study of raising uric acid levels for Parkinson's patients: Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial pubmed.ncbi.nlm.nih.gov/345... scholarlycommons.henryford....

They raised uric acid levels from 4.6mg/dL to 6.6mg/dL in the treatment arm, which more than triples the risk of gout and increases the risk of kidney disease. Want to guess the outcome of the study?

It was halted early for futility. ninds.nih.gov/Disorders/Cli... Patients in the treatment arm suffered five times as many kidney stones as the placebo arm: "7.0 vs 1.4 stones per 100 patient-years". The pain of passing a kidney stone "is described as a 9 or 10 out of a scale of 1 to 10." ref: Kidney Stone Emergencies, ncbi.nlm.nih.gov/books/NBK2...

So that is a serious adverse event. They do not calculate a p value for this result, but the confidence intervals shown in the text indicate it was statistically significant, thus demonstrating raising uric acid causes kidney stones. They also minimized the fact that patients in the treatment arm progressed more rapidly, because that measure did not achieve statistical significance: "participants randomized to inosine [progressed] (MDS-UPDRS score, 11.1 ...points per year) and placebo (MDS-UPDRS score, 9.9 ... points per year; "

When your treatment causes one type of serious adverse event, and is known to cause other types of serious adverse events, the fact that the adverse effect on Parkinson's was not stat sig does not rescue this idea from failure.

Additional information:

ncbi.nlm.nih.gov/books/NBK273/ " Hypouricemia [low uric acid] produces no symptoms or known morbidity. Its fortuitous discovery on automated chemistry screening requires no therapy but should alert the physician to search for an underlying cause."

ahajournals.org/doi/full/10... U‐Shaped Association Between Serum Uric Acid Levels With Cardiovascular and All‐Cause Mortality in the Elderly: The Role of Malnourishment " Remarkably, among the low SUA[serum uric acid] (<4 mg/dL) strata, only malnourished participants had greater all‐cause and CVD‐related mortality. This modifying effect of malnourishment remained consistent across subgroups." - Once again demonstrating that low uric acid is a result, not a cause, of disease.

Lesson Two: Studies Do Not Have An Expiration Date

Any study that is well done, gives clear answers, and is not contradicted by other studies, is valid. The uninformed who do not like it may object based on age, but that is mistaken. Validity of a study that remains undisputed in the literature improves with age. The more time that passes, the less likely new information will contradict the result. If, in addition, the study at hand fits into related work like a piece of a jig saw puzzle that further increases confidence.

The Epidemiology Of Gout study of the title image was published in 2010. It used the database of the Framingham heart study which followed over 4000 participants over the interval 1952-2002. A person objecting said (inaccurately) "That article is over 20 years old", as if the human physiology of gout was somehow subject to change in the intervening interval.

The way to check a study has not been contradicted by more recent work is to check citations, which are provided by Google Scholar: scholar.google.com/scholar?...

The Epidemiology Of Gout study has been cited 226 times. All kinds of additional studies have been published. From a study published in 2021: bmcrheumatol.biomedcentral.... "Elevated serum urate (SU) concentration is the central risk factor for the development of gout." Here is a systematic review published 2017: Serum Uric Acid and the Risk of Incident and Recurrent Gout: A Systematic Review jrheum.org/content/44/3/388... "Lowering serum uric acid (SUA) levels can essentially cure gout" So this result remains undisputed.

Moral of the story: Do not accept conclusions based solely upon associations. In the matter at hand, raising uric acid levels is a very bad idea. There is no benefit and a lot of risk.

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park_bear
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7 Replies
Hikoi profile image
Hikoi

Brilliant, thanks PB

VivaceLargo profile image
VivaceLargo

Well said 👏

Bravo! You have freed me of one of my sources of confusion! Dr. Richard Johnson of Colorado has researched uric acid and is a great source.

AmyLindy profile image
AmyLindy in reply to

Me too-Thanks PB

park_bear profile image
park_bear

youtube.com/watch?v=nXGTFDV...

Dr. Richard Johnson’s research is what inspired Dr. Perlmutter’s book. As mentioned a couple months ago in the comment above, he, Dr. Richard Johnson is the best resource I have found for uric acid information. His information on fructose is very fascinating as well. youtu.be/V02z9mqTWzg

MBAnderson profile image
MBAnderson

Thank you p b

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