uric acid

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jimmylegs
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Re: uric acid

Post by jimmylegs »

Low serum uric acid levels in patients with acute central nervous system viral infections
http://journals.lww.com/neuroreport/Abs ... te.11.aspx

'Most acute central nervous system (CNS) viral infections lead to either encephalitis or meningitis. Many neurotropic viruses may cause CNS dysfunctions through various mechanisms including oxidative stress. Serum uric acid (SUA) levels, which are associated with oxidative stress and antioxidant status, are reduced in patients with various neurological disorders, including multiple sclerosis. We investigated the possible correlation between SUA levels and clinical disease status in patients with acute CNS viral infections. We measured SUA concentrations in 336 individuals, including 179 healthy individuals and 157 patients with acute CNS viral infections. We found that the patients had lower SUA levels than the healthy individuals did irrespective of sex. Effective therapy significantly increased SUA levels. The patients’ SUA levels were correlated inversely with outcomes as measured with the Glasgow Outcome Scale. SUA levels may be a biomarker for predicting treatment outcomes and prognoses for patients with acute CNS viral infections with inflammatory components.

"In our hospital, the normal SUA range is 208–428 mM for men and 155–357 mM for women...

"... we observed significantly lower SUA levels in patients who had neurological abnormalities (P=0.001), seizures (P=0.006), abnormal EEG results (P<0.001), abnormal MRI findings (P<0.001), or a need for ICU treatment (P<0.001) than in patients who did not have these conditions (Table 4).

.......................................ua in cases with............ua in controls
Neurological abnormalities..181 +/- 82...................225 +/- 69
Cognitive dysfunction.........188 +/- 82...................208 +/- 77

.......................................ua before treatment......ua.after
viral meningitis...................223 +/- 57.................285 +/- 78
viral encephalitis.................205 +/- 96.................261 +/- 100

"SUA levels were evidently decreased in patients with viral CNS infections, but effective treatments restored them. More importantly, lower SUA levels may be related to several phenomena indicative of disease severity, including neurological abnormalities, seizures, abnormal EEG results, abnormal MRI findings, and a need for ICU treatment. Furthermore, lower SUA levels were correlated closely with poor prognoses. Therefore, SUA levels may be a useful biomarker of acute CNS viral infections with inflammatory components and may be useful indicators for prognoses and treatment outcomes."

very interesting. i'd like to have seen a serum zinc test somewhere in this mix.

reference range locally is 140-360. i remember years ago the first time i heard about ua being low in ms (on this forum, btw), had it tested and when it came back 194 i was like "meh, guess ua is fine in MY case" <- jimmylegs, right before figuring out 'normal range' bs
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Re: uric acid

Post by jimmylegs »

grr info on low ua status in ms deleted on the uric acid wikipedia page. looks like death by a thousand cuts -whittled and whittled until the last piece left was meaningless. needs an updated lit review because there is no way that info should be just *gone*.
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Re: uric acid

Post by jimmylegs »

a slightly different spin on an ms known:

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients (2018).
https://www.ncbi.nlm.nih.gov/pubmed/29651206

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.


yeah i wouldn't expect an ms patient to be excreting much uric acid in urine, when we aren't successfully making the stuff to match serum levels seen healthy controls in the first place.

while i know next to nothing about urine testing, in my opinion more research is needed to clarify interactions between serum uric acid, serum zinc and serum ammonia in MS.
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Re: uric acid

Post by jimmylegs »

ran across this one in passing, while hunting for something else. completely weird-looking uric acid results for ms patients.

Serum Metabolic Profile in Multiple Sclerosis Patients (2011)
https://bit.ly/2BRMf2H

.................Controls (n = 163).....MS patients (n = 170)
Uric acid.......258.08 ± 50.39........299.88 ± 70.17a

mine was stuck around 190 for ages. was ecstatic to finally get the level UP to 278.
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2006: zinc copper and uric acid in hemodialysis patients

Post by jimmylegs »

  • Longitudinal study of serum zinc and copper levels in hemodialysis patients and their relation to biochemical markers (2006)
    https://link.springer.com/article/10.13 ... :113:3:209

    Mean serum zinc and copper concentrations in HPs were significantly decreased (Zn) and increased (Cu), when compared with healthy controls (p<0.01). ... Uric acid and parathyroid hormone ... were significantly (p<0.05) and linearly related with serum zinc ... concentrations.
maybe at some point we'll get research looking at zinc and uric acid status in ms. maybe even treatment effects of oral zinc, too.
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1977 study: low zinc intake reduces serum ua

Post by jimmylegs »

another one linking low zinc intake with reduced uric acid levels.

Effect of Low Zinc Intake and Oral Contraceptive Agents on Nitrogen Utilization and Clinical Findings in Young Women (1977)
FRANCES M. H
https://bit.ly/2XrVYmg

"In a previous paper we reported that serum, urine and fecal zinc levels fell markedly in women taking a combination oral contraceptive agent (+OCA) and in women with normal menstrual cycles (-OCA) when they consumed a low-zinc diet (< 0.2 mg/day) for 35 days. ... Serum uric acid ... changed significantly in both groups. Clinical problems developed in all the subjects with serum zinc levels below 50 µg/dl during the study; three of the six with serum zinc levels above 50 µg/dl also complained of clinical symptoms. The results suggest that zinc deficiency through depletion of accessible body zinc stores developed during the 35-day study."

table 3 in full text shows ua status pre and post low zinc regimen. for both groups mean serum ua dropped to 3.6 mg/dl aka 214 umol/l ie well down into 'ms in remission' territory
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2018 study: serum UA in PwMS using DMT

Post by jimmylegs »

  • Assessment of Serum Uric Acid Levels in Multiple Sclerosis during Disease-Modifying Treatment (2018)
    https://pdfs.semanticscholar.org/d6bd/2 ... 94166a.pdf

    "Results: Serum UA levels of MS patients were significantly lower (4.2 ± 1.1 mg/dl) when compared with control group (4.9 ± 1.4 mg/dl, P=0.0092). Correlation between MS duration and serum UA concentration did not reach statistical significance, however the tendency showing that patients who are suffering from this disorder for a longer time have lower serum UA concentration was observed. ...

    Conclusion: Although we do not know exactly whether and how uric acid is involved in MS pathogenesis, data suggest that UA concentration is lower in MS patients than in control group. It seems that low uric acid levels indicate patients with a higher risk of disease progression. Whether or not UA concentration can be useful as a biomarker in MS requires further study."
that control group looks bang on per my understanding of healthy control serum ua levels, but even the patient group looks well above the 'ms average' from prior study (ie 3.2 mg/dl or 194 umol/l), which was where i was stuck for ages, before finally making the zinc connection (see related study posted above).

patients w mean ua levels at 4.2 could be bc the subjects are on a DMT. maybe mitoxantrone (MTX) improves ua status similar to the observed influence of beta interferon - see: viewtopic.php?p=250982#p250982

who needs a pesky ol essential nutrient, right?
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2018 study: u-shaped uric acid and mortality

Post by jimmylegs »

  • U‐Shaped Association Between Serum Uric Acid Levels With Cardiovascular and All‐Cause Mortality in the Elderly: The Role of Malnourishment (2018)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850189/

    "...Over a median follow‐up of 5.8 years, there were 16 439 all‐cause and 3877 CVD‐related deaths. Compared with the reference SUA strata of 4 to <5 mg/dL, all‐cause mortality was significantly higher at SUA <4 mg/dL (HR, 1.16; 95% confidence interval, 1.07–1.25) and ≥8 mg/dL (HR, 1.13; confidence interval, 1.06–1.21), with progressively elevated risks at both extremes. Similarly, increasingly higher CVD‐related mortality was found at the SUA level <4 mg/dL (HR, 1.19; confidence interval, 1.00–1.40) and ≥7 mg/dL (HR, 1.17; confidence interval, 1.04–1.32). Remarkably, among the low SUA (<4 mg/dL) strata, only malnourished participants had greater all‐cause and CVD‐related mortality. This modifying effect of malnourishment remained consistent across subgroups.

    Conclusions
    SUA ≥8 or <4 mg/dL independently predicts higher all‐cause and CVD‐related mortality in the elderly, particularly in those with malnourishment."
not sure why the smaller range (4-7) for reduced CVD mortality risk was removed in the conclusions. as an ms patient i'm taking away no less than 5 and no higher than 7. (and to avoid gout i'd be after no more than 6).
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2017 case: urea cycle disorder and MS misdx

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hmm interesting.
  • Urea cycle disorder misdiagnosed as multiple sclerosis: a case report and review of the literature (2017)
    https://europepmc.org/articles/pmc5882056

    "Urea cycle disorders are a group of inborn errors of metabolism caused by dysfunction of any of the six enzymes or two transport proteins involved in urea biosynthesis. In this paper, we report a patient who presented with neurological dysfunction and coma in the immediate postpartum period. She was misdiagnosed for many years as a case of multiple sclerosis. The importance of reporting this case is to illustrate that the wrong diagnosis of patients as being affected with multiple sclerosis for many years due to magnetic resonance imaging abnormalities rather than the classic relapsing–remitting nature of the disease may lead to catastrophic consequences. The patient was treated with intravenous steroids several times, which is contraindicated in patients with urea cycle disorders as it may precipitate acute hyperammonemic attacks. In addition, the management of urea cycle disorder could have started earlier and avoided multiple admissions to the intensive care unit. We believe that the presence of symmetric hyperintense insular cortical changes are seen in multiple hyperammonemic processes, and in the context of the clinical presentation and high ammonia levels can be suggestive of a urea cycle disorder. For any patient presenting with atypical clinical features, images should be reviewed and discussed in detail with an experienced neuroradiologist. In addition, the ammonia levels should be checked if a urea cycle disorder is suspected.

    ...
    As part of the work-up for metabolic coma, her serum ammonia level was found to be very high, up to 274 µmol/L (normal range 10.71–32.13 µmol/L), and the diagnosis of urea cycle disorder was suspected (Figure 3)."
consider also:
  • Zinc deficiency in patients with sickle cell disease (2002)
    https://academic.oup.com/ajcn/article/75/2/181/4689290

    "A significant increase in the activity of AMP deaminase—an enzyme involved in the purine catabolic pathway—in the muscle of the zinc-deficient rats was also observed; this alteration may also contribute to hyperammonemia in zinc-deficient animals and humans (2, 3). Zinc supplementation in patients with SCD resulted in a significant improvement in secondary sexual characteristics, in the normalization of plasma ammonia concentrations, and in the reversal of abnormalities in dark adaptation (3)."

    Function of zinc in liver disease (2018)
    https://www.ncbi.nlm.nih.gov/pubmed/27455801

    "...Ammonia is detoxified in liver to urea through urea cycle... The reduced ability of ammonia detoxification in liver cirrhosis is ascribed to zinc deficiency, because a member of urea cycle, ornithine transcarbamylase is a zinc enzyme. ... Attention should be given to the clinical significance of zinc in liver diseases."

    Fatal Nonhepatic Hyperammonemia in ICU Setting: A Rare but Serious Complication following Bariatric Surgery (2016)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842030/

    " Further investigations revealed elevated ammonia level (193 μmol/L), low zinc level, normal vitamin B12 and folate level ... plasma zn 23 (reference range 60–130) μg/dL "
(ouch and i thought my 56 was bad - although now that i say that i think mine was a serum value and would be even lower if tested for plasma zn content)
  • Overt hepatic encephalopathy precipitated by zinc deficiency (1991)
    https://www.sciencedirect.com/science/a ... 8591902902

    "Encephalopathy in liver disease may be unresponsive to protein restriction, lactulose, and neomycin. Zinc supplements have been reported to improve psychometric performance in liver cirrhosis, but the importance of zinc deficiency in overt hepatic encephalopathy has not yet been clearly established. A patient with severe recurrent hepatic encephalopathy was studied to determine the relation between her signs of encephalopathy and zinc deficiency. The study included a period in which zinc deficiency was artificially induced by oral histidine. An episode of overt encephalopathy occurred that was identical to earlier episodes and responded to oral zinc. The study showed an association between encephalopathy and zinc deficiency by successive zinc depletion and supplementation regimens. Long term zinc supplementation improved severe recurrent hepatic encephalopathy and therefore the quality of life."
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2013 review: hepatic/hyperammonemic encephalopathy

Post by jimmylegs »

can't get all the pieces in one article so far, but this one at least links encephalopathy, ammonia and ms:
  • Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy (2013)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545226/

    "Hepatic encephalopathy is a medical phenomenon that is described as a neuropsychiatric manifestation of chronic or acute liver disease that is characterized by psychomotor, intellectual and cognitive abnormalities with emotional/affective and behavioral disturbances. This article focuses on the underlying mechanisms of the condition and the differences between hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. Hepatic encephalopathy is a serious condition that can cause neurological death with brain edema and intracranial hypertension. It is assumed that approximately 60%-80% of patients with liver cirrhosis develop hepatic encephalopathy. This review explores the complex mechanisms that lead to hepatic encephalopathy. However, noncirrhotic hyperammonemic encephalopathy is not associated with hepatic diseases and has a completely different etiology. Noncirrhotic hyperammonemic encephalopathy is a severe occurrence that is connected with multiple pathogeneses.
    ...
    The idea of neuroinflammation
    Ammonia dysmetabolism does not exist as the sole factor of the neurological changes observed in patients with HE. ... The concept of neuroinflammation (microglial activation) is defined as a wide variety of neurological disorders including multiple sclerosis, Alzheimer’s disease, stroke and acquired immune deficiency syndrome dementia complex...

    Changes in the blood-brain barrier
    The BBB constitutes a highly specialized mechanism of brain microvasculature, and it is indispensable for the proper function of the central nervous system (CNS)[26]. T... There is evidence of BBB dysfunction in the pathogenesis of many CNS disorders (e.g., Alzheimer’s disease and multiple sclerosis). The pathological appearance of HE is closely related to BBB changes ... increased BBB ammonia permeability during hyperammonemia or HE is still a matter of controversy among scientists[66]. There are investigations that support and refute this theory. Several positron emission tomography studies have revealed elevated brain ammonia concentrations in HE..."
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Re: uric acid

Post by jimmylegs »

hmm ya don't say...

Urea cycle disorder misdiagnosed as multiple sclerosis: a case report and review of the literature (2018)
https://journals.sagepub.com/doi/abs/10 ... 0917715880

"...The patient was treated with intravenous steroids several times, which is contraindicated in patients with urea cycle disorders as it may precipitate acute hyperammonemic attacks. In addition, the management of urea cycle disorder could have started earlier and avoided multiple admissions to the intensive care unit. We believe that the presence of symmetric hyperintense insular cortical changes are seen in multiple hyperammonemic processes, and in the context of the clinical presentation and high ammonia levels can be suggestive of a urea cycle disorder. For any patient presenting with atypical clinical features, images should be reviewed and discussed in detail with an experienced neuroradiologist. In addition, the ammonia levels should be checked if a urea cycle disorder is suspected."

so much yes.
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Anonymoose
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Re: uric acid

Post by Anonymoose »

So I’ve not read this entire thread (yet) but had to woo hoo! @ you Jimmylegs. I think uric acid was at the heart of my too much vitamin d = ouch years ago. Mystery solved (maybe)! I’ve not yet found why Valtrex would magnify the uric acid lowering affect but I’m guessing it increased calcitriol far beyond the increase that would occur w just d3.

I’ve been busy for months, accidentally eating a low purine diet with loads of vitamin c rich fruits, drinking giant cups of coffee, and working in sun for a few weeks (D!). Then I bought a big bag of oranges, overindulged, and triggered days of a mild but still painful version of vitamin D ouch. I looked it up and found citrus fruit decreases Uric acid levels which can cause bone pain…so does vitamin D etc. Then there’s the whole increased risk of mono infection (maybe ebv reactivation too?) with low levels of Uric acid. Yadda yadda yadda. How low could the purine intake of a lazy, non-drinking vegan be? Imagine my geeked out excitement at all of the connections…Disney for nerds it was.

As soon as I started eating purine rich foods (chili and nutritional yeast) the ouches faded away. Before you get after me about zinc for Uric acid cycle, I can’t load up on zinc because it throws my copper off relatively easily (even just in my multi). I always have to add extra copper and that makes me a bit uncomfortable because my underachieving ceruloplasmin might be leaving a load of free copper running amok. I might change my mind after I read more though.

I’m wondering how Coimbra protocol could work now though… and thinking maybe low vitamin d levels are protective for msers. Could UA be an integral part of the ms trigger? Is it part of the reason for Wahl’s recovery? Uric acid is usually high with mono infection but it’s lower in relapsing mser. How does that work? Does that mean ebv reactivation not relapse trigger or msers respond stoopidly to reactivation or something else? One mystery solved (maybe) and a dozen new mysteries pop up. Figures.

Anyway. Thanks for creating this thread. I’ll be starting from page one later today. I’m hoping you’ve already addressed some of the questions bouncing around in my head.

Be well

EDIT. OOPS! You didn’t create it. I don’t even know how that could be. Thanks for being the most recent poster to it. 😆

EDIT 2. That was a far easier read than I had anticipated. It made me miss the old days…so many people silent now. Anyway…no answers to my questions and lots of missing studies/case reports that I am hoping are elsewhere on TIMS. Incidentally, I quit being vegan (MS onset 5 years after became vegan) and massively increased my purine intake pretty much at the same time I had my first round of rituxan (and the too much vitamin d = ouch events). Uric acid may very well play a part in my lack of clinical progression. Are you still staying on top of yours jimmy (and everyone else)? Does HRT impact UA? Also UA level usually lower in females and risk of mono w low UA is higher for females. So MSy!
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Re: uric acid

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Hi Anonymoose,
I'm not sure valacyclovir (the Valtrex) works the way you assume. It's an antiviral and you take it as a prodrug. Once consumed, it breaks into Valine (which makes an insignificant contribution to muscles) and Acyclovir. The acyclovir has a very strong affinity to bind to gamma herpes infected cells (e.g infected by EBV, zoster, HSV1 and 2 etc). Those infected cells produce something called viral thymidine kinase. The kinase adds one phosphate to the acyclovir so it become acyclovir monophosphate. In that form, the infected human cell is attracted to donate two more phosphate molecules, so it becomes acyclovir triphosphate. A uninfected human cell can only supply two phosphates and the ability to bind to DNA requires three phosphates. This makes acyclovir highly specific to infected cells.
As acyclovir triphosphate, it looks almost the same as guanosine triphosphate and the drug binds to the string of viral DNA in its place. From the perspective of the virus, that's a problem because it is a non-functional analogue and viral DNA breaks down ending its replication. After 11 hours we have excreted the acyclovir. We don't retain it.it will only be effective when the virus is replicating in a particular way (called lysis). A latent infection hides in a dividing cell and is unaffected.
Uric acid is the final breakdown product of the energy molecule, ATP.
This breaks down in the order ATP-ADP-AMP-Adenosine. Once it gets to AMP it starts washing from the cell. Avoiding fatigue relies on recycling ADP (2 phosphates) back to ATP (three phosphates).
Some Adenosine builds up in the brain causing fatigue and eventually we go to sleep. In the blood stream it continues to breakdown thus - Adenosine- Inosine-hypoxanthine-xanthine, and finally, -uric acid. There is a large body of anecdotal evidence that gout (an excess of uric acid) and MS are practically mutually exclusive.
If we are fatigued, we have too much adenosine relative to ATP. If we have low uric acid, then the breakdown process would have been stopped by a lack of an enzyme.
There are very similar structures in a small EBV RNA molecule (EBER-2) when compared to the particular enzyme that breaks down Adenosine (called adenosine deanimase). If it outcompetes the enzyme, the Adenosine accumulates rather than breaking down (i.e fatigue increases, the chance of gout decreases).
Vitamin D follows a completely different pathway. Too much vitamin D can accumulate in your body because it loves fat and that can create different issues.
I don't think the vitamin D- valtrex connection exists. it may have been coincidental.
Regards,
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Re: uric acid

Post by Anonymoose »

Hey scott1,

Yep. I’ve studied up on Valtrex too and not found a single clue as to it’s impact on calcitriol (which was lab measured high for an extended period after both vitamin d/Valtrex events). I’ve not yet found any connection to uric acid either. But you will never convince me it wasn’t hugely involved in the “ouch incidents.” Perhaps it was its effect upon the infected cells that caused the calcitriol spikes.

Hope you’re doing well. :)
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Scott1
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Re: uric acid

Post by Scott1 »

Hi,

I am well, thanks.
I don't take vitamin D and have never been sure about supplementing with it. Down here, even in our coldest months, we still have plenty of sunshine and I prefer to make it that way.

Regards
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