Men who have high levels of urate, also known as uric acid, in their blood may be less likely to develop Parkinson’s disease, according to a study published in the Jan. 13, 2016, online issue of Neurology.
Urate is formed when other chemicals, called purines, are broken down in the body. Purines are found in food, and some purines are the building blocks of DNA. Studies have suggested that urate may play a protective role with brain cells.
“These results suggest that urate could protect against Parkinson’s or slow the progression of the disease in its very early stages before symptoms are seen,” said study author Xiang Gao, MD, PhD, of Pennsylvania State University in University Park and a member of the American Academy of Neurology. “The findings support more research on whether raising the level of urate in people with early Parkinson’s may slow the disease down.”
Gao said the idea is exciting, as urate levels can be raised easily and inexpensively, but it must also be done cautiously, as excessively high levels of urate can cause kidney stones and gout.
The study looked at 90,214 participants in three large, ongoing studies. Blood tests measured the urate level of participants. A total of 388 people who developed Parkinson’s disease after the start of the studies were compared to 1,267 people who did not have the disease. The researchers also combined their results with the results from three previous studies on the topic for a meta-analysis.
The men with the lowest level of urate had levels of less than 4.9 milligrams per deciliter. Those with the highest levels had 6.3 to 9.0 mg/dL. Normal levels can range from 3.5 to 7.2 mg/dL. The men who had the highest levels of urate were nearly 40 percent less likely to develop Parkinson’s disease than those with the lowest levels. Among the men with Parkinson’s disease, 45 men had the highest level of urate and 58 men had the lowest level of urate. Among the healthy men, 111 were in the group with the highest level of urate; 107 were in the group with the lowest level. The researchers adjusted for other factors that could affect Parkinson’s disease risk, such as age, smoking and caffeine use. There was no relationship between the level of urate in women and whether they developed Parkinson’s disease.
Gao noted that the study does not prove that high levels of urate protect against Parkinson’s disease; it only shows an association consistent with a lower risk effect. He also notes more studies are needed to understand the sex differences in the relationship between urate and Parkinson’s disease.
Funding: The study was supported by the National Institutes of Health.
Source: Rachel Seroka – AAN
Image Source: The image is in the public domain
Original Research: Abstract for “Prospective study of plasma urate and risk of Parkinson disease in men and women” by Xiang Gao, Éilis J. O’Reilly, Michael A. Schwarzschild, and Alberto Ascherio in Neurology. Published online January 16 2016 doi:10.1212/WNL.0000000000002351 1526-632X
Prospective study of plasma urate and risk of Parkinson disease in men and women
Objective: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate–PD relationship.
Methods: We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk.
Results: In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; ptrend = 0.049) in men and 1.04 (95% CI 0.61, 1.78; ptrend = 0.44) in women (pheterogeneity = 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women.
Conclusion: We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease.
“Prospective study of plasma urate and risk of Parkinson disease in men and women” by Xiang Gao, Éilis J. O’Reilly, Michael A. Schwarzschild, and Alberto Ascherio in Neurology. Published online January 16 2016 doi:10.1212/WNL.0000000000002351 1526-632X
Hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body (e.g., through cell turnover), and the amount of urate that is excreted in urine or through the gastrointestinal tract. In humans, the upper end of the normal range is 360 µmol/L (6 mg/dL) for women and 400 µmol/L (6.8 mg/dL) for men.
Many factors contribute to hyperuricemia, including genetics, insulin resistance, hypertension, hypothyroidism, renal insufficiency, obesity, diet, use of diuretics (e.g. thiazides, loop diuretics), and consumption of alcoholic beverages. Of these, alcohol consumption is the most important.
Causes of hyperuricemia can be classified into three functional types: increased production of uric acid, decreased excretion of uric acid, and mixed type. Causes of increased production include high levels of purine in the diet and increased purine metabolism. Causes of decreased excretion include kidney disease, certain drugs, and competition for excretion between uric acid and other molecules. Mixed causes include high levels of alcohol and/or fructose in the diet, and starvation.
Increased production of uric acid
A purine-rich diet is a common but minor cause of hyperuricemia. Diet alone generally is not sufficient to cause hyperuricemia. Purine content of foods varies (see Gout). Foods high in the purines adenine and hypoxanthine may be more potent in exacerbating hyperuricemia.
Hyperuricemia of this type is a common complication of solid organ transplant. Apart from normal variation (with a genetic component), tumor lysis syndrome produces extreme levels of uric acid, mainly leading to renal failure. The Lesch-Nyhan syndrome is also associated with extremely high levels of uric acid.
Decreased excretion of uric acid
The principal drugs that contribute to hyperuricemia by decreased excretion are the primary antiuricosurics. Other drugs and agents include diuretics, salicylates, pyrazinamide, ethambutol, nicotinic acid, ciclosporin, 2-ethylamino-1,3,4-thiadiazole, and cytotoxic agents.
The gene SLC2A9 encodes a protein that helps to transport uric acid in the kidney. Several single nucleotide polymorphisms of this gene are known to have a significant correlation with blood uric acid. Hyperuricemia cosegregating with osteogenesis imperfecta has been shown to be associated with a mutation in GPATCH8 using exome sequencing
Elevated blood lead is significantly correlated with both impaired kidney function and hyperuricemia (although the causal relationship among these correlations is not known). In a study of over 2500 people resident in Taiwan, a blood lead level exceeding 7.5 microg/dL (a small elevation) had odds ratios of 1.92 (95% CI: 1.18-3.10) for renal dysfunction and 2.72 (95% CI: 1.64-4.52) for hyperuricemia.
Causes of hyperuricemia that are of mixed type have a dual action, both increasing production and decreasing excretion of uric acid.
High intake of alcohol (ethanol), a significant cause of hyperuricemia, has a dual action that is compounded by multiple mechanisms. Ethanol increases production of uric acid by increasing production of lactic acid, hence lactic acidosis. Ethanol also increases the plasma concentrations of hypoxanthine and xanthine via the acceleration of adenine nucleotide degradation, and is a possible weak inhibitor of xanthine dehydrogenase. As a byproduct of its fermentation process, beer additionally contributes purines. Ethanol decreases excretion of uric acid by promoting dehydration and (rarely) clinical ketoacidosis.
High dietary intake of fructose contributes significantly to hyperuricemia. In a large study in the United States, consumption of four or more sugar-sweetened soft drinks per day gave an odds ratio of 1.82 for hyperuricemia.Increased production of uric acid is the result of interference, by a product of fructose metabolism, in purine metabolism. This interference has a dual action, both increasing the conversion of ATP to inosine and hence uric acid and increasing the synthesis of purine. Fructose also inhibits the excretion of uric acid, apparently by competing with uric acid for access to the transport protein SLC2A9. The effect of fructose in reducing excretion of uric acid is increased in people with a hereditary (genetic) predisposition toward hyperuricemia and/or gout.
Starvation causes the body to metabolize its own (purine-rich) tissues for energy. Thus, like a high purine diet, starvation increases the amount of purine converted to uric acid. A very low calorie diet without carbohydrate can induce extreme hyperuricemia; including some carbohydrate (and reducing the protein) reduces the level of hyperuricemia. Starvation also impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones.
Precipitation of uric acid crystals, and conversely their dissolution, is known to be dependent on the concentration of uric acid in solution, pH, sodium concentration, and temperature. Established treatments address these parameters.
Following Le Chatelier’s principle, lowering the blood concentration of uric acid may permit any existing crystals of uric acid to be gradually dissolved into the blood, from whence the dissolved uric acid can be excreted. Maintaining a lower blood concentration of uric acid similarly should reduce the formation of new crystals. If the person has chronic gout or known tophi, then large quantities of uric acid crystals may have accumulated in joints and other tissues, and aggressive and/or long duration use of medications may be needed.
Medications most often used to treat hyperuricemia are of two kinds: xanthine oxidase inhibitors and uricosurics. Xanthine oxidase inhibitors decrease the production of uric acid, by interfering with xanthine oxidase. Uricosurics increase the excretion of uric acid, by reducing the reabsorption of uric acid once the kidneys have filtered it out of the blood. Some of these medications are used as indicated, others are used off-label. Several other kinds of medications have potential for use in treating hyperuricemia. In people receiving hemodialysis, sevelamer can significantly reduce serum uric acid, apparently by adsorbing urate in the gut. In women, use of combined oral contraceptive pills is significantly associated with lower serum uric acid.
Non-medication treatments for hyperuricemia include a low purine diet (see Gout) and a variety of dietary supplements. Treatment with lithium salts has been used as lithium improves uric acid solubility.
Serum pH is neither safely or easily altered. Therapies that alter pH principally alter the pH of urine, to discourage a possible complication of uricosuric therapy: formation of uric acid kidney stones due to increased uric acid in the urine (see Nephrolithiasis). Dietary supplements that can be used to make the urine more alkaline include sodium bicarbonate, potassium citrate, magnesium citrate, and Shohl’s Solution (now replaced by Bicitra). Medications that have a similar effect include acetazolamide.
Low temperature is a commonly reported trigger of acute gout: an example would be a day spent standing in cold water, followed by an attack of gout the next morning. This is believed to be due to temperature-dependent precipitation of uric acid crystals in tissues at below normal temperature. Thus, one aim of prevention is to keep the hands and feet warm, and soaking in hot water may be therapeutic.