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.
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Many factors contribute to hyperuricemia, including genetics, insulin resistance, hypertension, hypothyroidism, hyperthyroidism, renal insufficiency, obesity, diet, use of diuretics (e.g. thiazides, loop diuretics), and consumption of excess alcoholic beveragess. 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 acidEdit
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 acidEdit
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.
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- GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
- OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
- GeneReviews/NCBI/NIH/UW entry on Familial Juvenile Hyperuricemic Nephropathy Type 2
- OMIM entries on Familial Juvenile Hyperuricemic Nephropathy Type 2