Many factors contribute to hyperuricemia, including
genetics,
insulin resistance,
hypertension, 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 decreased
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 (see
Gout). Foods high in the purines
adenine and
hypoxanthine may aggravate symptoms of hyperuricemia. Various studies have found higher uric acid levels to be positively associated with consumption of meat and seafood and inversely associated with dairy food consumption. Myogenic hyperuricemia, as a result of the
myokinase (adenylate kinase) reaction and the
Purine Nucleotide Cycle running when ATP reservoirs in muscle cells are low (ADP>ATP), is a common pathophysiologic feature of
glycogenoses such as
GSD-III,
GSD-V and
GSD-VII, as they are
metabolic myopathies which impair the ability of ATP (energy) production for the muscle cells to use. In these metabolic myopathies, myogenic hyperuricemia is exercise-induced; inosine, hypoxanthine and uric acid increase in plasma after exercise and decrease over hours with rest. Apart from normal variation (with a genetic component),
tumor lysis syndrome produces extreme levels of uric acid, mainly leading to
kidney 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 A
ketogenic diet impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and
ketones. 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.
Mixed type Causes of hyperuricemia that are of mixed type have a dual action, both increasing production and decreasing excretion of uric acid.
Pseudohypoxia (disrupted NADH/NAD+ ratio), caused by diabetic hyperglycemia and excessive alcohol consumption, results in hyperuricemia. The lactic acidosis inhibits uric acid secretion by the kidney, while the energy shortage from inhibited oxidative phosphorylation leads to increased production of uric acid due to increased turnover of adenosine nucleotides by the
myokinase reaction and
purine nucleotide cycle. 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. 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 also impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones.
Gut microbiome Radioisotope studies suggest about 1/3 of uric acid is removed in healthy people in their gut with this being roughly 2/3 in those with kidney disease. Uric acid metabolism is done in the human gut by ~1/5 of bacteria that come from 4 of 6 major phyla. Such metabolism is anaerobic involving uncharacterized ammonia lyase, peptidase, carbamoyl transferase, and oxidoreductase enzymes. The result is that uric acid is converted into
xanthine or
lactate and the
short chain fatty acids such as
acetate and
butyrate. In mouse models, such bacteria compensate for the loss of uricase leading researchers to raise the possibility "that antibiotics targeting anaerobic bacteria, which would ablate gut bacteria, increase the risk for developing gout in humans". ==Diagnosis==