Hyperuricemia: Difference between revisions

'''Hyperuricaemia''' or '''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. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for men, and 5.5 mg/dL for youth (under 18 years old) are defined as hyperuricemia. The amount of urate in the body depends on the [[Homoeostasis|balance]] between the amount of [[purine]]s 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. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

Prehyperuricemia (pre-HU) may be defined as a metabolic condition where serum uric acid value is at a high normal level between 6–7 mg/dL in men and 5–6 mg/dl in women. This value is presently considered normal or high normal. At this level or even below this, UA-induced systemic inflammation develops.

Unless high blood levels of uric acid are determined in a [[Medical laboratory|clinical laboratory]], hyperuricemia may not cause noticeable symptoms in most people.<ref name=asc/> Development of [[gout]] {{ndash}} which is a painful, short-term disorder {{ndash}} is the most common consequence of hyperuricemia, which causes deposition of uric acid crystals usually in joints of the extremities, but may also induce formation of [[kidney stone]]s, another painful disorder. Gout symptoms are typically [[inflammation]], swelling and redness of a joint, such as a toe or knee, accompanied by intense pain. Not all people with hyperuricemia develop gout.

Many factors contribute to hyperuricemia, including [[genetics]], [[insulin resistance]], [[hypertension]], [[hypothyroidism]], [[chronic kidney disease]], [[obesity]], [[diet (nutrition)|diet]], [[iron overload]], use of [[diuretic]]s (e.g. [[thiazide]]s, [[loop diuretic]]s), and excessive consumption of [[alcoholic beverages|alcoholic beverage]]s. 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.

A purine-rich diet is a common but minor cause of hyperuricemia. Diet alone generally is not sufficient to cause hyperuricemia (see [[Gout#Cause|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 [[Adenylate kinase|myokinase (adenylate kinase)]] reaction and the [[Purine nucleotide cycle|Purine Nucleotide Cycle]] running when ATP reservoirs in muscle cells are low (ADP>ATP), is a common pathophysiologic feature of [[Glycogen storage disease|glycogenoses]] such as [[Glycogen storage disease type III|GSD-III]], [[Glycogen storage disease type V|GSD-V]] and [[Glycogen storage disease type VII|GSD-VII]], as they are [[Metabolic myopathy|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. Excess [[Adenosine monophosphate|AMP (adenosine monophosphate)]] is converted into uric acid. AMP → IMP → Inosine → Hypoxanthine → Xanthine → Uric Acid

Hyperuricemia experienced as [[gout]] is a common complication of [[organ transplant|solid organ transplant]]. 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.

The principal drugs that contribute to hyperuricemia by decreased excretion are the primary [[antiuricosuric]]s. Other drugs and agents include [[diuretic]]s, [[salicylate]]s, [[pyrazinamide]], [[ethambutol]], [[nicotinic acid]], [[ciclosporin]], 2-ethylamino-1,3,4-thiadiazole, and [[cytotoxic agent]]s.

The gene [[SLC2A9]] encodes a protein that helps to transport uric acid in the kidney. Several [[single nucleotide polymorphism]]s 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 [[ketone]]s.

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 ratio]]s 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.

[[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 [[Adenylate kinase|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]].

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 drink]]s 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 [[adenosine triphosphate|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]] lacking in [[carbohydrate]]s 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.

Hyperuricemia can be detected using blood and urine tests.

[[Medication]]s used to treat hyperuricemia are divided into two categories: [[xanthine oxidase inhibitor]]s and [[uricosuric]]s. For people who have recurring attacks of gout, one of these two categories of drugs is recommended. The evidence for people with asymptomatic hyperuricaemia to take these medications is not clear.

Xanthine oxidase inhibitors, including [[allopurinol]], [[febuxostat]] and [[topiroxostat]], decrease the production of uric acid, by interfering with [[xanthine oxidase]].

Some of these medications are used as [[Indication (medicine)|indicated]], others are used [[Off-label use|off-label]]. 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 pill]]s is significantly associated with lower serum uric acid. Following [[Le Chatelier's principle]], lowering the blood concentration of uric acid may permit any existing crystals of uric acid to gradually dissolve into the blood, 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 [[Tophus|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. 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.

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 nor 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]]). Medications that have a similar effect include [[acetazolamide]].

Low temperature is a 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.

Increased levels predispose for [[gout]] and, if very high, [[kidney failure]]. [[Metabolic syndrome]] often presents with hyperuricemia. Prognosis is good with regular consumption of [[allopurinol]] or [[febuxostat]].