Hyperuricemia/ja

Asymptomatic hyperuricemia
尿酸

高尿酸血症とは、血液中の尿酸が異常に高い状態である。体液のpH条件下では、尿酸は大部分が尿酸塩（イオン型）として存在する。血清尿酸濃度が女性で6 mg/dL以上、男性で7 mg/dL以上、青少年（18歳未満）で5.5 mg/dL以上を高尿酸血症と定義する。体内の尿酸塩の量は、食物に含まれるプリン体の量、体内で合成される尿酸塩の量（細胞のターンオーバーなど）、および尿中または消化管から排泄される尿酸塩の量の間のバランスに依存する。高尿酸血症は、尿酸の産生増加、尿酸の排泄減少、または産生増加と排泄減少の両方の結果である。

前高尿酸血症： 前高尿酸血症（pre-HU）は、血清尿酸値が男性で6-7 mg/dL、女性で5-6 mg/dlの間の高い正常値にある代謝状態として定義することができる。この値は現在、正常または高正常値と考えられている。このレベル、あるいはそれ以下でも、UAによる全身炎症が発症する。

徴候と症状

高尿酸血症は、臨床検査室で尿酸の高い血中濃度が測定されない限り、ほとんどの人に顕著な症状を引き起こさない。痛風を発症する。痛風の発症は高尿酸血症の最も一般的な結果であり、通常は四肢の関節に尿酸結晶が沈着するが、腎臓結石の形成を誘発することもある。痛風の症状は、典型的には、強い痛みを伴う、足指や膝などの関節の炎症、腫れ、発赤である。高尿酸血症のすべての人が痛風を発症するわけではない。

Causes

Many factors contribute to hyperuricemia, including genetics, insulin resistance, hypertension, hypothyroidism, chronic kidney disease, obesity, diet, iron overload, use of diuretics (e.g. thiazides, loop diuretics), and excessive 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

Main article: Uric acid § High 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. Excess AMP (adenosine monophosphate) is converted into uric acid. AMP → IMP → Inosine → Hypoxanthine → Xanthine → Uric Acid

Hyperuricemia experienced as gout 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 kidney failure. The Lesch–Nyhan syndrome is also associated with extremely high levels of uric acid.

Decreased excretion of uric acid

Main article: Uric acid § Low 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.

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 lacking in carbohydrates 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.

Diagnosis

Hyperuricemia can be detected using blood and urine tests.

Treatment

Medications that aim to lower the uric acid concentration

Medications used to treat hyperuricemia are divided into two categories: xanthine oxidase inhibitors and uricosurics. 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

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

Uricosurics

Uricosuric agents (benzbromarone, benziodarone, probenecid, lesinurad, sulfinpyrazone, ethebencid, zoxazolamine, and ticrynafen) increase the excretion of uric acid, by reducing the reabsorption of uric acid once it has been filtered out of the blood by the kidneys.

Some of these medications are used as indicated, others are used 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 pills 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 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.

pH

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.

Temperature

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.

Prognosis

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.

See also

• Hypouricemia
• Hyperuricosuria
• Metabolic myopathies (myogenic hyperuricemia)
• Purine nucleotide cycle
• Uric acid

Further reading

• Nuki G, Simkin PA (2006). "A concise history of gout and hyperuricemia and their treatment". Arthritis Research & Therapy. 8 (Suppl 1): S1. doi:10.1186/ar1906. PMC 3226106. PMID 16820040.

External links

• 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