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Hyperuricemia is a common disorder that affects patients of all ages and genders. The most common manifestation of hyperuricemia is gout, which can be very painful and is amenable to treatment. Hyperuricemia is also associated with uric acid and calcium nephrolithiasis. Hyperuricemia affects about 38 million Americans, over 11% of the population, and the incidence is increasing worldwide. Most patients with hyperuricemia are asymptomatic, and the diagnosis requires a high degree of suspicion as serum uric acid levels are no longer routinely measured on serum blood panels. Patients with hyperuricemia who develop gout are usually best treated with a xanthine oxidase inhibitor like allopurinol. Depending on the urinary chemistry and stone type, allopurinol, potassium citrate, or both may be recommended in nephrolithiasis. This activity reviews the pathophysiology, presentation, evaluation, and treatment of hyperuricemia, as well as highlights the interprofessional team's role in caring for affected patients. Objectives: Recognize individuals at risk of hyperuricemia by evaluating dietary habits, family history, and lifestyle factors, and regularly monitor serum uric acid levels. Initiate evidence-based management strategies, including lifestyle modifications, pharmacotherapy, and dietary interventions, to effectively control uric acid levels and reduce the risk of associated complications. Identify treatment modalities for both acute and chronic hyperuricemia. Facilitate coordinated care by ensuring seamless transitions among primary care, specialty care, and other healthcare providers, providing comprehensive management of hyperuricemia and its associated comorbidities. Access free multiple choice questions on this topic.

Hyperuricemia is defined as an elevated serum uric acid level, usually greater than 6 mg/dL in women and 7 mg/dL in men. Elevated serum uric acid is present in an estimated 38 million Americans, and the incidence is increasing worldwide as developing countries adopt more Western diets and lifestyles. Most people with this condition will not have obvious clinical manifestations, however, it is unclear what the long-term effects of hyperuricemia are on overall cardiovascular health, renal function, and overall morbidity.[1] Hyperuricemia results from increased uric acid production, decreased excretion, or a combination of both processes. Dietary purines are responsible for about one-third of the body's daily serum uric acid production; the rest is synthesized from endogenous sources. Elevated uric acid can also be seen with accelerated purine degradation in high cell turnover states (eg, hemolysis, rhabdomyolysis, tumor lysis) and decreased excretion (eg, genetic disorders, renal insufficiency, metabolic syndrome). About two-thirds of uric acid is excreted through the kidney and one-third through the gastrointestinal (GI) tract. However, these proportions can change depending on medications or dysfunction in the renal or GI systems. Most people with hyperuricemia are asymptomatic (85% to 90%), but elevated uric acid levels in the blood or urine can lead to gout or nephrolithiasis. Hyperuricemia and hyperuricosuria have also been linked with other disorders such as metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, atherosclerosis, obesity, and chronic renal disease.[2][3][4][5][6]

Uric Acid Overproduction Purine-rich diet: alcohol (especially beer); bacon; beef; lamb; turkey; veal; venison; organ meats; and certain fish and shellfish (anchovies, cod, tuna, sardines, herring, mussels, shrimp, lobster, codfish, scallops, trout, and haddock) Fructose causes hyperuricemia as its hepatic metabolism through the aldolase reductase pathway produces uric acid. High-fructose corn syrup and full-sugar sodas are especially harmful and are associated with obesity in children and adolescents. [7][8] Errors of purine metabolism: hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT) deficiency, phosphoribosylpyrophosphate (PRPP) synthetase overactivity. High cell breakdown or turnover: lymphoproliferative diseases, myeloproliferative disease, polycythemia vera, Paget disease, psoriasis, tumor lysis, hemolysis, rhabdomyolysis, extreme exercise, chemotherapy. Decreased Uric Acid Excretion Acute or chronic kidney disease, acidosis (eg, lactic acidosis, ketoacidosis), hypovolemia, medication/toxins (diuretics, niacin, pyrazinamide, ethambutol, cyclosporine, beryllium, salicylates, lead, alcohol), sarcoidosis, hyperparathyroidism, hypothyroidism, Bartter syndrome, Down syndrome.[9] Diuretic-induced Hyperuricemia Thiazide and loop diuretics tend to cause a dose-dependent type of hyperuricemia and possibly even gout.[10][11][12] They tend to increase renal uric acid reabsorption either directly or indirectly through volume depletion.[10][12][13][14] The net increase in relative risk of gout by diuretics is almost 80%.[15] An alternate or concurrent antihypertensive, including an angiotensin II receptor blocker (especially losartan) or an angiotensin-converting enzyme inhibitor, is recommended in patients with gout flares.[16][17][18][19][20][21][22] Most patients with diuretic-induced gout are treated with a xanthine oxidase inhibitor, such as allopurinol. However, if the patient is asymptomatic, no treatment is needed.

Up to 21% of the general population and 25% of hospitalized patients are estimated to have asymptomatic hyperuricemia, and uric acid levels can be elevated 10 to 15 years before clinical manifestations of gout.[23][24] Hyperuricemia does not indicate a pathological state because it is extremely prevalent in the general population and is asymptomatic in 90% to 95% of people.[25] The worldwide incidence of hyperuricemia is increasing in economically advantaged countries and the developing world as they adopt a Western diet and lifestyle.[23][26] Hyperuricemia is particularly high in Pacific islanders.[27] Men have higher rates than women, as estrogen is protective against hyperuricemia, and women can develop hyperuricemia after menopause.[28][29]

Clinical Manifestations Gout is a metabolic disorder that allows for the accumulation of uric acid in the blood and tissues. This leads to the precipitation of urate monohydrate crystals within a joint. Crystal deposition is enhanced in acidic and cold environments, leading to gout manifestations in peripheral joints, such as the big toe. Gout has a male predominance in a 4:1 ratio of men to women.[24] In uric acid nephrolithiasis, uric acid precipitates in the urine, most commonly due to acidic urine and metabolic syndrome. Acidic urine, hypovolemia, and hyperuricosuria are the most significant risk factors for uric acid nephrolithiasis. Hyperuricosuria is defined as uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. Uric acid stones comprise 5% to 10% of all urinary stones and can also have calcium components.[30] Hypertension is linked to hyperuricemia, even when adjusted for comorbidities of obesity and diabetes.[29][31][32] A large cross-sectional study showed that even at levels considered within the normal range (≥5.3 mg/dL in men, and ≥4.3 mg/dL in women), serum uric acid levels were directly related to hypertension after adjusting for other comorbidities. Mechanisms by which hyperuricemia may cause hypertension include activation of the renin-angiotensin system, oxidative stress, endothelial inflammation, endothelin-1 activation, and nitrous oxide reduction.[31][33] Obesity and hyperuricemia are also highly linked, and some analyses suggest that obesity is a cause of hyperuricemia. Proposed mechanisms are (1) visceral adipose tissue providing free fatty acids to the liver, inducing uric acid production and (2) dysregulation of adipocytes causing decreased uric acid and sodium excretion by the renal tubules. Small clinical trials have shown that urate-lowering drugs may decrease the development of hypertension in adolescents; however, these drugs can have serious adverse effects, so this is not recommended as treatment.[31]

Obesity and hyperuricemia are also highly linked, and some analyses suggest that obesity is a cause of hyperuricemia. Proposed mechanisms are (1) visceral adipose tissue providing free fatty acids to the liver, inducing uric acid production and (2) dysregulation of adipocytes causing decreased uric acid and sodium excretion by the renal tubules. Small clinical trials have shown that urate-lowering drugs may decrease the development of hypertension in adolescents; however, these drugs can have serious adverse effects, so this is not recommended as treatment.[31] Hyperuricemia is also highly associated with cardiac and renal disease. However, given the significant overlap among the risk factors for all 3 disease states, it is difficult to determine cause and effect.[32][33] One prospective study found that urate-lowering therapy did not decrease the development of CKD and was actually associated with worse kidney outcomes, so urate-lowering drugs are not indicated for primary prevention of kidney disease.[34][35] Mechanisms of Hyperuricemia Uric acid (2,6,8 thiopurine-C5H4N4O3) is the result of purine breakdown. At the normal physiological pH of 7.4, uric acid circulates in the ionized form of urate. Purine metabolism mainly occurs in the liver but can also happen in any tissue containing xanthine oxidase, such as cardiac or pulmonary tissue. About two-thirds of the body's total production of uric acid is excreted in the kidneys, and a third is passed into the intestine. Urate is filtered and secreted in the kidneys, then 90% is reabsorbed in the proximal tubule. Other mammals have much lower uric acid levels due to the activity of uricase, which converts urate to the more water-soluble allantoin. However, in humans and higher primates, this enzyme is nonfunctional.[36] Purine-rich diets, endogenous purine production, and high cell breakdown accelerate uric acid production. Beer, which is high in purines, especially increases uric acid levels.[37] Endogenous production of the purine production can be accelerated by phosphoribosylpyrophosphate (PRPP) synthetase activity and a defect in the regulatory enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).[38][39] Accelerated cell breakdown or turnover conditions include rhabdomyolysis, hemolysis, psoriasis, myeloproliferative disorders, and tumor lysis.[40] Urate Transport in the Kidney

Purine-rich diets, endogenous purine production, and high cell breakdown accelerate uric acid production. Beer, which is high in purines, especially increases uric acid levels.[37] Endogenous production of the purine production can be accelerated by phosphoribosylpyrophosphate (PRPP) synthetase activity and a defect in the regulatory enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).[38][39] Accelerated cell breakdown or turnover conditions include rhabdomyolysis, hemolysis, psoriasis, myeloproliferative disorders, and tumor lysis.[40] Urate Transport in the Kidney Urate excretion occurs primarily in the kidneys, and impaired urinary excretion is responsible for hyperuricemia in 90% of individuals. Underexcretion is a combination of decreased glomerular filtration, reduced tubular secretion, and enhanced tubular reabsorption. Proximal tubular reabsorption of uric acid is controlled by uric acid transporter 1 (URAT1) located in the apical cell membrane.[41][42] This transporter can be stimulated by organic acids (lactate, acetoacetate, and beta-hydroxybutyrate), medications (niacin, pyrazinamide, ethambutol, cyclosporin, and chemotherapeutic agents), and reduced extracellular fluid volume resulting in hyperuricemia.[2] URAT1 inhibitors are the most effective class of uricosuric agents available to treat hyperuricemia.[41] Urate is then transported into the renal interstitium by the GLUT9 transporter.[42]

Hyperuricemia can be visualized when monosodium urate crystals precipitate. Joint precipitation appears as the classic "needle-shaped crystals" seen in aspirated synovial fluid. Urinary uric acid will form crystals if urine pH is acidic (<5.5). These yellowish-brown crystals can be rhomboid or cluster to create a rosette shape.

History Hyperuricemia alone is not a specific indication for therapy (despite evidence linking it to the development of diabetes, hypertension, and cardiac disease). Most patients with elevated uric acid are asymptomatic and require no long-term therapy. The patient may give a history of a purine-rich diet or high alcohol consumption. Past medical history and current medications should be carefully reviewed for any correlation with poor renal excretion of urate or increased uric acid production. Gout and uric acid nephrolithiasis are the 2 most common complaints associated with hyperuricemia. During a gout attack, the patient complains of red, hot, swollen joints, often including the big toe (podagra).[43] The presentation of nephrolithiasis includes renal colic or severe, acute flank, abdominal, or back pain, often radiating to the groin; hematuria or brownish-colored urine; dysuria; and nausea and vomiting. Urinary tract symptoms, including fever, cloudy urine, and frequent urination, may also be present.[44] Physical Exam No specific physical exam findings will indicate hyperuricemia unless the patient presents with symptoms of acute gout attack or uric acid nephrolithiasis. With gout, there is evidence of an erythematous, warm, and swollen joint, most commonly affecting the big toe, but it can be present in any joint. Usually, gout affects only one joint at a time. Classically, this presents as "pain out of proportion to exam." Nephrolithiasis has no specific physical exam findings but may have reproducible costovertebral angle tenderness.

Laboratory Studies Elevated serum uric acid—normal values are typically less than 6.8 mg/dL and may vary by gender. Readings of 8 mg/dL or more are diagnostic of hyperuricemia. If nephrolithiasis is present, urinalysis may show microscopic hematuria, uric acid crystals, and low urinary pH (<5.5). A 24-hour urine uric acid collection should be optimally less than 600 mg/day on a low-purine diet. A level greater than 800 mg/d identifies hyperuricosuria but does not designate whether the cause is related to increased production or decreased excretion of uric acid. Other studies include a complete blood count (CBC) with differential, CMP, lipid profile, HgA1c, calcium, and phosphate levels. These laboratory studies are useful in assessing underlying diseases such as malignancy, sickle cell disease, diabetes, and metabolic syndrome. Consider joint x-rays to evaluate any unexplained swelling; however, x-ray findings are not required to diagnose gout. Renal ultrasounds or noncontrast CT scans are indicated in patients with suspected uric acid nephrolithiasis. The use of IV contrast can obscure the presence of stones. Procedures Consider joint aspiration to evaluate for uric acid crystals, which are needle-shaped and negatively birefringent under polarized microscopy.

Most patients with hyperuricemia are asymptomatic and do not need medical therapy, except for patients undergoing cytolytic therapy for malignancy to prevent tumor lysis syndrome.[45][46][47][48] This recommendation is based on the cost of unnecessary medications and the potential for adverse effects, which generally outweigh the benefit of starting medication in asymptomatic patients. The American College of Rheumatology recommends that patients with 2 or more gout attacks a year should be treated, but a lower threshold can be used based on the severity of the gout flares and patient preference.[49] Other indications for treatment include gouty bone erosion, structural joint injury, polyarticular disease, hyperuricosuric nephrolithiasis, and tophi. Colchicine is frequently used to treat acute gout.[50][51] It binds the tubulin protein, preventing microtubule formation and polymerization. It also has anti-inflammatory and anti-fibrotic effects.[52] See our companion StatPearls reference article on "Colchicine."[50] Patients starting uric acid lowering therapy should be considered for prophylactic colchicine to minimize the risk of an acute gouty flare. Slowly introducing hyperuricemia medications can also decrease the risk of gout flare attacks.[53] There are three types of uric acid-lowering medications: uricosuric agents, xanthine oxidase inhibitors, and recombinant uricases. Among these, only five are FDA-approved for use in the US: allopurinol, febuxostat, probenecid, rasburicase, and pegloticase. Uricosuric agents work by increasing the renal and urinary excretion of uric acid. Normally, 10% of filtered uric acid is excreted in the urine. Uricosuric agents work by inhibiting the URAT1 anion-exchanging uric acid transporter system in the brush border of renal proximal tubular cells.[54] This causes increased urinary excretion with a corresponding drop in serum uric acid levels. These agents are not generally suitable for patients with hyperuricosuric nephrolithiasis and are most useful when urinary uric acid is less than 800 mg daily. Losartan, atorvastatin, and fenofibrate have mild uricosuric effects and can be considered adjunctive agents in patients with hypertension (losartan) or hyperlipidemia (atorvastatin, fenofibrate).[16][55][56]

Uricosuric agents work by increasing the renal and urinary excretion of uric acid. Normally, 10% of filtered uric acid is excreted in the urine. Uricosuric agents work by inhibiting the URAT1 anion-exchanging uric acid transporter system in the brush border of renal proximal tubular cells.[54] This causes increased urinary excretion with a corresponding drop in serum uric acid levels. These agents are not generally suitable for patients with hyperuricosuric nephrolithiasis and are most useful when urinary uric acid is less than 800 mg daily. Losartan, atorvastatin, and fenofibrate have mild uricosuric effects and can be considered adjunctive agents in patients with hypertension (losartan) or hyperlipidemia (atorvastatin, fenofibrate).[16][55][56] Probenecid inhibits URAT1 and several other anion transporters, increasing renal uric acid excretion by reducing reabsorption.[57] It is typically used as second-line therapy for gout as it is considered less potent than other uric acid-lowering medications.[58] Probenecid can be used in patients who cannot tolerate xanthine oxidase inhibitors and is often used with colchicine for gout prophylaxis. It has many drug interactions limiting its clinical use.[58][59] Probenecid can also increase the incidence of uric acid nephrolithiasis, so this should be closely monitored. It is also relatively contraindicated in patients with grade 3 or higher CKD. Benzbromarone is a URAT1 inhibitor type uricosuric drug used for gout and hyperuricemia in some countries but was unapproved in the US and Europe due to hepatotoxicity.[60][61] While it is a potent URAT1 inhibitor and a more effective uricosuric agent than probenecid, it has low selectivity.[60][62] Dotinurad is a highly selective URAT1 inhibitor and effective uricosuric agent available only in Japan that appears to be equivalent to benzbromarone and febuxostat in overall uric acid-lowering ability.[63][64][65][66][67] It is being evaluated for possible approval in the US and Europe. Lesinurad is another uricosuric URAT1 inhibitor drug that significantly increases urinary uric acid excretion, thereby substantially lowering serum uric acid levels.[68][69][70] The manufacturers discontinued production of this drug in 2019 due to business considerations and concern for profit margins.

Dotinurad is a highly selective URAT1 inhibitor and effective uricosuric agent available only in Japan that appears to be equivalent to benzbromarone and febuxostat in overall uric acid-lowering ability.[63][64][65][66][67] It is being evaluated for possible approval in the US and Europe. Lesinurad is another uricosuric URAT1 inhibitor drug that significantly increases urinary uric acid excretion, thereby substantially lowering serum uric acid levels.[68][69][70] The manufacturers discontinued production of this drug in 2019 due to business considerations and concern for profit margins. Xanthine oxidase inhibitors block the hepatic oxidation of xanthine to uric acid.[71] Xanthine does not cause gout, is non-toxic until very high concentrations, and is much more soluble in urine than uric acid.[71] See our companion StatPearls reference article on "Biochemistry, Xanthine Oxidase."[72] Allopurinol is a purine-based structural analog of hypoxanthine that acts as a xanthine oxidase inhibitor.[73] It is the preferred agent for patients with symptomatic hyperuricemia, gout, and hyperuricosuric nephrolithiasis.[71] It is also used as prophylaxis against gouty arthritis and chemotherapy-related hyperuricemia. It is effective and inexpensive, but treatment usually is lifelong. Compared to febuxostat, allopurinol appears to offer superior renal protection.[74] For tumor lysis syndrome prophylaxis, allopurinol should be started two or three days before initiating chemotherapy and continued for up to a week after the chemotherapy course.[71] See our companion StatPearls reference article on "Allopurinol."[71] The overall use of allopurinol is suboptimal, as many patients with gout either do not receive long-term treatment or are significantly underdosed.[75]

Allopurinol is a purine-based structural analog of hypoxanthine that acts as a xanthine oxidase inhibitor.[73] It is the preferred agent for patients with symptomatic hyperuricemia, gout, and hyperuricosuric nephrolithiasis.[71] It is also used as prophylaxis against gouty arthritis and chemotherapy-related hyperuricemia. It is effective and inexpensive, but treatment usually is lifelong. Compared to febuxostat, allopurinol appears to offer superior renal protection.[74] For tumor lysis syndrome prophylaxis, allopurinol should be started two or three days before initiating chemotherapy and continued for up to a week after the chemotherapy course.[71] See our companion StatPearls reference article on "Allopurinol."[71] The overall use of allopurinol is suboptimal, as many patients with gout either do not receive long-term treatment or are significantly underdosed.[75] Allergic reactions to allopurinol have been reported in up to 25% of patients. Such reactions include rashes, itching, hives, and blistering skin.[76][77] Allopurinol hypersensitivity syndrome, a much more severe allergic reaction, presents with Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, renal failure, hepatic injury, and eosinophilia.[78] The risk is 1:1,000 patients, and the reported mortality is 20% to 25%.[59] Individuals of Han Chinese, Thai, and Korean ethnicity and African Americans have a much greater risk of a specific genetic predisposition (HLA-B*58:01 allele) for this hypersensitivity response.[79] Genetic testing for HLA-B*58:01 should be considered for individuals of these ethnic groups before starting allopurinol therapy.[79]  Patients with pre-existing renal failure are also at higher risk of developing allopurinol hypersensitivity syndrome.[78][80] This can be minimized by starting patients on a very low dose of <50 mg (<1.5 mg per mL/min of creatinine clearance) and titrating it upwards very gradually (such as every two to four weeks).[80]

Allergic reactions to allopurinol have been reported in up to 25% of patients. Such reactions include rashes, itching, hives, and blistering skin.[76][77] Allopurinol hypersensitivity syndrome, a much more severe allergic reaction, presents with Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, renal failure, hepatic injury, and eosinophilia.[78] The risk is 1:1,000 patients, and the reported mortality is 20% to 25%.[59] Individuals of Han Chinese, Thai, and Korean ethnicity and African Americans have a much greater risk of a specific genetic predisposition (HLA-B*58:01 allele) for this hypersensitivity response.[79] Genetic testing for HLA-B*58:01 should be considered for individuals of these ethnic groups before starting allopurinol therapy.[79]  Patients with pre-existing renal failure are also at higher risk of developing allopurinol hypersensitivity syndrome.[78][80] This can be minimized by starting patients on a very low dose of <50 mg (<1.5 mg per mL/min of creatinine clearance) and titrating it upwards very gradually (such as every two to four weeks).[80] Febuxostat is a non-purine-based xanthine oxidase inhibitor primarily used for patients who fail or cannot tolerate allopurinol. At standard dosages, febuxostat appears to have superior uric acid lowering ability than allopurinol and can be used in patients with a creatinine clearance as low as 15 mL/min.[81] However, compared to allopurinol, patients on febuxostat demonstrated a 34% higher risk of cardiovascular mortality and 22% higher overall mortality, prompting the FDA to issue a limited-use recommendation in 2019.[82] See our companion StatPearls reference article on "Febuxostat."[83] Topiroxostat is a xanthine oxidase inhibitor that, unlike allopurinol and febuxostat, is a non-purine agent. It is currently only approved for use in Japan. Unlike allopurinol, topiroxostat is unaffected by renal failure and can be used effectively in patients with chronic kidney disease. It was first approved for use in Japan in 2013. A post-marketing study of almost 4,500 patients over 5 years demonstrated efficacy and safety with no significant adverse drug reactions.[84]

Topiroxostat is a xanthine oxidase inhibitor that, unlike allopurinol and febuxostat, is a non-purine agent. It is currently only approved for use in Japan. Unlike allopurinol, topiroxostat is unaffected by renal failure and can be used effectively in patients with chronic kidney disease. It was first approved for use in Japan in 2013. A post-marketing study of almost 4,500 patients over 5 years demonstrated efficacy and safety with no significant adverse drug reactions.[84] Recombinant uricase drugs are intended for chronic gout inadequately controlled by xanthine oxidase inhibitors or uricosuric agents alone. It is estimated that about 2% of all patients with gout may be refractory to standard therapy.[85] Such patients either have intractable hyperuricemia, two or more gout attacks while on therapy, or persistent subcutaneous tophi unresponsive to maximum dosages of conventional therapy.[86] Uricase drugs work by enzymatically converting uric acid to the water-soluble, non-toxic, purine metabolite allantoin, which is then readily excreted by the kidneys.[87] Other than humans and higher primates, most mammals naturally produce uricase and have much lower normal uric acid. Recombinant uricase drugs do not interfere with uric acid production or change its excretion. They are very effective in lowering uric acid in serum and urine. Rasburicase was the first recombinant uricase to treat significant hyperuricemia from tumor lysis syndrome.[36] It was FDA-approved in 2002 for temporarily managing hyperuricemia in cancer patients with leukemia, lymphoma, and solid malignant lesions receiving chemotherapy likely to cause tumor lysis syndrome that would otherwise cause extremely high serum uric acid levels.[36] It works quickly (within 4 hours). It effectively controls uric acid levels in tumor lysis syndrome and avoids hemodialysis. Still, it is expensive, has a short half-life of 16 to 21 hours, and promotes the rapid development of antibodies to the drug.[88][89][90][91][92][93] See our companion StatPearls reference article on "Tumor Lysis Syndrome."[94] Pegloticase is a recombinant uricase (uric acid oxidase) that was FDA-approved in 2010 for chronic gout refractory to standard therapy.[87][95] (Its marketing authorization was discontinued in the European Union in 2016 due to business and commercial reasons.)

It works quickly (within 4 hours). It effectively controls uric acid levels in tumor lysis syndrome and avoids hemodialysis. Still, it is expensive, has a short half-life of 16 to 21 hours, and promotes the rapid development of antibodies to the drug.[88][89][90][91][92][93] See our companion StatPearls reference article on "Tumor Lysis Syndrome."[94] Pegloticase is a recombinant uricase (uric acid oxidase) that was FDA-approved in 2010 for chronic gout refractory to standard therapy.[87][95] (Its marketing authorization was discontinued in the European Union in 2016 due to business and commercial reasons.) To decrease immune reactivity and extend the half-life, an inert polyethylene glycol (PEG) was chemically attached to the rasburicase enzyme, making it "pegylated" and leading to pegloticase.[85][96][97][98] The half-life is longer than rasburicase at 8.5 days but remains highly immunogenic, requiring concomitant methotrexate as an immunosuppressive.[85] Pegloticase was created using a genetically altered variant of E. coli. Effectiveness was demonstrated in two multinational, six-month, randomized, double-blinded, placebo-controlled trials.[99][100] In addition to significantly lowering serum uric acid levels, pegloticase has been shown to shrink and resolve tophi, decrease joint pain, improve swelling, and even significantly reduce blood pressure in hyperuricemic patients without affecting kidney function.[85][100] Patients on pegloticase can develop infusion reactions and antidrug antibodies that reduce its effectiveness.[85] These side effects can be eliminated by stopping the medication when it starts to lose efficacy or at the start of an adverse reaction, as well as by using immunosuppressive drugs such as methotrexate.[85][101] The combination of pegloticase with methotrexate showed markedly increased response over pegloticase alone (71% vs. 38.5%) with similar adverse effects and much lower rates of infusion reactions and antidrug antibody production.[95][101][102] Gout flares are common (88%) when initiating pegloticase therapy.[100] Pegloticase is costly, and anaphylaxis has been reported.

The combination of pegloticase with methotrexate showed markedly increased response over pegloticase alone (71% vs. 38.5%) with similar adverse effects and much lower rates of infusion reactions and antidrug antibody production.[95][101][102] Gout flares are common (88%) when initiating pegloticase therapy.[100] Pegloticase is costly, and anaphylaxis has been reported. Folic acid supplementation should be started at least four weeks before beginning therapy. Other uric acid-lowering medications should be discontinued before starting pegloticase. Before every infusion, uric acid serum levels should be monitored, and patients should be premedicated with antihistamines and corticosteroids.[95] It is contraindicated in patients with glucose-6-phosphate deficiency and is not recommended for asymptomatic patients.[95] See our companion StatPearls reference article on "Pegloticase."[95] Treatment Summary Allopurinol is the preferred initial treatment for hyperuricemia. If this is ineffective or not tolerated, then febuxostat is recommended. Dosage is adjusted until optimal serum (<6 mg/dL) or 24-hour urine (<600 mg/day) uric acid levels are achieved.[71][103][104] Febuxostat is recommended if allopurinol is not well tolerated, ineffective, or if there is a genetic risk of allopurinol hypersensitivity syndrome. In uric acid urolithiasis, treatment primarily reduces urinary acidity (to pH >6.5) with potassium citrate or sodium bicarbonate rather than just reducing hyperuricosuria.[103] Increasing urinary volume is also recommended. See our companion StatPearls reference article on "Uric Acid Nephrolithiasis" and "Hyperuricosuria."[103][105] In hyperuricosuric calcium nephrolithiasis, treatment is focused on optimizing urinary citrate with potassium citrate (urinary citrate goal is 500-600 mg/day) and reducing uric acid urinary excretion (usually with allopurinol).[104][106] Probenecid with or without colchicine can be used for gout prophylaxis but is not recommended for patients with uric acid nephrolithiasis or hyperuricosuria (>800 mg urinary uric acid/24 hours). Pegloticase can be used for otherwise intractable, symptomatic hyperuricemia in patients with ineffective or intolerable alternative treatments.[95] Rasburicase is recommended for temporary use in acute hyperuricemia due to tumor lysis syndrome but not for gout.[36]

Hyperuricemia alone does not cause clinical symptoms. However, other conditions can cause the symptoms of gout or nephrolithiasis often seen with elevated uric acid. Some of these conditions are rheumatoid arthritis, pseudogout (calcium pyrophosphate deposition disease), arthritis, hypothyroidism, alcoholic ketoacidosis, non-urate-based nephrolithiasis, hemolytic anemia, hyperparathyroidism, and malignancies.

Most patients with hyperuricemia are asymptomatic. Patients can be easily treated with several medication classes if they develop symptoms. There is evidence that hyperuricemia is a precursor to the development of hypertension, metabolic disease, diabetes, and cardiovascular and renal disease, but a definitive causal link has not been established. Urate-lowering therapy for asymptomatic patients is not yet standard.

Hyperuricemia primarily is known to have complications related to nephrolithiasis and gout. Some of the potential side effects include: Bone loss Chronic kidney disease Gout Hypertension Joint damage and deformity Tophi deposits Loss of mobility Nephrolithiasis (uric acid and calcium oxalate) Restricted range of motion Skin rashes Allopurinol sensitivity syndrome

Patients with symptomatic hyperuricemia (gout, uric acid stones, or hyperuricosuric calcium nephrolithiasis) should be on prophylactic treatment, usually starting with allopurinol. Patients at risk for a flare, especially those with renal failure, should be started on a low dose of uric acid-lowering agents and gradually titrated upwards.[80] Dietary education should be prioritized regarding a low-purine, low-salt, and low-fructose diet. Many patients will benefit from seeing a dietician regularly.

Key facts regarding hyperuricemia are listed below. Most patients with gout are not on optimal doses of their uric acid-lowering medications.[75]  Many patients will need higher doses than the typical 300 mg daily to achieve optimal serum levels of 6 mg/dL or less.[75] Allopurinol hypersensitivity syndrome is a rare but potentially fatal reaction.[59] African Americans and individuals of Chinese, Korean, and Thai ancestry should be tested for the HLA-B*58:01 allele, which predisposes them to this dangerous hypersensitivity reaction, before starting allopurinol therapy.[79] Allopurinol should be avoided in those who test positive for this gene. Patients with chronic kidney disease are also at higher risk.[78][80] In these patients, use low doses of allopurinol initially and gradually titrate upwards only every 2-4 weeks.[80] Pegloticase should generally only be used with methotrexate.[95] Stop all other uric acid-lowering drugs and start folic acid supplementation.[95] At every infusion, patients should be premedicated with steroids and antihistamines.[95] In patients with chronic kidney disease, xanthine oxidase inhibitors are generally preferred, but possibly at a lower starting dose. Among uricosuric agents, only benzbromarone  (not available in the United States and Europe)can be used in patients with significant chronic kidney disease. Patients with diuretic-induced hyperuricemia and gout can be treated with losartan or allopurinol but do not need any therapy if they are asymptomatic.

Because there are many causes of hyperuricemia, the condition is best managed by an interprofessional team that may include internists, primary care providers, endocrinologists, urologists, rheumatologists, and oncologists. Most patients are asymptomatic and do not need medical therapy for hyperuricemia. The cost of unnecessary drugs and the potential for adverse effects outweigh the benefit of starting medication for most asymptomatic patients with hyperuricemia. Uric acid-lowering medications in such patients are only indicated in those undergoing cytolytic therapy for malignancy to prevent tumor lysis syndrome.[107][108] The outlook for benign causes of hyperuricemia is good, but those with malignancy may develop complications like gout or renal