Hyperuricemia

In the body, uric acid is the final product of purine metabolism. Synthesis of uric acid occurs mainly in the liver, and to a small degree in the small intestine. Normally, two thirds of uric acid excretion occurs through the kidneys and one third through the intestines.[4]  Uric acid in the blood is saturated at 6.4-6.8 mg/dL at ambient conditions, with the upper limit of solubility placed at 7 mg/dL.

In the kidney, urate is freely filtered at the glomerulus, reabsorbed, secreted, and then again reabsorbed in the proximal tubule. The cloning of certain urate transporters will facilitate the understanding of specific mechanisms by which urate is handled in the kidney and small intestines.

A urate/anion exchanger (URAT1) has been identified in the brush-border membrane of the kidneys and is inhibited by an angiotensin II receptor blocker, losartan.[5] A human organic anion transporter (hOAT1) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs,[6] while another urate transporter (UAT) has been found to facilitate urate efflux out of the cells.[7] These transporters may account for the reabsorption, secretion, and reabsorption pattern of renal handling of urate.

Intestinal excretion of urate is handled by uric acid transporters in intestinal epithelial cells, which transport uric acid from the blood to the intestinal lumen. Multiple transporters participate in this process, but mainly ABCG2 and SLC2A9. Intestinal excretion also involves the catabolism of uric acid by intestinal flora.[4]

Urate excretion does appear to correlate with the serum urate concentration because a small increase in the serum concentration results in a marked increase in urate excretion.

Hyperuricemia may occur because of decreased excretion (underexcretors), increased production (overproducers), or a combination of those two mechanisms.

Underexcretion accounts for most causes of hyperuricemia. Urate handling by the kidneys involves filtration at the glomerulus, reabsorption, secretion, and, finally, postsecretory reabsorption. Consequently, altered uric acid excretion can result from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption.

While decreased urate filtration may not cause primary hyperuricemia, it can contribute to the hyperuricemia of kidney insufficiency. Decreased tubular secretion of urate occurs in patients with acidosis (eg, diabetic ketoacidosis, ethanol or salicylate intoxication, starvation ketosis). The organic acids that accumulate in these conditions compete with urate for tubular secretion. Finally, enhanced reabsorption of uric acid distal to the site of secretion is the mechanism thought to be responsible for the hyperuricemia observed with diuretic therapy and diabetes insipidus.

Overproduction accounts for only a minority of patients presenting with hyperuricemia. The causes for hyperuricemia in overproducers may be either exogenous (diet rich in purines) or endogenous (increased purine nucleotide breakdown). A small percentage of overproducers have enzymatic defects that account for their hyperuricemia. These include a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) as in Lesch-Nyhan syndrome, partial deficiency of HGPRT (Kelley-Seegmiller syndrome), and increased production of 5-phospho-alpha-d-ribosyl pyrophosphate (PRPP) activity. Accelerated purine degradation can result from rapid cell proliferation and turnover (blast crisis of leukemias) or from cell death (rhabdomyolysis, cytotoxic therapy). Glycogenoses types III, IV, and VII can result in hyperuricemia from excessive degradation of skeletal muscle adenosine triphosphate (ATP).

Combined mechanisms (underexcretion and overproduction) can also cause hyperuricemia. The most common cause under this group is alcohol consumption,[8] which results in accelerated hepatic breakdown of ATP and the generation of organic acids that compete with urate for tubular secretion. Enzymatic defects such as glycogenoses type I and aldolase-B deficiency are other causes of hyperuricemia that result from a combination of overproduction and underexcretion.

Urate crystals can engage an intracellular pattern recognition receptor, the macromolecular NALP3 (cryopyrin) inflammasome complex.[9, 10] NALP3 inflammasome may result in interleukin 1 (IL-1) beta production, which, in turn, incites an inflammatory response. Inhibition of this pathway has been targeted as a treatment for hyperuricemia-induced crystal arthritis, with reports documenting the efficacy of the IL-1 inhibitors canakinumab and rilonacept for preventing gout flares during the initiation of allopurinol therapy.[11]

Zinc and magnesium are important nutrients with anti-inflammatory properties. Studies have linked low dietary levels to hyperuricemia in men. A study by Xie et al in 2697 men and 2471 women indicated that dietary zinc intake was inversely associated with hyperuricemia in middle-aged and older men, but not in women.[12] Wang et al reported that in 5168 subjects, dietary magnesium intake was inversely associated with hyperuricemia, independent of some major confounding factors, but only in men.[13] Studies of approximately 25,000 adults in the United States, using data from the National Health and Nutrition Examination Survey (NHANES), found that in both men and women, lower magnesium and zinc intake was associated with increased hyperuricemia risk.[14, 15]

Hyperuricemia is generally divided into the following three pathophysiologic categories:

• Uric acid underexcretion
• Uric acid overproduction
• Combined causes

Underexcretion

Causes of uric acid underexcretion include the following:

• Idiopathic

• Familial juvenile gouty nephropathy: This is a rare autosomal dominant condition characterized by progressive renal insufficiency. Affected persons have a low fractional excretion of urate (typically 4%). Kidney biopsy findings indicate glomerulosclerosis and tubulointerstitial disease but no uric acid deposition.

• Kidney insufficiency: Kidney failure is one of the more common causes of hyperuricemia. In chronic kidney disease, the uric acid level does not generally become elevated until the creatinine clearance falls below 20 mL/min, unless other contributing factors exist. This is due to a decrease in urate clearance as retained organic acids compete for secretion in the proximal tubule. In certain kidney disorders, such as medullary cystic disease and chronic lead nephropathy, hyperuricemia is commonly observed even with minimal kidney insufficiency.

• Metabolic syndrome: This syndrome is characterized by hypertension, obesity, insulin resistance, dyslipidemia, and hyperuricemia,[16]  and is associated with a decreased fractional excretion of urate by the kidneys.

• Drugs: Causative drugs include diuretics, low-dose salicylates, cyclosporine, pyrazinamide, ethambutol, levodopa, and nicotinic acid.

• Hypertension

• Acidosis: Types that cause hyperuricemia include lactic acidosis, diabetic ketoacidosis, alcoholic ketoacidosis, and starvation ketoacidosis.

• Preeclampsia and eclampsia: The elevated uric acid associated with these conditions is a key clue to the diagnosis because in healthy pregnancies, uric acid levels are lower than normal.

• Hypothyroidism

• Hyperparathyroidism

• Sarcoidosis

• Lead intoxication (chronic): History may reveal occupational exposure (eg, lead smelting, battery and paint manufacture) or consumption of moonshine (ie, illegally distilled corn whiskey) because some, but not all, moonshine was produced in lead-containing stills).

• Trisomy 21

Overproduction

Uric acid overproduction may be idiopathic. Known causes include the following:

• Hypoxanthine guanine phosphoribosyltransferase (HGPRT) deficiency (Lesch-Nyhan syndrome): This is an inherited X-linked disorder. HGRPT catalyzes the conversion of hypoxanthine to inosinic acid, in which PRPP serves as the phosphate donor. The deficiency of HGPRT results in accumulation of 5-phospho-alpha-d-ribosyl pyrophosphate (PRPP), which accelerates purine biosynthesis with a resultant increase in uric acid production. In addition to gout and uric acid nephrolithiasis, these patients develop a neurologic disorder that is characterized by choreoathetosis, spasticity, growth, mental function retardation, and, occasionally, self-mutilation.

• Partial deficiency of HGPRT (Kelley-Seegmiller syndrome): This is also an X-linked disorder. Patients typically develop gouty arthritis in the second or third decade of life, have a high incidence of uric acid nephrolithiasis, and may have mild neurologic deficits.

• Increased activity of PRPP synthetase: This is a rare X-linked disorder in which patients make mutated PRPP synthetase enzymes with increased activity. These patients develop gout when aged 15-30 years and have a high incidence of uric acid kidney stones.

• Diet: A diet rich in high-purine meats, organ foods, and legumes can result in an overproduction of uric acid.

• Increased nucleic acid turnover: This may be observed in persons with hemolytic anemia and hematologic malignancies such as lymphoma, myeloma, or leukemia.

• Tumor lysis syndrome: This may produce the most serious complications of hyperuricemia.

• Glycogenoses III, V, and VII

• Exposure to persistent organic pollutants (eg, organochlorine pesticides)[17]

Combined causes

Combined causes include the following:

• Alcohol[8] : Ethanol increases the production of uric acid by causing increased turnover of adenine nucleotides. It also decreases uric acid excretion by the kidneys, which is partially due to the production of lactic acid.

• Fructose-sweetened soft drinks: Fructose raises serum uric acid levels by accentuating degradation of purine nucleotides and increasing purine synthesis, and epidemiologic studies have documented a link between sugar-sweetened soft drink intake and serum uric acid levels in several populations.[18, 19, 20, 21]  More recently, Lecoultre et al found that fructose-induced hyperuricemia is associated with a decreased uric acid excretion by the kidneys.[22]

• Exercise: Exercise may result in enhanced tissue breakdown and decreased kidney excretion due to mild volume depletion.

• Deficiency of aldolase B (fructose-1-phosphate aldolase): This is a fairly common inherited disorder, often resulting in gout.

• Glucose-6-phosphatase deficiency (glycogenosis type I, von Gierke disease): This is an autosomal recessive disorder characterized by the development of symptomatic hypoglycemia and hepatomegaly within the first 12 months of life. Additional findings include short stature, delayed adolescence, enlarged kidneys, hepatic adenoma, hyperuricemia, hyperlipidemia, and increased serum lactate levels.

According to the National Health and Nutrition Examination Survey (2007-2016), the prevalence rate of hyperuricemia in the general population of the United States is estimated at 20%. The prevalence of gout is 5.2% in men and 2.7% in women, with the rates for both remaining stable over the decade.[23]

Worldwide, the prevalence of hyperuricemia has increased substantially in recent decades. The progressive increase in serum levels of uric acid levels may be linked to the rising prevalence of overweight and obesity, as well as the increase in consumption of sugar-sweetened beverages, foods rich in purines, and alcohol.[24, 25]

A Japanese study that used an administrative claims database to ascertain 10-year trends in the prevalence of hyperuricemia concluded that the prevalence of hyperuricemia in the overall study population increased during the 10-year follow-up. When stratified by age, the prevalence increased among groups older than 65 years in both sexes. In those younger than 65 years, men had a prevalence 4 times higher than that in women, but in those older than 65 years, the gender gap narrowed to 1:3 (female-to-male ratio) with gout and/or hyperuricemia.

A high prevalence of hyperuricemia exists in indigenous races of the Pacific, which appears to be associated with a low fractional excretion of uric acid.[26] In the United States, Blacks develop hyperuricemia more commonly than whites.

Hyperuricemia, and particularly gouty arthritis, are far more common in men than in women. Only 5% of patients with gout are female, but uric acid levels increase in women after menopause.[27]

The normal serum uric acid level is lower in children than in adults. The upper limit of the reference range for children is 5 mg/dL (0.30 mmol/L). The upper limit of the reference range for men is 7 mg/dL (0.42 mmol/L) and for women is 6 mg/dL (0.36 mmol/L).[28] The tendency to develop hyperuricemia increases with age.

Hyperuricemia has a higher prevalence (25-40%) in individuals with hypertension and has been associated with increased morbidity in these patients.[29]  In a study of 837 elderly patients with hypertension followed up over 3.5 years, Lin et al found that increases in uric acid levels were independently associated with decline in renal function.[30]  Ding et al reported that serum uric acid concentration and prevalence of hyperuricemia were positively associated with osteoarthritis of the knee in a cohort of Chinese women.[31]

The cause for these associations is unknown, but hyperuricemia is probably a marker for comorbid risk factors rather than a causative factor, per se. Results of a cross-sectional study by Yang et al suggested that levels of high-sensitivity C-reactive protein (a nonspecific marker for inflammation) are positively associated with the prevalence of hyperuricemia.[32]

Although observational studies on hyperuricemia and stroke have yielded conflicting results, a meta-analysis by Li et al concluded that hyperuricemia may modestly increase the risk of stroke incidence and mortality.[33]  The authors reviewed 15 studies that together included 22,571 cases of stroke and 1,042,358 participants. The risk ratio (RR) for the incidence of stroke in patients with hyperuricemia was 1.22 (95% CI, 1.02-1.46) and the RR for mortality was 1.33 (95% CI, 1.24-1.43). The pooled estimate of multivariate RRs of both stroke incidence and mortality were higher in women than in men (1.25 vs 1.08 and 1.41 vs  1.26, respectively).[33]

Possible complications of hyperuricemia include the following:

• Gout
• Acute uric acid nephropathy
• Uric acid nephrolithiasis
• Chronic kidney disease ^[34]

In patients with hyperuricemia, the history involves determining whether the patient is symptomatic or asymptomatic and identifying causative etiologies and comorbid conditions.

Symptoms are those of gout and nephrolithiasis, as follows:

• Gout typically manifests as an acute monoarthritis, most commonly in the great toe and less frequently in the tarsal joint, knee, and other joints.

• Uric acid nephrolithiasis may manifest as hematuria; pain in the flank, abdomen, or inguinal region; and/or nausea and vomiting

Patients are usually asymptomatic, and no specific physical findings are recognized. Symptomatic presentations may include the following:

• In acute gouty arthritis, the affected joint is typically warm, erythematous, swollen, and exquisitely painful

• Patients with chronic gouty arthritis may develop tophi in the helix or antihelix of the ear, along the ulnar surface of the forearm, in the olecranon bursa, or in other tissues

• In uric acid nephrolithiasis, patients may present with abdominal or flank tenderness

Laboratory studies may include the following:

• Serum uric acid

• Complete blood cell count (CBC): Values may be abnormal in patients with hemolytic anemia, hematologic malignancies, or lead poisoning.

• Electrolytes, blood urea nitrogen (BUN), and serum creatinine values: These are abnormal in patients with acidosis or renal disease.

• Liver function tests: These are part of the general workup for patients with a possible malignancy or metabolic disorders; in addition, the results are useful as a baseline if allopurinol is used for treatment

• Serum glucose level: This may be abnormal in patients with diabetes or glycogen storage diseases.

• Lipid profile: Results are abnormal in those with dyslipidemia.

• Calcium and phosphate levels: This measurement is needed for the workup of hyperparathyroidism, sarcoidosis, myeloma, and kidney disease.

• Thyroid-stimulating hormone level: Obtain this value to help rule out hypothyroidism.

• Urinary uric acid excretion

• Fractional excretion of urate on a low-purine diet

• Spot urine ratio of uric acid to creatinine

Urinary uric acid secretion

If uric acid levels are found to be persistently elevated, an estimation of total uric acid excretion may be needed. The estimation of uric acid excretion is recommended in young males who are hyperuricemic, females who are premenopausal, patients with a serum uric acid value greater than 11 mg/dL, and patients with gout.

One protocol recommends obtaining two 24-hour urine collections for creatinine clearance and uric acid excretion. The first collection is performed while patients are on their usual diet and alcohol intake. At the end of the first 24-hour collection, serum creatinine and urate levels are checked for an estimation of the creatinine clearance. The patient then goes on a low-purine, alcohol-free diet for 6 days, with a repeat 24-hour urine collection performed on the last day, followed by a serum creatinine and uric acid evaluation.

On the basis of the 24-hour urine uric acid levels before and after the purine-restricted diet, patients who are hyperuricemic can be categorized into the following three groups:

• High-purine intake - Prediet value greater than 6 mmol/d, postdiet value less than 4 mmol/d
• Overproducers - Prediet value greater than 6 mmol/d, postdiet value greater than 4.5 mmol/d
• Underexcretors - Prediet value less than 6 mmol/d, postdiet value less than 2 mmol/d

Fractional excretion of urate on a low-purine diet

This test should be used to investigate the degree of underexcretion in patients with hyperuricemia or gout in patients for whom the cause cannot be determined. The fractional excretion of urate is calculated by the following formula:

Fractional excretion of urate = [(urine uric acid)×(serum creatinine)×(100%)]÷[(serum uric acid)×(urine creatinine)]

The reference intervals for patients on a low-purine diet and normal renal function are as follows:

• Males - 7-9.5%
• Females - 10-14%
• Children - 15-22%

Values less than the lower limits of the reference range indicate underexcretion. The formula also circumvents any inaccuracy that may have occurred during urine collection.

Spot urine ratio of uric acid to creatinine 

If a 24-hour urine collection is not possible, measure the ratio of uric acid to creatinine from a spot urine collection. A ratio greater than 0.8 indicates overproduction.

The ratio also helps differentiate acute uric acid nephropathy from the hyperuricemia that occurs secondary to renal failure. The ratio is greater than 0.9 in acute uric acid nephropathy and usually less than 0.7 in hyperuricemia secondary to kidney insufficiency.

In patients with gout, radiographs may reveal evidence of joint swelling and subcortical cysts. In patients with hyperuricemia and kidney disease, a renal sonogram is an important tool for kidney evaluation. Images from this study also may reveal the presence of uric acid stones.

Joint aspiration may be important in the diagnosis of acute gouty arthritis, in which uric acid crystals are found to be negatively birefringent under polarized microscopy.

Asymptomatic hyperuricemia

Most patients with asymptomatic hyperuricemia never develop gout or stones. Pharmacologic treatment for asymptomatic hyperuricemia carries some risk, is not considered beneficial or cost-effective, and generally is not recommended. However, these patients can be advised on lifestyle changes such as changes in diet, reduction in alcohol intake, and exercise, which may lower uric acid levels.[35] The exception to this is in an oncologic setting, in which patients receiving cytolytic treatment may receive prophylaxis against acute uric acid nephropathy.

In addition to avoiding foods that are high in purines, dietary measures may include ensuring adequate magnestium and zinc intake, as higher intake is associated with decreased hyperuricemia risk.[14, 15] Use of probiotics (eg, Bifidobacteria,Lactobacilli) may promote purine and uric acid catabolism by the gut microbiota.[36, 37]

Symptomatic hyperuricemia

The clinical scenarios under which hyperuricemia can be symptomatic are gout, uric acid stones, or uric acid nephropathy.

Acute gouty arthritis

The initial goal in acute gouty arthritis is to provide symptomatic relief from pain. Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. NSAIDs are prescribed for approximately a 7- to 10-day course or until 3-4 days after all signs of inflammation have resolved. Use NSAIDs with caution or avoid them in patients in edematous states, such as heart failure, and in patients with peptic ulcer disease or kidney insufficiency.

Colchicine, which inhibits neutrophil activation, is effective but is currently used less frequently because of its adverse effects. Traditionally, colchicine is administered as a 0.6-mg dose every hour until improvement occurs, adverse gastrointestinal effects occur, or a total of 10 doses is reached and no relief is noted. The adverse gastrointestinal effects include abdominal pain, diarrhea, and nausea, which occur in most patients started on colchicine. Although colchicine can be administered intravenously, this is usually avoided because of its potential for serious toxicity.

Use intra-articular glucocorticoids in patients with contraindications to NSAID or colchicine use. Occasionally, intra-articular glucocorticoids may be used in patients with gouty arthritis refractory to NSAIDs or colchicine. 

Chronic gout therapy

After the symptoms of acute gout subside, patients enter the intercritical period during which a decision must be made regarding the need for treatment with a urate-lowering medication. One important point to consider is that abrupt lowering of urate levels can precipitate an attack of acute gout during the intercritical period. Thus, these patients should receive prophylactic colchicine coverage irrespective of which urate-lowering medication is used.

The choice of urate-lowering medications is uricosuric drugs (which promote uric acid excretion) or xanthine oxidase inhibitors (which inhibit uric acid production).

Probenecid, which is a uricosuric drug, inhibits the tubular reabsorption of filtered and secreted urate, thereby increasing urate excretion. The ideal candidates for probenecid therapy are those with a 24-hour urine uric acid excretion of less than 800 mg, no history of nephrolithiasis, and good kidney function (creatinine clearance >80 mL/min). The starting dose for probenecid is 250 mg twice a day, which can be increased gradually to a maximum daily dose of 3 g/d. Some degree of gastrointestinal irritation is experienced by approximately 2% of patients.

Allopurinol is the most widely used antihyperuricemic agent. The major metabolite of allopurinol is oxypurinol, and both allopurinol and oxypurinol are competitive inhibitors of the enzyme xanthine oxidase.

The ideal candidates for allopurinol treatment are as follows:

• Uric acid overproducers (24-h urinary uric acid excretion >800 mg on general diet or >600 mg on a purine-restricted diet)
• Patients with kidney insufficiency, nephrolithiasis, or tophaceous gout
• Patients at risk for developing uric acid nephropathy

Although allopurinol can be used in almost any hyperuricemic state, the above-mentioned conditions are more specific indications for allopurinol use. The usual maintenance dose for adults is 200-300 mg/d. The long half-life of oxypurinol makes once-daily dosing possible. Very importantly, adjust the dose in persons with chronic kidney disease because a higher incidence of adverse effects is observed if the dose is not adjusted.

Allopurinol is well tolerated by most patients, but hypersensitivity reactions may develop, which can be severe or fatal. Because a skin rash may progress to a severe hypersensitivity reaction, patients who develop a skin rash should discontinue allopurinol. Hepatotoxicity, bone marrow depression, and interstitial nephritis are rare but serious adverse effects of allopurinol.

Febuxostat is an orally administered xanthine oxidase inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the long-term treatment of hyperuricemia in patients with gout. In the CONFIRMS trial, a 6-month study that compared febuxostat and allopurinol in 2269 subjects with gout and serum urate levels ≥8.0 mg/dL, febuxostat 80 mg daily proved superior to allopurinol in lowering uric acid levels in patients with normal renal function, and febuxostat 40 mg daily was equivalent to allopurinol in such patients. In patients with mild-to-moderate renal impairment, febuxostat at any dose was superior to allopurinol in lowering uric acid levels.[38]

Overall, febuxostat was as safe as allopurinol in the CONFIRMS trial.[38] However, previous studies have identified cardiovascular events with febuxostat, and large ongoing trials are comparing the cardiovascular safety of febuxostat versus allopurinol.[39]

Lesinurad (Zurampic) is the first selective uric acid reabsorption inhibitor (SURI) approved by the FDA. It acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia.

Lesinurad must be coadministered with a xanthine oxidase inhibitor and is indicated for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. It is not approved for asymptomatic hyperuricemia and it is contraindicated for increased uric acid levels caused by tumor lysis syndrome or Lesch-Nyhan syndrome.

Monotherapy or higher than recommended doses are associated with an increased serum creatinine level. Kidney function should be assessed before initiating therapy and periodically thereafter. More frequent monitoring is required for an estimated creatinine clearance (CrCl) below 60 mL/min. Do not initiate therapy if the CrCl is below 45 mL/min and discontinue if CrCl decreases persistently to below 45 mL/min.

Approval was based on three randomized, placebo-controlled studies involving 1537 participants for up to 12 months. Serum uric acid levels were lower in participants treated with lesinurad plus allopurinol or febuxostat than in those who received placebo in combination with a xanthine oxidase inhibitor.[40]

Pegloticase (Krystexxa) is a recombinant, pegylated, uric acid–specific enzyme that catalyzes the oxidation of uric acid to allantoin. It is approved for use in adults with chronic gout that is refractory to conventional therapy. It is administered by intravenous infusion.

Uric acid nephrolithiasis

Allopurinol is the mainstay of drug therapy in patients with hyperuricemia who develop uric acid stones. Patients with calcium stones who are hyperuricosuric may also benefit from allopurinol because urate crystals in the urine may act as a nidus for other stones to form.

Potassium citrate and occasionally sodium bicarbonate or acetazolamide may be required to alkalinize the urine and to increase the solubility of uric acid.

Adequate hydration is recommended to maintain a high urine output of at least 2 L daily, unless otherwise contraindicated for other medical conditions where volume overload may be a concern.

Uric acid nephropathy

Over the years, efforts to prevent uric acid nephropathy, especially in the oncological setting, have resulted in a decrease in mortality from uric acid nephropathy. Intravenous hydration with saline and the administration of furosemide or mannitol (to dilute the urine) are necessary to prevent further precipitation of uric acid. Alkalinizing the urine with sodium bicarbonate or acetazolamide may be necessary to further enhance uric acid elimination.

Rasburicase (Elitek), a recombinant urate oxidase, is approved for use in preventing complications of hyperuricemia during the tumor lysis syndrome in both adults and children. It facilitates the conversion of urate to a more soluble product, allantoin. Although rasburicase treatment has become the standard of care for patients at high risk of tumor lysis syndrome, debate continues on whether the profound and rapid lowering of plasma uric acid levels produced by rasburicase has a significant effect on patient outcomes (eg, need for renal replacement therapy and mortality).[41]

Higher doses than usual of rasburicase (600-900 mg/d) are administered to decrease uric acid production prior to chemotherapy in patients with leukemias and lymphomas; allopurinol and hydration are continued for several days. If acute kidney injury develops despite these measures, then early hemodialysis is indicated to reduce the total body burden of uric acid, thereby facilitating recovery of kidney function.

Consultations with the following specialists may be indicated:

• A rheumatologist, for patients with acute or chronic gouty arthritis
• A nephrologist, for patients with acute urate nephropathy or chronic kidney disease
• A urologist, for patients who present with symptomatic uric acid nephrolithiasis

The use of a low-purine diet may significantly lower serum uric acid levels. This diet principally consists of sugars, starches, and fats, with protein supplied by eggs and cheese. The following foods should be avoided:

• Meats
• Poultry
• Fish
• Seafood
• Organ meats
• Alcohol
• Beans
• Peas

High consumption of dairy products has been associated with a lower risk of hyperuricemia.[42]

No limitation exists on activity for patients with hyperuricemia, although strenuous exercise may raise serum uric acid levels.

Dietary measures that may help prevent hyperuricemia include the following:

• Avoidance or restricted consumption of high-purine foods (eg, organ meats, sardines)
• Avoidance of excess ingestion of alcoholic drinks, particularly beer
• Avoidance of soft drinks and other beverages or foods sweetened with high-fructose corn syrup

A review of data from the National Health and Nutrition Examination Survey (NHANES) found that in women, higher folate intake was associated with lower risk of hyperuricemia. In men, both higher folate and higher vitamin B12 intake were associated with lower risk.[43]  

For patients with symptomatic hyperuricemia, provide regular follow-up evaluations with serum uric acid level determinations. For patients with gout, attempt to maintain uric acid levels below 6 mg/dL.

For patients with a history of uric acid nephrolithiasis, provide follow-up determinations of 24-hour urine excretion of uric acid to ensure that therapy has helped lower the excretion into the reference range.

In 2020, the American College of Rheumatology released updated guidelines on the management of gout. The guidelines strongly recommend initiation of urate-lowering therapy (ULT) for patients the following indications[44] :

• 1 or more subcutaneous tophi
• Evidince of radiographic damage attributable to gout
• Frequent gout flares (>2/year)

ULT is conditional recommended for patients with following indications[44] :

• History of  >1 flare and infrequent flares (< 2/year)
• First flare and CKD stage >3, SU >9 mg/dl, or urolithiasis

The guidelines included the following additional strong recommendations[44] :

• Allopurinol is the preferred first-line urate-lowering therapy (ULT) for all patients
• An xanthine oxidase inhibitor is recommended over probenecid for patients with CKD stage >3.
• Allopurinol and febuxostat should be initiated at a low dose with subsequent titration to target
• Concomitant antiinflammatory prophylaxis therapy (e.g., colchicine, NSAIDs, prednisone/prednisolone) for 3–6 months with ongoing evaluation and continued prophylaxis as needed if the patient continues to experience flares.
• The choice of specific antiinflammatory prophylaxis should be based upon patient factors.
• Oral colchicine, NSAIDs, or glucocorticoids (oral, intraarticular, or intramuscular) are appropriate first-line therapy for gout flares over IL-1 inhibitors or ACTH
• The choice of colchicine, NSAIDs, or glucocorticoids should be made based on patient factors and preferences
• When colchicine is the chosen agent, low-dose colchicine is preferred over high-dose colchicine given its similar efficacy and fewer adverse effects.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Pharmacotherapy for hyperuricemia is based on whether patients are overproducers or undersecretors. Allopurinol continues to be the mainstay for the treatment of patients who are overproducers, but febuxostat has become an established alternative to allopurinol. Febuxostat is a nonpurine selective xanthine oxidase inhibitor that does not require dose reduction in patients with renal impairment.

Rasburicase is another antihyperuricemic medication. It is a recombinant urate oxidase that is indicated for preventing complications of hyperuricemia during the tumor lysis syndrome. Since losartan has been found to have an uricosuric property, it may be worthwhile to use it in hypertensive patients with hyperuricemia that lack any contraindication to angiotensin receptor blockers. Other uricosuric drugs used in underexcretors are mentioned below.

Class Summary

Management of pain and inflammation in gout. Have analgesic, anti-inflammatory, and antipyretic properties. Inhibit the enzyme cyclooxygenase, thus inhibiting biosynthesis of prostaglandins and thromboxanes from arachidonic acid.

Indomethacin (Indochron E-R, Indocin)

Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.

Discontinue 3-4 d following symptom resolution.

Class Summary

Prevent gouty arthritis attacks and nephropathy. Used to treat hyperuricemia secondary to diuretics or antineoplastics. Prevent recurrent uric acid nephrolithiasis.

Allopurinol (Zyloprim)

Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. Reduces synthesis of uric acid without disrupting biosynthesis of vital purines.

Febuxostat (Uloric)

Xanthine oxidase inhibitor. Prevents uric acid production and lowers elevated serum uric acid levels. Indicated for long-term management of hyperuricemia associated with gout.

Lesinurad (Zurampic)

Lesinurad is the first selective uric acid reabsorption inhibitor to be approved in the United States. It acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia. It is indicated in combination with a xanthine oxidase inhibitor for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.

Class Summary

Competitively inhibit reabsorption of uric acid in proximal renal tubule. This promotes excretion of uric acid and lowers serum uric acid levels.

Probenecid (Benemid)

Used to treat and prevent hyperuricemia associated with gout and gouty arthritis.

Class Summary

Treatment of gouty arthritis attacks and prevention of their recurrence. Used in management of familial Mediterranean fever.

Colchicine

Reduces formation of uric acid crystals in affected joint, thereby reducing amount of acute inflammation and pain; also decreases uric acid levels in blood. Can be used in combination with probenecid on long-term to prevent gout or can be used alone to treat pain and inflammation of acute gout attacks. Discontinue when pain of gout attack begins to subside, when maximum dose is reached, or when GI symptoms (eg, nausea, vomiting, diarrhea) indicate cellular poisoning. Decreases leukocyte motility and phagocytosis in inflammatory responses.

Class Summary

Decrease solubility of uric acid. Adequate hydration recommended to maintain high urine output.

Acetazolamide (Diamox, Diamox sequels)

Used to further enhance uric acid elimination.

Class Summary

Have both anti-inflammatory (glucocorticoid) and salt retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects and modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone (Decadron, AK-Dex, Alba-Dex)

Decreases inflammation by suppressing migration of PMN leukocytes and reducing capillary permeability.

Class Summary

These agents facilitate conversion of urate to a more soluble product, allantoin.

Pegloticase (Krystexxa)

Pegylated uric acid–specific enzyme, which is a polyethylene glycol conjugate of recombinant uricase. Achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Indicated for gout in adults refractory to conventional therapy (ie, serum uric acid levels have failed to normalize and signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at maximum appropriate dose or xanthine oxidase inhibitors are contraindicated).

Rasburicase (Elitek)

A recombinant form (derived from Saccharomyces cerevisiae -synthesized, Aspergillus flavus) of the enzyme urate oxidase, which oxidizes uric acid to allantoin. Indicated for treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Elimination half-life is 18 h.

Class Summary

These agents are used to raise the pH in the urine.

Potassium citrate (Citra K, Polycitra K)

Pleasant-tasting oral systemic alkalizer containing potassium citrate and citric acid in a sugar-free base.

Each unit dose packet contains potassium citrate monohydrate 3300 mg and citric acid monohydrate 1002 mg. Each unit dose packet, when reconstituted, supplies the same amount of active ingredients as is contained in 15 mL (1 tablespoonful) Polycitra-K oral solution and provides 30 mEq potassium ion and is equivalent to 30 mEq bicarbonate.

Absorbed and metabolized to potassium bicarbonate, thus acting as a systemic alkalizer. Effects are essentially those of chlorides before absorption and those of bicarbonates subsequently. Oxidation is virtually complete so that < 5% of the potassium citrate is excreted in the urine unchanged.

Highly concentrated and, when administered after meals and before bedtime, allows one to maintain an alkaline urinary pH at all times, usually without necessity of 2 am dose. Alkalinizes urine without producing systemic alkalosis in recommended dosage.