eMedicine Specialties > Urology > Stones

Hyperuricosuria and Gouty Diathesis

Author: Bijan Shekarriz, MD, Director, Laparoscopy and Minimally Invasive Surgery, Associate Professor of Urology, Department of Urology, State University of New York Upstate Medical University
Coauthor(s): Marshall L Stoller, MD, Medical Director of Urinary Stone Center, Professor, Department of Urology, University of California at San Francisco; Brian H Eisner, MD, Instructor in Surgery, Department of Urology, Massachusetts General Hospital-Harvard Medical School; Fellow in Endourology, Department of Urology, University of California
Contributor Information and Disclosures

Updated: Jul 28, 2008

Introduction

Background

Hyperuricosuria is defined as urinary excretion of uric acid greater than 800 mg/day in men and greater than 750 mg/day in women. Uric acid, the major end-product of purine metabolism, is relatively insoluble in water. This excess uric acid leads to the formation of uric acid calculi. Such high levels may be due to either excess dietary intake of purine-rich foods or endogenous uric acid overproduction. Hyperuricosuria may be associated with hyperuricemia. In contrast, the term gouty diathesis describes the formation of urinary stones in persons with primary gout. These patients may present with other manifestations of gout (eg, gouty arthritis).

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Uric acid–related nephrolithiasis may involve pure calcium stones, uric acid stones, or a combination of both. Furthermore, uric acid stones may develop in persons with normal urinary and serum levels of uric acid. Unlike most other forms of urolithiasis, medical therapy is an integral part of management of uric acid stones. Therefore, an understanding of the pathophysiology of uric acid–related nephrolithiasis is important for a cost-effective treatment approach.

Pathophysiology

The urinary solubility of uric acid depends on its concentration in urine and the urinary pH. At a pH below 5.5, nearly 100% of uric acid exists in an undissociated form. The 3 mechanisms responsible for uric acid related stone formation include (1) an acidic urinary milieu, (2) dehydration, and (3) hyperuricosuria. One or more of these factors may be found in patients with uric acid–related calculi. However, persistently acidic urine (ie, pH <5.5) is the most important factor observed in patients with uric acid stones. Patients with gouty diathesis have consistently acidic urine (pH <5.5) and elevated levels of serum uric acid. Urine uric acid levels in these patients may be elevated or within the reference range.

Although the mechanism of low urinary pH in many patients may not be completely clear and can be multifactorial, recent studies suggest an association between diabetes and insulin resistance in patients with normal urinary uric acid levels and acidic urine.¹ Therefore, a subset of patients with idiopathic uric acid stones may have a broader systemic disorder of insulin resistance. A manifestation of insulin resistance is a mild defect in ammonium excretion that can result in stone formation. Acidic urine and uric acid stones have been reported as more common in patients with non–insulin-dependent diabetes than in patients with stones who do not have diabetes. The loss of diurnal variation in urinary pH and dietary content are other factors that contribute to acidity of the urine.

Hyperuricosuria is defined as urinary uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. The most common cause of hyperuricosuria is increased dietary purine intake, but many other hereditary or acquired factors (eg, gout) may result in this condition. Individuals with hyperuricosuria may develop uric acid or calcium oxalate stones due to supersaturation of urine with monosodium urate. Monosodium urate may initiate calcium oxalate stone formation by the induction of heterogeneous nucleation or by absorption of certain inhibitors. Patients with calcium oxalate stones have a urinary pH of greater than 5.5.

Finally, all conditions that contribute to low urinary volume may increase uric acid supersaturation in urine and result in uric acid stone formation.

Frequency

United States

Uric acid stones account for 5-10% of urinary stones. Approximately 15-20% of patients with calcium stones have hyperuricosuria. Up to 20% of patients with gout develop uric acid stones.

International

The frequency of uric acid–related stones in other Western countries is similar to that in the United States; however, the incidence varies in other countries, and some geographic differences may exist. In Israel, for example, uric acid stones have been found in approximately 40% of individuals who form stones. Uric acid bladder stones are a common problem in children in rural Southeast Asia.

Mortality/Morbidity

• With appropriate diagnosis and treatment, most patients survive with minimal long-term morbidity. The prognoses of the familial and genetic forms depend on the primary disease and associated abnormalities.

Sex

• Between 80 and 90% of persons with hyperuricosuric calcium nephrolithiasis are men. Similarly, most individuals (70%) with calcium stones who do not have hyperuricosuria are also men.
• Gout is mainly a disorder of men, and only 5% of cases occur in women.
• Uric acid stones are more common in men than in women. Most uric acid stones are not associated with gout. Dehydration and urine acidity predispose patients to uric acid stones.

Age

• Hyperuricosuric calcium nephrolithiasis and gouty diathesis usually manifest in middle-aged individuals. In men, the peak age of onset of clinical gout is approximately 45 years.

Clinical

History

• Acute phase
  • Pain symptoms are as follows:
    • As with many other stone types, patients with uric acid–related urinary calculi may present with acute renal or ureteral colic.
    • A typical episode occurs suddenly during the night. The episode is abrupt and does not resolve with rest or change in position. In contrast to someone with an acute abdomen who is stationary, patients experiencing acute renal colic frequently move in unusual positions in an effort to relieve their severe pain.
    • Some patients may experience a gradual onset of pain, resulting in a dull chronic ache in the flank region. The location of pain varies depending on stone location and may shift from the flank to the anterior abdominal wall, groin, and, eventually, to the ipsilateral testicle or labia.
    • When the stone is lodged in the ureterovesical junction, patients frequently report marked urinary frequency and urgency.
    • The severity of pain is often inversely proportional to the size of the stone. Large renal staghorn calculi rarely result in acute renal colic, as is observed with smaller ureteral stones.
    • The degree and type of pain is not specific to any particular stone composition.
  • GI symptoms include the following:
    • Nausea and vomiting are frequently associated with urolithiasis.
    • Patients may report altered bowel habits, including diarrhea or constipation.
  • Urinary symptoms include the following:
    • Patients with ureteral stones near the bladder often report dysuria, frequency, and urgency. Furthermore, gross hematuria may be observed. Eighty-five percent of patients present with either gross or microscopic hematuria.
    • Some patients may present with an associated urinary tract infection. Rare, severe, gas-forming infections may result in pneumaturia.
    • The vast majority of ureteral stones that pass into the bladder transit the urethra uneventfully. A ureteral stone passed into the bladder rarely causes urinary obstruction; these persons usually report an interrupted stream. Unlike in cats, in whom stones frequently become inspissated in the urethra, resulting in renal failure and/or death, stones rarely become obstructed in the human urethra.
• Chronic phase
  • A history of gout and associated joint disease are important clues in discerning the etiology. The use of probenecid (a known uricosuric agent) in patients with gout may result in hyperuricosuria and increase the risk of uric acid stone formation. Uricosuric agents such as probenecid specifically increase urinary uric acid levels to help decrease hyperuricemia and to reduce gout attacks. When they cause hyperuricosuria or uric acid calculi, alternate therapies for the hyperuricemia should be used.
  • Myeloproliferative disorders, especially in children, may result in hyperuricosuria and associated urinary stones. Furthermore, a massive increase in the endogenous purine pool due to tumor necrosis may result in severe hyperuricosuria, crystalluria, and acute urinary obstruction during chemotherapy for myeloproliferative disorders. In these patients, the rate of uric acid stone formation is approximately 40%, which is much higher than in patients with gout.
  • Obtaining a dietary history is important to help elucidate iatrogenic causes of hyperuricosuria, including an excessive intake of purine-rich foods and excessive weight loss, which result in a catabolic state and increased uric acid production.
  • A hereditary form of hyperuricemia and hyperuricosuria is Lesch-Nyhan syndrome, which may be associated with urinary calculi. These patients have a deficiency in the enzyme hypoxanthine-guanine phosphoribosyl-transferase. This enzyme catalyzes the salvage pathway of purines and is responsible for the conversion of hypoxanthine to inosinic acid and guanine to guanylic acid. If the enzyme is deficient, low levels of guanylic and inosinic acid occur with a subsequent increase in de novo purine synthesis because these nucleotides modulate purine synthesis by feedback inhibition.
  • Long-standing malaise and lethargy may be an associated symptom of urinary obstruction with or without infection.

Physical

• Costovertebral angle tenderness is common during acute renal colic. Abdominal distention and tenderness secondary to ileus may also occur.
• In cases with associated urinary tract infection, fever is common.
• After resolution of the acute stone event, patients may be asymptomatic or may present with physical findings related to the underlying disease. For example, patients with gout may present with chronic joint changes (ie, tophi) due to gouty arthritis.

Causes

Hyperuricosuric calcium nephrolithiasis is characterized by calcium oxalate or calcium phosphate stones in persons with hyperuricosuria. The hyperuricosuria is most commonly due to an excessively purine-rich diet; however, hyperuricosuria may be related to overproduction of uric acid in as many as 30% of these patients. This may represent a latent form of gout. In contrast to calcium-based stones, uric acid stones form in an acidic environment with a urinary pH that is always below 5.5. The solubility of uric acid depends on 3 factors: (1) urinary pH, (2) uric acid concentration, and (3) urinary volume. Based on these factors, the causes of uric acid stones can be categorized as follows:

• Acidic urine  
  • Gouty diathesis
  • Chronic diarrhea
  • Inflammatory bowel disease
  • Exercise/dehydration
  • Familial
• Hyperuricosuria 
  • Gouty diathesis
  • An excessively purine-rich diet
  • Inborn errors of metabolism
    • Hypoxanthine-guanine phosphoribosyl-transferase deficiency
    • Phosphoribosylpyrophosphate synthetase overactivity
    • Glucose-6-phosphatase synthetase deficiency
  • Myeloproliferative disorders
    • Leukemia
    • Hemolytic anemia
    • Neoplasia
  • Medications
  • Chemotherapy
• Low urinary volume  
  • GI disorders
  • Strenuous exercise/dehydration

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