AUTHOR INFORMATION

Section 1 of 12

Authored by Sahar Fathallah-Shaykh, MD, Assistant Professor in Pediatric Nephrology, Northwestern University Feinberg School of Medicine; Consulting Staff, Division of Kidney Diseases, Children's Memorial Hospital

Coauthored by Steven C Diven, MD, Medical Director of Pediatric Dialysis Unit, Assistant Professor, Department of Pediatrics, University of Texas Medical Branch at Galveston

Sahar Fathallah-Shaykh, MD, is a member of the following medical societies: American Society of Nephrology

Edited by Richard Neiberger, MD, PhD, Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital; Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Professor, Department of Pediatrics, Division of Nephrology, Albert Einstein College of Medicine; and Craig B Langman, MD, Professor, Department of Pediatrics, Northwestern University School of Medicine; Head, Division of Kidney Diseases, Children's Memorial Hospital of Chicago

Author's Email:	Sahar Fathallah-Shaykh, MD
Editor's Email:	Richard Neiberger, MD, PhD

eMedicine Journal, August 15 2006, VOLUME 7, Number 8

INTRODUCTION

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Background: Xanthinuria is a descriptive term for excess urinary excretion of the purine base xanthine. Two inherited forms of xanthinuria principally result from a deficiency of the enzyme xanthine dehydrogenase, which is the enzyme responsible for degrading hypoxanthine and xanthine to uric acid. Deficiency of xanthine dehydrogenase results in plasma accumulation and excess urinary excretion of the highly insoluble xanthine, which may lead to arthropathy, myopathy, crystal nephropathy, urolithiasis, or renal failure. Hypoxanthine does not accumulate to an appreciable degree because it is recycled through a salvage pathway by the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT). Xanthine continues to accumulate, despite the recycling of hypoxanthine, because of the metabolism of guanine to xanthine by the enzyme guanase (see Image 1).

Classic xanthinuria

Classic xanthinuria is one form of xanthinuria that is divided into 2 types based on the enzyme deficiency. Both types are inherited in an autosomal recessive manner.

• Classic xanthinuria type I is the result of an isolated deficiency of xanthine dehydrogenase.

• Type II xanthinuria is characterized by a deficiency of xanthine dehydrogenase and a related enzyme, aldehyde oxidase.

The distinction between the 2 types is based on the ability or inability to oxidize allopurinol, a substrate for xanthine dehydrogenase and aldehyde oxidase. Allopurinol is oxidized to oxypurinol by the normal function of aldehyde oxidase in patients with type I, but allopurinol is not converted in patients with type II, who lack aldehyde oxidase activity. Other substrates that are oxidized by aldehyde oxidase, such as pyrazinamide and N-methylnicotinamide, can be used to distinguish between types I and II.

Molybdenum cofactor deficiency

The other inherited form of xanthinuria, termed molybdenum cofactor deficiency, presents in the neonatal period with microcephaly, hyperreflexia, and other central nervous system manifestations. Other reported manifestations include severe metabolic acidosis and intracranial hemorrhage. This condition is inherited recessively and is caused by a congenital defect of a molybdenum-containing cofactor essential for the function of 3 distinct enzymes (ie, xanthine dehydrogenase, aldehyde oxidase, sulfite oxidase). This defect is caused by the mutation of molybdenum cofactor genes (MOCS1 or MOCS2). Xanthinuria is only a marker in this setting since (1) the clinical presentation is overshadowed by neurologic manifestations and (2) death in the first year of life is caused by the deficiency of sulfite oxidase, which is the final step in cysteine metabolism.

Iatrogenic xanthinuria

Iatrogenic xanthinuria can occur during allopurinol therapy, which is used to reduce urine uric acid excretion in conditions with endogenous overproduction of uric acid. Inhibition of xanthine dehydrogenase by allopurinol may lead to accumulation and urinary excretion of xanthine. Patients with Lesch-Nyhan syndrome or patients with partial HGPRT deficiency have developed xanthine nephropathy and stones following treatment with allopurinol. A few incidents of xanthine nephropathy and renal failure have been reported in patients treated with allopurinol during chemotherapy for malignancy. The latter occurred either when large doses of allopurinol were used or during aggressive therapy for a large tumor cell burden with concomitant allopurinol therapy.

This discussion focuses on the classic and iatrogenic forms of xanthinuria in children.

Pathophysiology: The primary organs affected in xanthinuria are the kidney and, to a lesser extent, skeletal muscle and joints. Kidney complications are initiated by the formation of xanthine crystals in the tubules leading to parenchymal deposition and/or radiolucent stone formation. Xanthine’s high rate of renal clearance and low solubility in urine creates an environment in the urine favoring crystallization. Thus, volume-depleted patients with xanthinuria are at particular risk of forming xanthine crystals. Irritation of the tubular epithelium by xanthine crystals results in hematuria, while renal tissue deposits induce an inflammatory reaction and consequent interstitial nephritis. Urolithiasis is the most common clinical manifestation of the xanthinuric states. Further renal complications include acute and chronic renal failure and even end-stage renal disease.

Myopathy and arthropathy are rare clinical manifestations of xanthinuria that have been described in older patients. Clinical manifestations of the myopathy (eg, muscle cramps, muscle pain, muscle stiffness) are believed to be the result of long-term accumulation of xanthine and hypoxanthine crystals in the muscle because this has been demonstrated in skeletal muscle biopsies in a few symptomatic patients. A form of myopathy has been described in one patient following vigorous exercise, which led to the postulate that heavy muscle use leads to an intracellular acid environment favoring xanthine and hypoxanthine crystal formation and deposition in muscle tissue. Hypoxanthine serum levels are also increased after vigorous exercise (eg, distance running) in healthy subjects and in patients with xanthinuria.

Arthropathy induced by xanthine crystal deposition has been demonstrated in animals. Although not demonstrated clearly in humans, arthritis and arthralgia are believed to be secondary to xanthine crystal deposition in the joints.

Frequency:

• In the US: True incidence of classic xanthinuria is unknown since it is reported rarely. Surveys suggest a population incidence of 1 in 6,000 to 1 in 69,000. Distribution of patients with type I and type II is approximately equal. Incidence of iatrogenic xanthinuria is unknown.

• Internationally: Most reported cases are from Mediterranean and Middle Eastern countries.

Mortality/Morbidity: Although the death rate is unknown and unexpected, death can result as a complication of unrecognized or untreated renal failure. Nearly 40% of patients with classic xanthinuria present with symptoms related to urolithiasis (eg, hematuria, renal colic, urinary tract infection, acute renal failure).

Race: Xanthinuria or xanthine dehydrogenase deficiency is reported in diverse ethnicities, although most reported incidents occur in Mediterranean and Middle Eastern countries. Consanguinity and an arid climate appear to have a significant role in the higher incidence in these populations.

Sex: Classic xanthinuria is more common in males than in females.

Age: Nephrotoxicity from classic xanthinuria can occur at any age, although more than one half of the incidents of urolithiasis occur in children younger than 10 years. Myopathy and arthropathy occur more often in older patients with xanthinuria.

CLINICAL

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History: Symptoms are nonspecific and relate to the underlying pathophysiology and secondary complications. In young children, irritability, vomiting, and failure to thrive may be the presenting symptoms. At any age, the patient may present with gross or microscopic hematuria, pyuria, renal colic, dysuria, urinary frequency, urine incontinence, polyuria, abdominal pain, or symptoms of a urinary tract infection. Joint pain and muscle cramps or muscle pain are symptoms of the arthropathy and myopathy, respectively.

• Renal system symptoms are not specific to xanthinuria and are typical of any cause of crystal nephropathy and stone formation



• Gross or microscopic hematuria may occur as a result of crystalluria or nephrolithiasis.



• Renal colic is characterized by sudden onset of severe usually unilateral flank pain that may radiate toward the inguinal area.


• • Nausea and vomiting may accompany the episode.
  
  
  
  • In young children or infants, renal colic may present as irritability or unexplained abdominal pain.
  
  
  
• Urinary tract infection is a frequent complication of any foreign body in the urinary system.



• Acute renal failure may be the presenting feature of bilateral obstructing urolithiasis or crystal nephropathy.



• Passing a urinary stone may be the initial clinical manifestation.



• Myopathy usually occurs in older patients and is related to accumulation of xanthine. The symptoms may include muscle cramps, pain, or tightness in the hands, legs, or jaw. Muscle pain can follow vigorous exercise.



• Joint pain and stiffness are features of arthropathy.

Physical:

• No specific physical examination findings lead to the diagnosis of xanthinuria.



• Failure to thrive, recurrent emesis, and irritability are nonspecific findings in young children with renal failure or urolithiasis.



• Fever, flank pain, dysuria, frequency, and urgency are features of a urinary tract infection, which can accompany xanthinuria.



• Renal colic is a common presenting feature of urolithiasis.



• Hematuria is a typical feature of urolithiasis and crystalluria.

Causes:

• Genetic causes


• • Classic xanthinuria types I and II are autosomal recessive inherited conditions that result in dysfunction of the enzyme xanthine dehydrogenase.
  
  
  
  • Xanthine dehydrogenase catalyzes 2 reactions, conversion of hypoxanthine to xanthine and conversion of xanthine to uric acid.
  
  
  
  • The accumulation of xanthine is caused by the catabolism of guanine to xanthine by guanase and the lack of a salvage pathway for xanthine.
  
  
  
  • Hypoxanthine does not accumulate appreciably since it is metabolized efficiently through a salvage pathway.
  
  
  
• Iatrogenic causes


• • Allopurinol is administered to block xanthine dehydrogenase and prevent uric acid overproduction, which leads to the accumulation of xanthine. Rarely, in the setting of aggressive chemotherapy with rapid tumor lysis and allopurinol therapy, patients can develop complications of renal failure from xanthine crystal nephropathy. Volume depletion also may be involved.
  
  
  
  • In complete HGPRT deficiency (ie, Lesch-Nyhan syndrome) or in partial deficiency of HGPRT, an overproduction of uric acid occurs. Allopurinol is administered to reduce uric acid production, and this leads to xanthine and hypoxanthine accumulation. Hypoxanthine accumulates since HGPRT is the enzyme for the hypoxanthine salvage pathway.
  
  
  

DIFFERENTIALS

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Uric Acid Stones
Urolithiasis

Other Problems to be Considered:

Cystine nephropathy
Cystinuria

WORKUP

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Lab Studies:

• The laboratory evaluation should proceed in a manner to confirm the presence of urinary system disease due to crystal or stone formation. Initially seek common etiologies because xanthinuria is an extremely rare cause of nephropathy and urolithiasis. Laboratory clues that may suggest the diagnosis of xanthinuria include a radiolucent stone, low serum and urine uric acid levels, or crystal nephropathy of undetermined etiology.



• Obtain the following urine studies:


• • Urinalysis can exhibit evidence of crystal nephropathy or urolithiasis, including blood and possibly pyuria. Most laboratories should identify common types of urine crystals.
  
  
  
  • Obtain urine culture.
  
  
  
  • Obtain 24-hour urine collection for calcium, oxalate, uric acid, and creatinine. Uric acid levels are low or undetectable in the hereditary xanthinurias.
  
  
  
  • If xanthinuria is suspected, identify a laboratory that accurately can measure urine xanthine and hypoxanthine. Determine the type of urine collection (ie, timed, spot) necessary. Xanthine and hypoxanthine levels in the urine in healthy individuals are less than 0.01 mmol per millimole of creatinine. In classic xanthinuria, xanthine and hypoxanthine levels are increased significantly, and the ratio of xanthine to hypoxanthine is approximately 4:1. Urine xanthine levels can approach 1 mmol per millimole of creatinine.
  
  
  
• Stone analysis is the most direct method to assist the clinician in making the diagnosis of xanthinuria.



• Obtain serum studies as follows:


• • Serum electrolytes, creatinine, BUN, calcium, magnesium, phosphorus, and uric acid are appropriate studies in patients with suspected crystal nephropathy or urolithiasis.
  
  
  
  • Serum uric acid levels are low or undetectable and suggest the possibility of xanthinuria. Note that xanthinuria is not the only disorder with low serum uric acid levels.
  
  
  
  • Determine xanthine and hypoxanthine blood levels in patients with suspected xanthinuria. Identifying a laboratory capable of assaying the purines and receiving instructions to properly obtain the specimen is important. In general, plasma concentrations of xanthine and hypoxanthine in healthy individuals are less than 1 mmol and less than 5 mmol, respectively. The possible range of xanthine plasma levels is 10-40 mmol in classic xanthinuria.
  
  
  
• Liver, duodenal, or jejunal mucosa biopsy material is used to determine tissue xanthine dehydrogenase deficiency; however, measurement of xanthine dehydrogenase activity usually is not necessary to make the diagnosis of classic xanthinuria.

Imaging Studies:

• Kidneys, ureters, and bladder


• • Kidneys, ureters, and bladder (KUB) test with plain radiographic film of the abdomen is always obtained in patients with suspected urolithiasis.
  
  
  
  • Xanthine stones are radiolucent and are not observed routinely on a KUB. Further imaging of the urinary tract is necessary to determine the presence of a xanthine stone.
  
  
  
• Intravenous pyelogram: Intravenous pyelogram may indicate recent stone passage or a filling defect in the renal pelvis or ureter, consistent with the presence of a radiolucent stone. The study is also helpful in identifying obstruction of urine flow by a stone.



• Renal ultrasound


• • Sensitive enough to identify large radiolucent stones, this imaging study may miss smaller stones, generally less than 1 cm.
  
  
  
  • The study can determine the presence of hydronephrosis or crystal nephropathy.
  
  
  
• Computed tomography and magnetic resonance imaging


• • CT scan and MRI are very sensitive for identifying radiolucent stones throughout the urinary system.
  
  
  
  • However, these studies are more expensive; reserve them for situations when a high index of suspicion exists for nephrolithiasis despite a negative renal ultrasound.
  
  
  

Other Tests:

• Allopurinol challenge


• • Patients with classic xanthinuria type I are deficient in xanthine dehydrogenase, while patients with type II have a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Allopurinol is oxidized to oxypurinol by aldehyde oxidase. In patients with type I, allopurinol is metabolized to oxypurinol, whereas patients with type II do not metabolize allopurinol.
  
  
  
  • No specific clinical guidelines exist to perform the allopurinol challenge. Generally, oxypurinol is measured in a 24-hour urine specimen on a standard dose of allopurinol for 3-5 days.
  
  
  
  • Before administering allopurinol, identifying a laboratory that is capable of measuring oxypurinol is important.
  
  
  
  • Pyrazinamide and N-methylnicotinamide are also substrates for aldehyde oxidase and have been used to classify the type of classic xanthinuria.
  
  
  

TREATMENT

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Medical Care:

• Alkalinization of the urine has little effect on the solubility of xanthine.



• No specific therapies are available for classic xanthinuria; however, some general measures are recommended as follows:


• • High fluid intake: A reasonable goal for fluid intake is 1.5-2 times maintenance spaced over the 24-hour period. Drinking water at night is important to prevent the usual development of a concentrated morning urine.
  
  
  
  • Dehydration prevention: Educate the patient about the importance of preventing dehydration.
  
  
  
  • Low-purine diet: Sources of food with lower purine content include cheese and eggs, grains, fruits, nuts, and most vegetables. The foods that contain higher amounts of purines are beef, pork, poultry, seafood, liver, kidney, and heart as well as peas, beans, spinach, and lentils.
  
  
  
  • Xanthine dehydrogenase and aldehyde oxidase metabolize certain medications, and the enzyme-deficient or inhibited state can lead to toxic accumulation of the parent drug. Xanthine dehydrogenase is involved in degradation of azathioprine or 6-mercaptopurine, and aldehyde oxidase metabolizes allopurinol, cyclophosphamide, methotrexate, and quinine.
  
  
  

Surgical Care:

• Xanthine stones are sensitive to extracorporeal shockwave lithotripsy. Consultation with a urologist is warranted because other techniques are available for stone removal.

Consultations:

• Nephrology



• Urology

Diet:

• Advise a low-purine diet (see Medical Care section).

Activity:

• Advise older patients with xanthine myopathy to avoid vigorous physical activity (eg, long-distance running).

MEDICATION

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No specific medication exists to reduce xanthine production in the inherited forms of xanthinuria.

FOLLOW-UP

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Further Inpatient Care:

• Inpatient care may be necessary for the secondary complications of pyelonephritis, obstructive urolithiasis, or acute renal failure.

Further Outpatient Care:

• Monitor frequency of symptoms, renal function, and passage of stones.



• Ensure consistent high intake of fluid to maintain dilute urine.



• Monitor purine intake.

Complications:

• Urolithiasis



• Crystal nephropathy



• Renal failure



• Obstructive uropathy



• Urinary tract infection



• Hematuria



• Myopathy



• Arthropathy



• Arthritis

Prognosis:

• Prognosis depends on the degree of renal injury from crystal nephropathy, urinary obstruction, and/or pyelonephritis.

Patient Education:

• Advise patients regarding the importance of the following:


• • Maintaining a dilute urine
  
  
  
  • Avoiding dehydration
  
  
  
  • Intervening early for conditions that may lead to dehydration
  
  
  
  • Avoiding high-purine foods
  
  
  
  • Providing proper home therapy for renal colic
  
  
  

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to consider the diagnosis in a patient with renal colic and evidence of a radiolucent stone

Special Concerns:

• Infants and young children may have nonspecific symptoms related to the urinary system, including persistent emesis, irritability, anorexia, poor weight gain, or hematuria.



• Older patients are more likely than children to have muscle symptoms from xanthine and hypoxanthine tissue deposits.

TEST QUESTIONS

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CME Question 1: A 10-year-old boy presents with symptoms of renal colic and a history of passing a small stone. Results from a kidneys, ureters, and bladder test are negative, while an intravenous pyelogram reveals a dilated right ureter. Initial laboratory studies reveal a low serum uric acid level. Which of the following is the next most appropriate diagnostic laboratory study to obtain?

A: Urine uric acid
B: Serum hypoxanthine
C: Urine xanthine
D: Urine hypoxanthine
E: Urine xanthine and hypoxanthine

The correct answer is E: A low level of serum or urine uric acid suggests but does not prove the diagnosis of classic xanthinuria because other causes of low uric acid production are possible. The levels of xanthine to hypoxanthine in the urine in a ratio of 4:1 or 5:1 are diagnostic of a defect in xanthine dehydrogenase activity (ie, classic xanthinuria).

CME Question 2: A 5-year-old child is diagnosed with xanthinuria. Which of the following is the most important long-term intervention for the prevention or xanthine crystalluria?

A: Allopurinol
B: Dilute urine
C: Alkalinization of urine
D: Acidification of urine
E: Low-carbohydrate diet

The correct answer is B: No specific therapy exists for xanthinuria. Allopurinol is a substrate for other enzymes besides xanthine dehydrogenase and should not be used for therapy. Changing the pH of the urine has no effect on the solubility of xanthine. Persistent dilute urine and a low-purine diet are the most beneficial interventions.

Pearl Question 1 (T/F): A defect in xanthine dehydrogenase activity is the most common cause of pathologic xanthinuria.

The correct answer is True: Other important causes include allopurinol therapy in the treatment of malignancies and neonatal molybdenum containing cofactor deficiency.

Pearl Question 2 (T/F): Allopurinol challenge is a useful diagnostic test but does not differentiate between classic xanthinuria types I and II.

The correct answer is False: Allopurinol is converted to oxypurinol in individuals with type I but not in persons with type II.

Pearl Question 3 (T/F): Xanthine stones are a common cause of urolithiasis in children.

The correct answer is False: Xanthine stones are an extremely rare cause of urolithiasis in children.

Pearl Question 4 (T/F): Negative findings from a kidneys, ureters, and bladder radiographic study in a patient with obvious renal colic increase the likelihood of xanthinuria as the diagnosis.

The correct answer is True: Xanthine stones are radiolucent.

PICTURES

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Caption: Picture 1. Purine metabolic pathway.
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BIBLIOGRAPHY

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• Cameron JS, Moro F, Simmonds HA: Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993 Feb; 7(1): 105-18[Medline].
• Carpenter TO, Lebowitz RL, Nelson D, Bauer S: Hereditary xanthinuria presenting in infancy with nephrolithiasis. J Pediatr 1986 Aug; 109(2): 307-9[Medline].
• Fildes RD: Hereditary xanthinuria with severe urolithiasis occurring in infancy as renal tubular acidosis and hypercalciuria. J Pediatr 1989 Aug; 115(2): 277-80[Medline].
• Gomez GA, Stutzman L, Chu TM: Xanthine nephropathy during chemotherapy in deficiency of hypoxanthine- guanine phosphoribosyltransferase. Arch Intern Med 1978 Jun; 138(6): 1017-9[Medline].
• Leimkuhler S, Charcosset M, Latour P, et al: Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Hum Genet 2005; 117(6): 565-70[Medline].
• Macaya A, Brunso L, Fernandez-Castillo N, et al: Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics.Dec; 2005; 36(6): 389-94[Medline].
• Reiter S, Simmonds HA, Zollner N, et al: Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol. Clin Chim Acta 1990 Mar 15; 187(3): 221-34[Medline].
• Simmonds HA, Reiter S, Nishino T: Hereditary xanthinuria. In: The Metabolic and Molecular Bases of Inherited Disease. 7. 1995: 1781-97.
• Teksam O, Yurdakok M, Coskun T: Molybdenum cofactor deficiency presenting with severe metabolic acidosis and intracranial hemorrhage. J Child Neurol 2005; 20(2): 155-7[Medline].
• van Gennip AH, Mandel H, Stroomer LEM: Effects of allopurinol on the xanthinuria in a patient with molybdenum cofactor deficiency. In: Purine and Pyrimidine Metabolism in Man. 8: 1995: 375-78.
• Zannolli R, Micheli V, Mazzei MA, et al: Hereditary xanthinuria type II associated with mental delay, autism, cortical renal cysts, nephrocalcinosis, osteopenia, and hair and teeth defects. J Med Genet 2003 Nov; 40(11): e121[Medline].

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