History

Fact Explanation
Loin to groin pain Xanthinuria is excess urinary excretion of the xanthine which is a hereditary condition. This is due to the genetic deficiency of enzyme, xanthine dehydrogenase [1] that is responsible for degrading hypoxanthine and xanthine to uric acid leaving excess hypoxanthine and xanthine amounts. Out of these two, hypoxanthine can be metabolized using hypoxanthine guanine phosphoribosyltransferase where xanthine is accumulated in plasma. Xanthine can form crystals in the tubules, later parenchymal deposits and calculi formation. Unlike the other stones, these are radiolucent stones. Sometimes they might experience the passage of multiple brownish yellow stones with urine. [1]
Nausea and vomiting May accompany the ureteric colic. [2]
Dysuria, urinary frequency, urine incontinence They may experience pain while passing urine, increased frequency of micturition due to the calculi formation. These can also be due to the urinary tract infection. [2]
Haematuria [2] Calculi can damage the tubules and parenchyma and may cause haematuria. [2]
Reduced urine output Stones can invade the kidney and urinary tract, causing destruction of parenchyma, [2] therefore acute and chronic renal failure are complications of xanthinuria. If there is bilateral obstruction due to the calculi they will presenting with acute renal failure of sudden onset.
Muscle cramps, muscle pain, muscle stiffness Accumulation of xanthine inside the muscles can cause muscle pathology-"myopathy". [3] This might be aggravated after exercise.
Joint pain and swelling Accumulation of xanthine in the joints over a long period of time may result in joint problems. [3] This is a rare manifestation of the disease.
History of volume depletion: Fasting, blood loss, reduced iurine output Xanthine is well cleared from the kidney [4] therefore if there is volume reduction, it favours the calculi formation.
Age of presentation Commonly presents in the paediatric age group. Young children [4] may present with nonspecific symptoms such as crying, vomiting, poor feeding and failure to thrive.
Family history of renal and ureteric stones This is hereditary condition with a genetic basis. [1]
References
  1. MATEOS FA, PUIG JG, JIMéNEZ ML, FOX IH. Hereditary xanthinuria. Evidence for enhanced hypoxanthine salvage. J Clin Invest [online] 1987 Mar, 79(3):847-852 [viewed 22 July 2014] Available from: doi:10.1172/JCI112893
  2. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825
  3. LEVARTOVSKY DAVID, LAGZIEL AYALA, SPERLING ODED, LIBERMAN URI, YARON MICHAEL, HOSOYA TATSUO, ICHIDA KIMIYOSHI, PERETZ HAVA. XDH gene mutation is the underlying cause of classical xanthinuria: A second report. Kidney Int [online] 2000 June, 57(6):2215-2220 [viewed 22 July 2014] Available from: doi:10.1046/j.1523-1755.2000.00082.x
  4. ZANNOLLI R. Hereditary xanthinuria type II associated with mental delay, autism, cortical renal cysts, nephrocalcinosis, osteopenia, and hair and teeth defects. Journal of Medical Genetics [online] 2003 November, 40(11):121e-121 [viewed 22 July 2014] Available from: doi:10.1136/jmg.40.11.e121

Examination

Fact Explanation
Febrile Due to the superadded urinary tract infections. [3]
Flank tenderness They might have tenderness on palpation due to the calculus disease. [2]
Speech problems, delayed psychomotor development and behavioural problems Mental delay and autistic disorders are associated with xanthinuria in some children. [1].
References
  1. ZANNOLLI R. Hereditary xanthinuria type II associated with mental delay, autism, cortical renal cysts, nephrocalcinosis, osteopenia, and hair and teeth defects. Journal of Medical Genetics [online] 2003 November, 40(11):121e-121 [viewed 22 July 2014] Available from: doi:10.1136/jmg.40.11.e121
  2. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825
  3. ICHIDA KIMIYOSHI, AMAYA YOSHIHIRO, OKAMOTO KEN, NISHINO TAKESHI. Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans. IJMS [online] 2012 November, 13(12):15475-15495 [viewed 14 September 2014] Available from: doi:10.3390/ijms131115475

Differential Diagnoses

Fact Explanation
Calculus disease Most of the ureteric calculi are due to the calcium, phosphate and oxalate stones. They also present with loin to groin pain as the xanthine stones. [3] These are radio opaque on radiography. Causes for the calculus disease include hypercalciuric states, cystinuria, hyperoxaluria, distal renal tubular acidosis. [1]
Uric Acid Stones This is the most common cause of radiolucent kidney stones. Xanthine stones are also radiolucent in appearance. But xanthinuria has to be considered if there is hyperuricaemia, reduced urinary uric acid excretion and increased urinary xanthine excretion. [2]
Combined xanthine dehydro­genase and aldehyde oxidase deficiency. [2] Type 1 xanthinuria is due to the deficiency of xanthine oxidase and type 2 xanthinuria is due to the deficiency of both xanthine dehydro­genase and aldehyde oxidase. [2] Both types of defects are clinically similar,and can be only detected by urinary screening.
References
  1. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825
  2. MATEOS FA, PUIG JG, JIMéNEZ ML, FOX IH. Hereditary xanthinuria. Evidence for enhanced hypoxanthine salvage. J Clin Invest [online] 1987 Mar, 79(3):847-852 [viewed 23 July 2014] Available from: doi:10.1172/JCI112893
  3. RULE AD, BERGSTRALH EJ, MELTON LJ III, LI X, WEAVER AL, LIESKE JC. Kidney Stones and the Risk for Chronic Kidney Disease Clin J Am Soc Nephrol [online] 2009 Apr, 4(4):804-811 [viewed 13 September 2014] Available from: doi:10.2215/CJN.05811108

Investigations - for Diagnosis

Fact Explanation
Urinalysis This can reveal xanthine crystals, red blood cells and pus cells. They can have microscopic haematuria even in the absence of macroscopic haematuria. [2]
24-hour urine collection of urine for calcium, oxalate, uric acid Uric acid levels are low or undetectable in the hereditary xanthinuria. [1] Xanthine and hypoxanthine excretion in the urine may be elevated.
Fractional excretion of uric acid Fractional excretion of uric acid is reduced. [1]
Xanthine and hypoxanthine levels Serum levels are markedly increased in these patients. [1,3]
X-ray and ultrasoundscan Kidney, ureters, and bladder (KUB) Assessment and management of of calculus disease requires these investigations. Xanthine stones appear as radiolucent stones on radiography. [1] Ultrasound can demonstrate both the function and structure of the kidney and any hydronephrosis with dilatation of the pelvicalyceal system. [2]
Intravenous pyelography Will demonstrate filling defect due to the calculus in pelvis or the ureters. [2]
Analysis of renal stones using an X-ray diffractometer Renal stones can be analysed using an X-ray diffractometer which will demonstrate the xanthine. [3]
References
  1. MATEOS FA, PUIG JG, JIMéNEZ ML, FOX IH. Hereditary xanthinuria. Evidence for enhanced hypoxanthine salvage. J Clin Invest [online] 1987 Mar, 79(3):847-852 [viewed 22 July 2014] Available from: doi:10.1172/JCI112893
  2. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825
  3. GOK F.. Mutational analysis of the xanthine dehydrogenase gene in a Turkish family with autosomal recessive classical xanthinuria. Nephrology Dialysis Transplantation [online] 2003 November, 18(11):2278-2283 [viewed 22 July 2014] Available from: doi:10.1093/ndt/gfg385
  4. PARKER R, SNEDDEN W, WATTS RW. The quantitative determination of hypoxanthine and xanthine ("oxypurines") in skeletal muscle from two patients with congenital xanthine oxidase deficiency (xanthinuria). Biochem J [online] 1970 Jan, 116(2):317-318 [viewed 23 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1185362

Investigations - Fitness for Management

Fact Explanation
Serum creatinine, serum electrolytes and blood urea Stones can invade the kidney and urinary tract, causing destruction of parenchyma, [1] therefore acute and chronic renal failure are complications of xanthinuria. Therefore assessment of the renal function is important.
References
  1. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825

Investigations - Followup

Fact Explanation
X-ray and ultrasound scan kidney ureter bladder Important to assess the recurrence of the calculus disease. [1]
Urine uric acid level Should be increased with the improvement. [1]
References
  1. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825

Investigations - Screening/Staging

Fact Explanation
Urine culture It is important to see the presence of any infection as it can cause damage to the kidney especially in the presence of an infection. [5]
Serum electrolytes, calcium, magnesium, phosphorus, and uric acid levels Important in evaluating the calculus disease. [3]
Serum creatinine, blood urea Assessment of renal function is important as they can develop acute and chronic renal failure as a complication. [3,4]
Serum uric acid levels in the patient's family Serum uric acid levels in the patient's family should be checked [1] and most of the time this reveals asymptomatic xanthinuria.
Allopurinol loading test Xanthinuria is divided into 2 main types as type 1 and 2, by the allopurinol loading test. This test checks the 2 enzymes: xanthine dehydrogenase and aldehyde oxidase. In type I disease there is lack of xanthine dehydrogenase activity with intact aldehyde oxidase activity. In type 2 disease both the enzymes are lacking. [2]
References
  1. MATEOS FA, PUIG JG, JIMéNEZ ML, FOX IH. Hereditary xanthinuria. Evidence for enhanced hypoxanthine salvage. J Clin Invest [online] 1987 Mar, 79(3):847-852 [viewed 23 July 2014] Available from: doi:10.1172/JCI112893
  2. LEVARTOVSKY DAVID, LAGZIEL AYALA, SPERLING ODED, LIBERMAN URI, YARON MICHAEL, HOSOYA TATSUO, ICHIDA KIMIYOSHI, PERETZ HAVA. XDH gene mutation is the underlying cause of classical xanthinuria: A second report. Kidney Int [online] 2000 June, 57(6):2215-2220 [viewed 22 July 2014] Available from: doi:10.1046/j.1523-1755.2000.00082.x
  3. POLITO C., MANNA A. L., SIGNORIELLO G., MARTE A.. Recurrent Abdominal Pain in Childhood Urolithiasis. PEDIATRICS [online] December, 124(6):e1088-e1094 [viewed 23 July 2014] Available from: doi:10.1542/peds.2009-0825
  4. RULE AD, BERGSTRALH EJ, MELTON LJ III, LI X, WEAVER AL, LIESKE JC. Kidney Stones and the Risk for Chronic Kidney Disease Clin J Am Soc Nephrol [online] 2009 Apr, 4(4):804-811 [viewed 13 September 2014] Available from: doi:10.2215/CJN.05811108
  5. ICHIDA KIMIYOSHI, AMAYA YOSHIHIRO, OKAMOTO KEN, NISHINO TAKESHI. Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans. IJMS [online] 2012 November, 13(12):15475-15495 [viewed 14 September 2014] Available from: doi:10.3390/ijms131115475

Management - General Measures

Fact Explanation
High fluid intake Dehydration and concentrated urine favours the formation of stones, therefore it is necessary to maintain a daily good input. [1]
Restrict the high purine containing food The foods that contain higher amounts of Purines are rich in beef, pork, poultry, seafood, liver, kidney, peas, beans, spinach, and lentils. [1]
Caution with certain drugs Xanthine dehydrogenase enzyme is important for the degradation of azathioprine or 6-mercaptopurine. Aldehyde oxidase whose deficiency can be sometimes accompanied with xanthine oxidase deficiency [3] , important for the metabolism of allopurinol [2] , cyclophosphamide, methotrexate, and quinine. Therefore these drugs can reach toxic levels in the presence of xanthine oxidase deficiency.
References
  1. ICHIDA KIMIYOSHI, AMAYA YOSHIHIRO, OKAMOTO KEN, NISHINO TAKESHI. Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans. IJMS [online] 2012 November, 13(12):15475-15495 [viewed 14 September 2014] Available from: doi:10.3390/ijms131115475
  2. YAMANAKA H, NISHIOKA K, SUZUKI T, KOHNO K. Allopurinol metabolism in a patient with xanthine oxidase deficiency. Ann Rheum Dis [online] 1983 Dec, 42(6):684-686 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1001330
  3. PACHER P.. Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol. Pharmacological Reviews [online] 2006 March, 58(1):87-114 [viewed 14 September 2014] Available from: doi:10.1124/pr.58.1.6

Management - Specific Treatments

Fact Explanation
Treatment of calculi Medical management with follow up or surgical care may be needed in calculus disease. Extracorporeal shock wave lithotripsy and pyelolithotomy [1] are some of the methods used to treat the stones.,
Sodium bicarbonate Oral sodium bicarbonate therapy is used to make the urine alkaline, increase the solu­bility of xanthine and maintain the urine pH at 7. [1]
Management of complications Renal disease may require dialysis and transplantation. [1]
References
  1. ICHIDA KIMIYOSHI, AMAYA YOSHIHIRO, OKAMOTO KEN, NISHINO TAKESHI. Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans. IJMS [online] 2012 November, 13(12):15475-15495 [viewed 14 September 2014] Available from: doi:10.3390/ijms131115475