1. Uric Acid Metabolism & Gout

2. Nucleic Acids Mononucleotide Base + Sugar + Phosphoric Acid Base: Purine or Pyrimidine Polynucleotide (DNA or RNA) Mononucleotides bound by PDE bonds DNA

3. Purine Bases (Adenine or Guanine)

4. Dietary nucleic acids (DNA & RNA) Dietary nucleic acids (DNA & RNA) lumen 1- Dietary DNA & RNA are degraded in the small intestine lumen to give free purine & pyrimidine bases. intestinal mucosal cells 2- Purine bases are transported to intestinal mucosal cells uric acid 3- Inside intestinal mucosal cells, purine bases are catabolized into uric acid bloodkidney 4- Uric acid is transported to blood & finally excreted in the kidney to appear in urine urine Cellular nucleic acids (DNA & RNA) Cellular nucleic acids (DNA & RNA) 1- DNA & RNA in cells are degraded to purine & pyrimidine nucleotides uric acid 2- Purine bases in purine nucleotides are degraded to uric acid blood kidneysurine 3- Uric acid is carried by blood to kidneys to be excreted in urine. Purine nucleotides degradation

5. Fate of Dietary Nucleic Acids Nucleic acids (DNA & RNA) of diet in lumen of GIT Purines (adenine & guanine) ABSORBED in intestinal mucosal cells Uric Acid to blood circulation URINE

6. Degradation of Purine Nucleotides The end product of purine nucleotides degradation is uric acidThe end product of purine nucleotides degradation is uric acid in primates (higher mammals including humans) in primates (higher mammals including humans) Uric acid is oxidized to allantoin (by uricase enzyme)Uric acid is oxidized to allantoin (by uricase enzyme) in mammals other than primates in mammals other than primates Allantoin is further degraded to urea or ammoniaAllantoin is further degraded to urea or ammonia in animals other than mammals in animals other than mammals

7. Fate of uric acid in humans Excessive production of uric acid causes: Hyperuricemia Hyperuricemia : increased uric acid level in blood (laboratory investigation) Gout Gout: Clinical manifestations that appear due to hyperuricemia may that may lead to deposition of uric acid crystals in joints & kidneys (urate crystals) Hyperuricemia does not always cause gout Hyperuricemia does not always cause gout

8. Renal handling of uric acid is complex and involves four sequential steps:  Glomerular filtration of virtually all the uric acid in capillary plasma entering the glomerulus.  Reabsorption in the proximal convoluted tubule of about 98 to 100% of filtered uric acid.  Subsequent secretion of uric acid into the lumen of the distal portion of the proximal tubule.  Further reabsorption in the distal tubule.  Hyperuricemia is defined by serum or plasma uric acid concentrations higher than 7.0 mg/dl (0.42mmol/L) in men or greater than 6.0 mg/dl (0.36mmol/L) in women

9. Gout 1- The hyperuricaemia can lead to sodium urate crystals in the gouty arthritis joints causing an acute then chronic gouty arthritis leading to pain in joints with limitation of movements especially big toe (start in small joints then to big joints) uric acid stones in the kidney 2- Formation of uric acid stones in the kidney may be also seen (nephrolithiasis)

11. Gouty Arthritis

12. Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc. Sodium urate crystals in urine

13. Hyperuricemia Hyperuricemia: Elevation of uric acid level in blood above than 7.0 mg/dL Uric acid level in blood is increased due to : Underexcretion (more common) Overproduction Causes of hyperuricemia (& Gout)

14. Under excretion of uric acid (Renal causes): 1- Under excretion of uric acid (Renal causes): Primary Inherent excretory defect of urates Secondary Chronic renal disease Lactic acidosis Ketosis

15. Overproduction of uric acid 2- Overproduction of uric acid: Primary : Inherited metabolic disorders in one of enzymes of purine degradation Secondary: turnover 1- increased nucleic acid turnover : as in cancer, chemotherapy, radiotherapy. purine-rich foods 2- Excessive intake of purine-rich foods such as meat Causes of hyperuricemia (& Gout)

16. Diagnosis of gouty arthritis gouty arthritis The definitive diagnosis of gouty arthritis requires aspiration and examination of synovial fluid from an affected joint (or material from a tophus) using polarized light microscopy to confirm the presence of needle-shaped monosodium urate crystals VERY IMPORTANT Hyperuricemia alone is not enough for diagnosis of gouty arthritis (i.e. not conclusive) Diagnosis is confirmed by synovial fluid aspiration

17. Monosodium urate crystals

18. Treatment of hyperuricemia & gout Symptomatic treatment Symptomatic treatment Medications to reduce pain & inflammation (analgesics, anti- Medications to reduce pain & inflammation (analgesics, anti- inflammatory drugs) inflammatory drugs) Increasing uric acid excretion (uricosuric agents) Increasing uric acid excretion (uricosuric agents) Reducing uric acid production Reducing uric acid production Allopurinol (xanthine oxidase inhibitor) Allopurinol (xanthine oxidase inhibitor) Avoidance of purine-rich food Avoidance of purine-rich food