Uric Acid Metabolism & Gout

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

Purine Bases (Adenine or Guanine)

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

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

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

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

Gout 1- The hyperuricaemia can lead to sodium urate crystals in the 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) 2- Formation of uric acid stones in the kidney may be also seen (nephrolithiasis)

Gouty Arthritis

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

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

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

Diagnosis of 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

Monosodium urate crystals

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