Uric Acid Metabolism Uric Acid Metabolism & Gout& Gout

Nucleic AcidsNucleic Acids

MononucleotideMononucleotideBase + Sugar + Phosphoric AcidBase + Sugar + Phosphoric Acid

BaseBase: Purine or Pyrimidine: Purine or Pyrimidine

Polynucleotide (DNA or RNA)Polynucleotide (DNA or RNA)Mononucleotides bound by PDE bondsMononucleotides bound by PDE bonds

DNA

Purine Bases (Purine Bases (AAdenine or denine or GGuanine)uanine)

Dietary nucleic acids (DNA & RNA) Dietary nucleic acids (DNA & RNA) 1- Dietary DNA & RNA are degraded in the small intestine lumenlumen to give free

purine & pyrimidine bases.

2- Purine bases are transported to intestinal mucosal cells intestinal mucosal cells

3- Inside intestinal mucosal cells, purine bases are catabolized into uric aciduric acid

4- Uric acid is transported to bloodblood & finally excreted in the kidneykidney to appear in

urineurine

Cellular nucleic acids (DNA & RNA)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 uric acid

3- Uric acid is carried by bloodblood to kidneyskidneys to be excreted in urineurine.

Purine nucleotides degradationPurine nucleotides degradation

Fate of Dietary Nucleic AcidsFate of Dietary Nucleic Acids

Nucleic acids (DNA & RNA) of diet

in lumen of GIT

Purines (adenine & guanine) ABSORBED

in intestinal mucosal cells

Uric AcidUric Acid to blood

circulation

URINE

Degradation of Purine NucleotidesDegradation of Purine Nucleotides

• The end product of purine nucleotides degradation is The end product of purine nucleotides degradation is uric aciduric acid

in primates (higher mammals including humans)in primates (higher mammals including humans)

• Uric acid is oxidized to Uric acid is oxidized to allantoinallantoin (by uricase enzyme) (by uricase enzyme)

in mammals other than primatesin mammals other than primates

• Allantoin is further degraded to Allantoin is further degraded to urea or ammoniaurea or ammonia

in animals other than mammalsin animals other than mammals

Fate of uric acid in humansFate of uric acid in humans

Excessive production of uric acid causes:

HyperuricemiaHyperuricemia : increased uric acid level in blood (laboratory investigation)GoutGout: Clinical manifestations that appear due to hyperuricemia that maymay lead to deposition of uric acid crystals in joints & kidneys (urate crystals)

Hyperuricemia does Hyperuricemia does not always not always cause goutcause gout

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

GoutGout

1- The hyperuricaemia can lead to sodium urate crystals in the joints causing an acute then chronic gouty arthritisgouty 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 uric acid stones in the kidney may be also seen (nephrolithiasis)

Gouty ArthritisGouty Arthritis

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Sodium urate crystals in urineSodium urate crystals in urine

HyperuricemiaHyperuricemia: Elevation of uric acid level in blood above than 7.0 mg/dL

Uric acid level in blood is increased due to :Uric acid level in blood is increased due to :Underexcretion (more common)Overproduction

Causes of hyperuricemia (& Gout)Causes of hyperuricemia (& Gout)

Causes of hyperuricemia (& Gout)Causes of hyperuricemia (& Gout)

1- Under excretion of uric acid (Renal causes):Under excretion of uric acid (Renal causes):

PrimaryPrimary

Inherent excretory defect of urates

SecondarySecondary

Chronic renal disease

Lactic acidosis

Ketosis

2- Overproduction of uric acidOverproduction of uric acid:

Primary : Inherited metabolic disorders in one of enzymes of purine degradation Secondary: 1- increased nucleic acid turnoverturnover : as in cancer, chemotherapy, radiotherapy .2- Excessive intake of purine-rich foods purine-rich foods such as meat

Causes of hyperuricemia (& Gout)Causes of hyperuricemia (& Gout)

Diagnosis of gouty arthritisDiagnosis of gouty arthritis

The definitive diagnosis of gouty arthritis 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 Hyperuricemia alone is notnot enough for enough for diagnosis of gouty arthritisdiagnosis of gouty arthritis

(i.e. not conclusive)

Diagnosis is confirmed by synovial fluid Diagnosis is confirmed by synovial fluid aspirationaspiration

Monosodium urate crystalsMonosodium urate crystals

Treatment of hyperuricemia & goutTreatment of hyperuricemia & gout

Symptomatic treatmentSymptomatic treatment

Medications to reduce pain & inflammation (analgesics, anti-Medications to reduce pain & inflammation (analgesics, anti-

inflammatory drugs)inflammatory drugs) Increasing uric acid excretion Increasing uric acid excretion (uricosuric agents)(uricosuric agents)Reducing uric acid productionReducing uric acid productionAllopurinol (xanthine oxidase inhibitor)Allopurinol (xanthine oxidase inhibitor)Avoidance of purine-rich foodAvoidance of purine-rich food