Gout (hyperuricemia): disorder characterized by high level of uric acid.

Causes Of Gout

• under excretion of uric acid

• over production of uric acid

1. Under excretion of uric acid

Main cause in most patients with gout:

1. Inherited excretory defect of the kidney

2. Excessive consumption of ethanol (because it decreases excretion of uric acid)

2. Over production of uric acid

Primary Causes

defect of one or more of enzymes of purine synthesis

1. Genetic mutation of PRPP synthetase (Phosphoribosyl pyrophosphate)

   • responsible for purine synthesis

   • purines are synthesized in excess and degraded to uric acid

2. Lesch-Nyhan syndrome

   • genetic defect in HGPRT (Hypoxanthine-guanine phosphoribosyltransferase)

   • leads to inability to reuse purines so they are degraded to uric acid

   • X-linked recessive disease

     • Lesch-Nyhan syndrome symptoms:

       • abnormally increased levels of uric acid

       • mental retardation and neurological symptoms

       • self-mutilating behaviors, such as: lip and finger biting and/or head banging

     • In Infants:

       • Urate crystal formation

       • presence of orange colored deposits (“orange sand”)

Secondary Causes

a cause outside the pathway of purine synthesis

1. Increase nuclei acids in diet by eating excess meat

2. Increased cellular breakdown as in malignancy and treatment with anticancer drugs that destroy cancer cells

3. Von-Gierke disease: a genetic disease, deficiency of glucose-6-phosphatase

Clinical Picture

Arises from low solubility of uric acid in body fluids, so insoluble sodium urate crystals precipitate into:

• joints

• kidneys

• soft tissues

Joints

• deposition of needle shaped urate crystals in joints causing severe inflammation (gouty arthritis)

• big toe joint most commonly affected

• joints of: feet, ankles, knees, wrists, fingers, and elbows also affected

• may be accompanied by fever

• joints are: swollen, red, hot, painful

Kidneys

Deposition of sodium urate crystals in the kidney causing uric acid stones

Soft tissue

Nodular masses of sodium urate crystals (tophi) may be deposited under the skin

Treatment

Goals of treatment for gout:

• Rapid pain relief in acute attacks

• Prevention of future gout attacks and the complications, by decreasing formation of uric acid

Acute Attacks

• analgesics and anti-inflammatory

• colchicine decreases movement of granulocytes into affected area

• colchicine and non-steroidal anti-inflammatory drugs can be used prophylactically to prevent acute attacks in patients with gout

Xanthine Oxidase Inhibitors (Allopurinol)

• analog of hypoxanthine

• competitive inhibitor to xanthine oxidase

• accumulation of hypoxanthine (more soluble than uric acid)

• used for long term therapy of gout

Allopurinol is a suicide enzyme inactivator

suicide inhibition: a type of inhibition in which a substrate analog is converted to an inhibitor not released from the enzyme active site

Drugs that increase uric acid excretion (Probenecid)

• effective in regulation of hyperuricemia and prevention of tophii

Alkalinization of urine

• increase solubility of uric acid in urine

Dietary therapy

• avoid purine rich foods

• drink a lot of water