Disorders of purine metabolism, hyperuricemia, gout

Question 1

Congenital Causes of hyperuricemia

Answer 1

Congenital:

• HPRT deficiency, Lesh Nyan syndrome, Hpoxanthine-guanine phosphoribosyl transferase.
  
  • No purine salvage so there is excessive breakdown
  • Excessive PRPP stimulates constant purine synthesis.
  • hyperuricemia
  • Mental retardation and self mutilation
  • X linked, affects males. females can be affected but are just prone to hyperuricemia and spared the other symptoms (heterozygous)
• Von Gierke’s disease
  
  • G6Phosphatase
  • Liver can’t perform glycogenolysis
  • Liver can’t release glucose from gluconeogenesis (trapped in cells by phosphorylation)
  • Causes trapping of phosphate, and buildup of AMP and ADP.
  • AMP and ADP get degraded, causing hyperuricemia.
• Fructose intolerance,
  
  • aldolase B deficiency
  • normally exogenous fructose is taken up by the liver and phosphorylated to F-1-P and cleaved by aldolase B.
  • Deficiency causes phosphate trapping as aldolase A is much slower at cleaving this.
  • F-1-P also inhibits:
    
    • glycogen phosphorylase
    • aldolase A
    • F1-6-bisphosphatase
  • Essentially F-1-P buildup halts gluconeogenesis glycogenolysis, inducing hypoglycemia.
  • Phosphate trapping causes buildup of AMP, generating hyperuricemia.

Question 2

Acquired hyperuricemia

Answer 2

Idiopathic, primary gout is the most common due to unknown cause of hyperuricemia.

Myeloproliferative disorders

Leukemia

Renal insufficiency and decreased excretion

Tumor lysis syndrome

Cytotoxic drugs - Thiazide

Obesity

Alcoholism - alcohol induces lactic acid in the kidneys, competes with uric acid (both weak acids) for excretion, causing uric acid buildup.

Diuretics - also weak acids and compete for uric acid exretion.

Question 3

Symptoms of hyperuricemia

Answer 3

Sodium Urate deposits

• Uric acid renal stones
• Deposits in soft issues, bones, cartilage –> joint inflammation, pain, chronically ulceration and atrophy
• Causes acut inflammation, swelling, and severe pain.
• Prediliction to affect the metatarsophalangeal joint of the first toe.

Question 4

Diagnosis of gout

Answer 4

Location of inflammation,

Definitive diagnosis is by synovial fluid aspiration of the joing.

Negative birefringence of urate crystals in the fluid and tissue. blue or yellow coloration depending on the crystals orientation wit hrespect to the polarizing filter.

Question 5

Consequences of chronic hyperuricemia/gout

Answer 5

Tophus development, a stone formation of chalky white aggregated uric acid crystals within a joint or soft tissue. Most often in the fingers and toes. Painful, disfiguring.

Chroinc Renal Failure - Urate crystal nephropathy from tubular damage.