Gout

• Gout can result from:
• 1) Overproduction of purines
• 2) Increased catabolism of nucleic acids due to greater cell turnover
• 3) decreased salvage of free purine bases
• 4) decreased urinary uric acid excretion

No. Gout is a condition which exemplifies the interplay between genetic predisposition and environmental factors.

Hypoxanthine, which is converted to uric acid and subsequently excreted in the urine.

• - 85% of the time results from an as-yet unexplained impairment of renal uric acid excretion. In the remainder, there's an overproduction of uric acid, but the cause remains unknown.
• - Defects in hypoxanthine phosphoribosyl transferase (HPRT) lead to enhanced levels of purine synthesis. Lesch-Nyhan Syndrome represents total lack of HPRT.

• - Associated with a number of conditions which lead to hyperuricaemia.
• - Increased uric acid production is most often associated with an increased nucleic acid turnover, as seen in leukaemias and lymphomas after chemo.
• - Alcohol abuse due to accelerated ATP catabolism & decreased renal excretion of uric acid.
• - Reduced urate excretion may result from primary renal disease.
• - Dehydration and diurectics increase tubular reabsorption of uric acid, resulting in hyperuricaemia.

• - The absorb fibronectin, complement and a number of other proteins on their surface. 
• - Neutrophils that have ingested urate crystals release ROS and lysosomal enzymes, which mediate tissue injury and promote inflammatory response.

- An extracellular soft tissue deposit of urate crystals surrounded by foreign-body giant cells and an associated inflammatory response of mononuclear cells.

• - Between tubules, esp at the apex of the medulla
• - Grossly visible as yellow/golden streaks in the medulla

• 1. Asymptomatic hyperuricemia
• 2. Acute gouty arthritis
• Pain that usually involves 1 joint. Later, polyarticular involvement w/ fever. 50% of pts have a painful first metatarso-phalangeal join - podagra
• 3. The intercritical period
• Asymptomatic interval between initial acute attack and subsequent attacks.
• 4. Tophaceous gout
• Appears in the untreated pt in the form of tophi in the cartilage, synovial membranes, tendons and soft tissues.

Purine nucleotides > Hypoxanthine > Xanthine > Uric Acid

*Hypoxanthine to Xanthine and Xanthine to Uric Acid catalysed by Xanthine Oxidase

• - Chronic renal disease
• - Drugs: thiazide diuretics, aspirin
• - Hypertension
• - Lead toxicity
• - Primary hyperparathyroidism or hypothyroidism
• - Increased lactic acid production from alcohol, exercise, starvation
• - G-6-P deficiency

• - Increased purine synthesis due to:
• 1) HGPRT reduction due to x-linked error; Lesch-Nyhan syndrome.
• 2) G-6-P deficiency with glycogen storage disease type I
• 3) Phosphoribsyl-pyrophosphate synthase overactivity

• Increased turnover of purines due to:
• 1) Myeloproliferative disorders (eg polycythemia)
• 2) Lymphoproliferative disorders (eg leukemia)
• 3) Others inc carcinoma and psoriasis

• - URAT-1 acts in the PCT to reabsorb 98% of uric acid (although 40% is subsequently resecreted into the tubule)
• - GLUT9 transports uric acid along with glucose and fructose.

- Increases resorption therefore increases levels.

Receptor NLRP3 activates IL-1beta, which in turn activates more cells and triggers and IL-8 mediated influx of neutrophils. Ingestion of sodium urat crystals by polymorphonuclear leucocytes causes release of pro-inflammatory cytokines.

• - Joint Fluid Microscopy
• - Serum Uric Acid
• - Serum Urea, Creatinine, eGFR