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Provide a brief overview of the 4 main factors which can result in 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
Can a diet high in purine-rich foods lead to gout in a healthy person?
No. Gout is a condition which exemplifies the interplay between genetic predisposition and environmental factors.
What do degradation of nucleic acids and dietary purines lead to the formation of and how is this removed from the body?
Hypoxanthine, which is converted to uric acid and subsequently excreted in the urine.
Mechanism of primary gout?
- - 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.
Mechanism of secondary gout?
- - 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.
What happens when sodium urate crystals precipitate from supersaturated body fluids?
- - 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.
What is a tophus?
- An extracellular soft tissue deposit of urate crystals surrounded by foreign-body giant cells and an associated inflammatory response of mononuclear cells.
Where can renal urate deposits be seen?
- - Between tubules, esp at the apex of the medulla
- - Grossly visible as yellow/golden streaks in the medulla
What are the four clinical stages of gout?
- 1. Asymptomatic hyperuricemia
- 2. Acute gouty arthritisPain that usually involves 1 joint. Later, polyarticular involvement w/ fever. 50% of pts have a painful first metatarso-phalangeal join - podagra
- 3. The intercritical periodAsymptomatic interval between initial acute attack and subsequent attacks.
- 4. Tophaceous goutAppears in the untreated pt in the form of tophi in the cartilage, synovial membranes, tendons and soft tissues.
Steps of purine metabolism?
Purine nucleotides > Hypoxanthine > Xanthine > Uric Acid
*Hypoxanthine to Xanthine and Xanthine to Uric Acid catalysed by Xanthine Oxidase
Impaired secretion of uric acid causes hyperuricemia. What factors affect this?
- - 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 production of uric acid also causes hyperuricemia. What factors affect this?
- - 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
Uric acid is reabsorbed in the tubule by URAT-1 and GLUT9. Describe their function.
- - 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.
How does insulin resistance affect uric acid levels?
- Increases resorption therefore increases levels.
Briefly describe gout as an autoinflammatory disease
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.
Investigations to diagnose gout:
- - Joint Fluid Microscopy
- - Serum Uric Acid
- - Serum Urea, Creatinine, eGFR