GOUT

Gout is a type of arthritis that causes sudden swelling and severe pain in the joints.

Hyperuricaemia ( too much Uric acid that stays in the body. Hyperuricaemia causes uric acid to clump together in sharp crystals that settle in your joints = GOUT. Can also build up in your kidneys and form kidney stones.

Deposition of monosodium urate monohydrate crystals in joints & soft tissues Caused by increased production or decreased excretion or both ➔ acute inflammation & eventually tissue damage

Prevalence (UK 2012) of gout = 2.49% Incidence (UK) of gout = 1.77/1000/yr. More common in men (30-60years) and in older people (rare in those under 20 years) – Ratio – 4.3 : 1 (M:F) More likely if FHx - genetic link

Uric acid is end product of purine (adenine & guanine) metabolism Hypoxanthine - Xanthine ( xanthine oxidase) Xanthine - Uric acid (xanthine oxidase)

Completely filtered by glomerulus 90-100% reabsorbed in proximal tubule (URAT-1 specific anion transporter) 50% actively secreted in distal tubule 40-45% post secretary reabsorption ~ 5-10% of original glomerular load is excreted

2/3 of urate excreted in urine 1/3 of urate excreted in gastrointestinal tract

Gout is caused by: Increased rate of synthesis of Purine Precursors of Uric acid (10%) Decreased Elimination of Uric acid by the Kidneys (90%)

Primary: – Due to rare inborn errors of metabolism or renal excretion (not covered here) Secondary: – Occur due to drugs or consequence of other disorder

Over consumption of foods high in purines: – Offal (liver, kidney, heart, sweetbreads), game, oily fish (anchovies, herring, mackerel, sardines, sprats, trout), seafood, yeast or meat extracts

Only about 10% of cases Excessive cell turnover (E.g: neoplastic disease, psoriasis, haemolytic anaemias) Cell lysis caused by cancer chemotherapy & radiotherapy Excessive synthesis of uric acid due to rare enzyme mutation defects.

Occurs in remaining 90% of cases Hyperuricaemia ➔ large urate loads filtered through glomerulus ➔ Increased urate reabsorption to avoid dumping of insoluble urate into urinary tract Also decrease tubular secretion

Renal failure Alcohol (beer, red wine) Drugs: – Diuretics - Especially thiazides, furosemide – aspirin, ciclosporin,, omeprazole, ethambutol, pyrazinamide, niacin, didanosine, levodopa, cytotoxics

Physical Stress – Tight shoes, hill walking, hiking, history of joint trauma Other independent risk factors: hypertension, obesity hypertriglyceridemia

Hyperuricaemia is the most important risk factor for gout Uric acid levels: – Formation and deposition of monosodium urate crystals is more likely to occur when levels are persistently > 380 micromol/mL (solubility limit) HIGHER plasma urate level ➔ Increased incidence of gout PROLONGED DURATION of increased urate levels ➔ increase likelihood of developing gout.

Uric acid = weak acid (pKa 5.8) At physiological pH ➔ ionised ➔ monosodium urate (MSU) If supersaturation occurs ➔ crystal formation Solubility is influenced by: – Temperature, pH, cation concentration, articular dehydration and presence of nucleating agents (nonaggregate proteoglycans, insoluble collagens and chondroitin)

Crystal deposition may continue for many months or years without causing symptoms Only cause symptoms when shed into bursa (small sacs of synovial fluid surrounding joint) ➔ inflammatory reaction Shedding can be triggered by e.g: – Trauma, dehydration, rapid weight loss, illness & surgery

Humoral and cellular inflammatory mediators Complement system Overall this causes: a proinflammatory cascade of cytokines, chemotactic factors, TNF Inflammatory cell accumulation (monocytes and mast cells in the early phase and neutrophils in the later phase) IL-1beta has been shown to be critically related to the inflammatory response in gout

– Asymptomatic hyperuricaemia (long period before gout manifests) – Acute gouty arthritis – Interval gout/Intercritical gout – Chronic tophaceous gout – Gouty nephropathy

90% acute attacks monoarticular 80% first metatarsophalangeal joint of great toe (podagra) Severe pain with hot, red, swollen and extremely painful joints Begin abruptly – max intensity 8-12hrs, Weight bearing impossible, Erythema, Synovitis, Leucocytosis, Confusion in elderly

Left untreated last around 7 days ➔ desquamation of overlying skin Attack at anytime but can be caused by trigger factors (E.g: food, alcohol, dehydration, starting diuretic)

Time between acute attacks of gout Variable intervals of months to years when there are no symptoms

Presence of tophi: – White deposits of monosodium urate – Nodule formation affecting joints – Subcutaneous and periarticular areas – Ear lobes, Achilles tendon, fingers

Crystals of urate deposited around renal tubules ➔ inflammatory response (interstitial nephritis) Proteinuria & renal impairment Renal stone formation