Pathophysiology

Gout is abnormal accumulation and precipitation of monosodium urate(MSU) crystals into tissue, usually around the joints, causing recurrent acute or chronic arthritis.

Gout is a classic example of the inflammatory response. When the uric acid comes out of solution, it forms crystals in one or several joints. This will attract large numbers of phagocytic white blood cells to that area in order to clear away the crystals. By doing so, the white blood cells release a package of inflammatory mediator substances(will be discussed later) which, in addition to destroying the crystals, also damage the surrounding tissues - hence the pain, swelling and redness occur.

Although the presence of urate crystals in the soft and synovial tissues is a prerequisite for a gouty attack, the fact that urate crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the presence of intrasynovial urate crystals is not sufficient to cause gouty arthritis. This is because clumps or microtophi of highly negatively charged and reactive MSU crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of MSU crystals to cell receptors. A gout attack may be triggered by either a release of uncoated crystals (for example, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (for example, release of urate due to cellular damage). Naked urate crystals are then interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system of our body.

This interaction may be enhanced by immunoglobulin G (IgG) binding. Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU, results in the production of interleukin (IL)–1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)–alpha. Neutrophil phagocytosis leads to another burst of inflammatory mediator production.

Subsidence of an acute gout attack is due to multiple mechanisms, including the clearance of damaged neutrophils, recoating of urate crystals, and the production of anti-inflammatory cytokines including, IL-1RA, IL-10, and transforming growth factor (TGF)–beta.

Pathophysiology
The greater the duration and degree of hyperuricemia, the greater is the likelihood of getting gout and the more severe are the symptoms of it. Urate levels in the body can be elevated due to 3 causes which are:
• Decreased renal excretion
• Increased production
• Increased purine intake

Decreased renal excretion is the most common cause of hyperuricemia. It may be hereditary and also occurs in patients who are receiving diuretics and in those with diseases that decrease glomerular filtration rate(GFR).

Besides that, ethanol will also increase purine catabolism in the liver and thus increase the formation of lactic acid, which blocks urate secretion by the renal tubules. Therefore, heavy alcoholic drinkers predispose to gout.

Lead poisoning and cyclosporine, usually given to transplant patients, irreversibly damages renal tubules, leading to urate retention in the body.

Increased production of urate may be caused by increased rates of nucleoprotein turnover in haematological conditions (for example, lymphoma, leukaemia, haemolytic anaemia) and in conditions with increased rates of cellular proliferation and cell death (for example, psoriasis, cytotoxic cancer therapy, radiation therapy).

Increased urate production may also occur as a primary hereditary abnormality, and in obesity as the urate production correlates with body surface area. In most cases, the cause is unknown, but a few cases are attributable to enzyme abnormalities, for example, deficiency of hypoxanthine-guanine phosphoribosyltransferase (complete deficiency in Lesch-Nyhan syndrome) is one of the possible causes.

Increased intake of purine-rich foods (eg, liver, kidney, anchovies, asparagus, consommé, herring, meat gravies and broths, mushrooms, mussels, sardines, sweetbreads) can contribute to hyperuricemia. Foods rich in protein such as red meat, kidney and liver contain a high proportion of nucleic material (purines) that is broken down to uric acid. Some wines and beers are also high in purines. However, a strict low-purine diet lowers serum urate by only about 1 mg/dL.

Urate precipitates as needle-shaped monosodium urate (MSU) crystals, which are deposited extracellularly in avascular tissues (for example, cartilage) or in relatively avascular tissues (for example, tendons, tendon sheaths, ligaments, walls of bursae) and skin around cooler distal joints and tissues (for example, ears).

In severe, long-standing hyperuricemia, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such as the kidney. At the acid pH of urine, urate precipitates readily as small platelike or irregular crystals that may aggregate to form gravel or stones, which may cause obstruction. Tophi are MSU crystal aggregates that most often develop in joint and cutaneous tissue.