Uric acid and gout

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How and why uric acid cause gout? Let’s see relation between uric acid and gout.

Uric acid and gout is a bit synonymous. So we start from hyperuricaemia. Hyperuricaemia is defined as rise of serum uric acid level greater than 2 standard deviations above the mean for the population. The risk of developing gout increases with age and with serum uric acid levels. Levels are higher in men, increase with age and are associated with body weight. Levels are higher in some ethnic groups (such as Maoris and Pacific islanders e.g. Filipinos and Samoans). When the serum urate concentration exceeds the limit of solubility of monosodium urate in the serum, which is 6.8 mg/dL at 37°C it is called hyperuricemia. In most epidemiologic studies, the upper limit has been rounded off at 7 mg/dL in men and 6 mg/dL in women. A serum urate value in excess of 7 mg/dL begins to carry an increased risk of gouty arthritis or renal stones.

About one third of the body uric acid pool is derived from dietary sources and two thirds from endogenous purine metabolism. The concentration of uric acid in body fluids depends on the balance between endogenous synthesis, and elimination by the kidneys (two thirds) and gut (one third). Purine nucleotide synthesis and degradation are regulated by a network of enzyme pathways. Xanthine oxidase catalyse the end conversion of hypoxanthine to xanthine and then xanthine to uric acid. When balance between formation and excretion of uric acid is hampered uric acid level rises in blood.

uric acid and gout
uric acid and gout

The ionized forms of uric acid readily form salts, which are monosodium and disodium or potassium urates. In extracellular fluids, in which sodium is the principal cation, approximately 98% of uric acid is in the form of monosodium salt at a pH of 7.4. As the urine is acidified along the renal tubule, a portion of urinary urate is converted to uric acid. The solubility of uric acid in aqueous solutions is substantially less than that of urate. At pH 5, urine is saturated with uric acid at 15 mg/dL; at pH 7, urine accommodates 158 to 200 mg/dL in solution. The limited solubility of uric acid in urine of pH 5 is of particular significance in patients with gout, many of whom display a tendency toward the excretion of unusually acidic urine. Then uric acid deposited due to precipitation in joints, kidney and other cavities where pH is greater. This uric acid causes inflammatory reaction and that is gout.

During the initial phase of an acute gout attack, there is an influx of polymorphonuclear leukocytes into the synovial fluid. Inflammatory cytokines stimulate the synovial lining layer to become hyperplastic and infiltrated with neutrophils, monocyte-macrophages, and lymphocytes. These inflammatory responses are triggered by monosodium urate crystals that are either formed de novo or released from preformed deposits in or around the joint. Debris or other factors within the synovial cavity may also provide an initial nucleus for early crystal development. Mast cells may play a critical role in the initial event. They contain preformed proinflammatory substances, including histamine, cytokines, and enzymes, all of which may contribute to the promotion of downstream inflammatory cascades. Depletion of endogenous mast cells has been found to significantly inhibit neutrophil influx in a murine monosodium urate crystal induced peritonitis model.

It appears, however, that innate immunity the system that provides the first line of defense against infectious agents plays a critical role in the initial inflammatory response in acute gout. Monosodium urate crystals activate both the classic and the alternative complement pathways, leading to the production of C5a, which is chemotactic for leukocytes, and the formation of C5b-C9, the membrane attack complex.

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