Gout pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shivam Singla, M.D.[2]

Overview

Pathophysiology

The pathophysiology of Gout mainly relates to hyperuricemia. Greater is the degree of hyperuricemia greater is the likelihood of developing Gout. There are numerous reasons that can lead to the development of increase in level of uric acids:

Enhanced or increased purine uptake.
Decreased excretion of uric acid
Increased production of uric acid

Although these are the most common responsible factors for the development of gout but still for lot of cases the rise in uric acid levels is still unknown.

Increased intake

The increased uptake is mainly related to the increases intake of purine rich food substances by the patient such as

Asparagus, met broths, mushrooms, liver, kidney, sweetbreads, .
The increased intake of all of these substances can increase the risk of accumulation of more and more purines ultimately resulting in the excess of uric acid.

Beer is also particularly rich in guanosine which is a purine nucleotide.

Increased production

The increased production is mainly related to conditions associated with

Increase in turn over of of cells like in various hematological conditions such as Hemolytic anemia, leukemia and lymphoma.
Conditions associated with increase rate of cell proliferation and cell death.
- Cytotoxic therapy
- Radiation
- Psoriasis
Obesity - As the urate production is directly proportional to the body surface area
Hereditary conditions
Enzyme abnormalities
- Overactivity of Phosphoribosyl transferase
- Deficiency of HGPRT
- Absence of HGPRT ( Lesch-nyhan syndrome)

Decreased renal excretion is by far the most common cause of hyperuricemia. It may be hereditary and also occurs in patients receiving diuretics and in those with diseases that decrease GFR. Ethanol increases purine catabolism in the liver and increases the formation of lactic acid, which blocks urate secretion by the renal tubules, and ethanol may also stimulate liver urate synthesis. Lead poisoning and cyclosporine, usually in the higher doses given to transplant patients, damage renal tubules, leading to urate retention.

Increased production of urate may be caused by increased nucleoprotein turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis, cytotoxic cancer therapy, radiation therapy). Increased urate production may also occur as a primary hereditary abnormality and in obesity, because urate production correlates with body surface area. In most cases, the cause of urate overproduction is unknown, but a few cases are attributable to enzyme abnormalities; deficiency of hypoxanthine-guanine phosphoribosyltransferase (complete deficiency is Lesch-Nyhan syndrome) is a possible cause, as is overactivity of phosphoribosylpyrophosphate synthetase.

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. Beer is particularly rich in guanosine, a purine nucleoside. 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 (eg, cartilage) or in relatively avascular tissues (eg, tendons, tendon sheaths, ligaments, walls of bursae) and skin around cooler distal joints and tissues (eg, 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 diamond-shaped uric acid crystals that may aggregate to form gravel or stones, which may obstruct urine outflow. Tophi are MSU crystal aggregates that most often develop in joint and cutaneous tissue. They are usually encased in a fibrous matrix, which prevents them from causing acute inflammation.

Acute gouty arthritis may be triggered by trauma, medical stress (eg, pneumonia or other infection), surgery, use of thiazide diuretics or drugs with hypouricemic effects (eg, allopurinol, febuxostat, probenecid, nitroglycerin), or indulgence in purine-rich food or alcohol. Attacks are often precipitated by a sudden increase or, more commonly, a sudden decrease in serum urate levels. Why acute attacks follow some of these precipitating conditions is unknown. Tophi in and around joints can limit motion and cause deformities, called chronic tophaceous gouty arthritis. Chronic gout increases the risk of developing secondary osteoarthritis.