Gout pathophysiology

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

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
• Etiology in lot of cases with rise in uric acid levels is still unknown.
  

Increased intake

The increased uptake is mainly related to

• 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/Reduced renal excretion

This is the most common cause of hyperuricemia. Various factors responsible for its reduced elimination are:

• Hereditary
• Compromised renal function ( Reduced GFR)
• On Diuretics
• Alcohol intake
  • The lactic acid blocks the excretion of urate from the from the renal tubules. Alcohol induces the purine metabolism in the liver and increases the formation of lactic acid and
  • Alcohol also directly stimulates the synthesis of urate by the liver

• Drugs like cyclosporine that are toxic to the renal tubules leads to the decreased elimination of uric acid and ultimately resulting in the 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.

Microscopic Pathology

Gout (Needles, no birefringence, monosodium urate)

Skin: Tophus: Micro med mag H&E uric acid deposits with giant cells. Easily recognizable as gout or uric acid tophus

Skin: Tophus: Micro med mag H&E easily recognized uric acid deposit lesion from elbow

Bones-Joints: Gout

Sources

Copyleft images obtained courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA) Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology