Pathophysiology

 

Gout = inflammatory response to excess amounts of uric acid (UA) in the body resulting in acute attacks of arthritis.

UA = byproduct of purine metabolism, normally excreted by kidneys

  • At low levels, UA = important antioxidant
  • At higher levels, UA = pro-oxidant, pro-inflammatory

If hyperuricemia continues, chronic illness will develop that is characterized by the presence of inflammatory nodules in the joint and subcutaneous tissue, severe pain, limited movement, and grotesque deformity.

Clinical manifestations

  • hyperuricemia
  • recurrent attacks of acute gout limited to one joint
  • monosodium urate (MSU) crystals form tophi in and around the joints
  • renal disease
  • formation of MSU renal stones

Three clinical stages

  1. asymptomatic hyperuricemia – may go unnoticed, may persist throughout life if disease does not progress
  2. acute gouty arthritis – acute attack of pain, heat, swelling, and erythema localized to one joint
  3. tophaceous gout – progressive tophi deposition in cartilage, tendons, synovial membranes, and soft tissues
    Figure 5. Tophaceous gout (Johns Hopkins Arthritis Center, 2019.)

Pathophysiology

Over time, elevated ↑UA → formation and deposition of monosodium urate (MSU) crystals

  • In and around joints
  • In subQ tissues
  • In kidneys

MSU crystal deposition causes

  • Cytokine-mediated inflammatory response characterized by
    • Release of TNF-α
    • Release of chemokines and interleukins
    • Initiation of complement system
  • Triggers activation of macrophages and neutrophils
    • Release of cellular contents exacerbates inflammation
      Figure 6. Gout pathology (Journal of Advanced Research, 2017).

Long-term accumulation of MSU crystals results in

  • Gouty arthritis – ranges from acute attacks of monoarticular arthritis to chronic arthritis characterized by permanent joint damage
  • Tophi – small, white, nodular crystal deposits in subcutaneous tissues
  • Renal calculi
  • Acute nephropathy resulting from crystal deposition in renal tubules
    Gout Tophi

Figure 7. Gout Tophi (Barbara Brody, 2019).

CKD ⇔ gout

Primary gout – underexcretion or overproduction of ↑UA caused by an unknown metabolic defect

  • Majority of individuals with gout have primary gout

Secondary gout –  underexcretion or overproduction of ↑UA due to known etiology

  • Accelerated rate of purine synthesis
  • Accelerated rate of purine catabolism
  • Genetic deficiency in HGPRT enzyme
  • Lesch-Nyhan syndrome – X-linked genetic disorder, complete absence of HGPRT