Page 802 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

788 C H A P T E R 20 Bones, Joints, and Soft Tissue Tumors

HGPRT, an enzyme essential in the salvage pathway, gives rise release proteases (e.g., collagenase) that exacerbate tissue
to the Lesch-Nyhan syndrome. In secondary gout, injury. The resulting acute arthritis typically remits in days to
hyperuricemia can be caused by increased urate production weeks, even if untreated. Repeated bouts, however, can lead
(e.g., rapid cell lysis during chemotherapy for lymphoma or to the permanent damage seen in chronic tophaceous
leukemia) or decreased excretion (chronic renal insuffi- arthritis.
ciency), or both. Reduced renal excretion may also be caused
by drugs such as thiazide diuretics, presumably because of Clinical Features
effects on uric acid tubular transport. Gout is more common in men than in women; it does not
usually cause symptoms before the age of 30. Risk factors
Whatever the cause, increased levels of uric acid in the for the disease include obesity, excess alcohol intake, con-
blood and other body fluids (e.g., synovium) lead to the sumption of purine-r ich foods, diabetes, the metabolic
precipitation of monosodium urate crystals. This, in turn, syndrome, and renal failure. Polymorphisms in genes
triggers a chain of events that culminate in joint injury (Fig. involved in the transport and homeostasis of urate such as
20–22). Urate crystals are thought to directly activate the URAT1 and GLUT9 also are associated with hyperuricemia
complement system, leading to production of chemotactic and gout.
and pro-inflammatory mediators. The crystals are phagocy-
tosed by macrophages and recognized by the intracellular Four stages are classically recognized: (1) asymptomatic
sensor called the inflammasome (Chapter 2), which is acti- hyperuricemia, (2) acute gouty arthritis, (3) “intercritical”
vated and stimulates the production of the cytokine IL-1. IL-1 gout, and (4) chronic tophaceous gout. Asymptomatic hyper-
is a mediator of inflammation, and causes local accumulation uricemia appears around puberty in males and after meno-
of neutrophils and macrophages in the joints and synovial pause in women. After a long interval of years, acute
membranes. These cells become activated, leading to the arthritis appears in the form of sudden onset, excruciating
release of a host of additional mediators including chemo- joint pain associated with localized erythema, and warmth;
kines, other cytokines, toxic free radicals, and leukotrienes— constitutional symptoms are uncommon, except possibly
particularly leukotriene B4. The activated neutrophils also mild fever. The vast majority of first attacks are monoar-
liberate destructive lysosomal enzymes. The cytokines can ticular; 50% occur in the first metatarsophalangeal joint
also directly activate synovial cells and cartilage cells to

Hyperuricemia
Precipitation of urate crystals in joints

Complement
activation

Neutrophil chemotaxis Phagocytosis by
monocytes
Phagocytosis of crystals Rperolesatasgeloanf dLTinBs4,,
by neutrophils free radicals Release of IL-1,
Release TNF, IL-6
of crystals
Cartilage
Synovium

Lysis and activation of neutrophils

Release of Release of
lysosomal enzymes proteases

Tissue injury and
inflammation

Figure 20–22 Pathogenesis of acute gouty arthritis. IL, interleukin; LTB4, leukotriene B4; TNF, tumor necrosis factor.