Gout (urate crystal deposition disease) is characterized by hyperuricemia and manifested by recurrent attacks of acute inflammatory arthritis; accumulation of urate crystals to form tophaceous deposits; uric acid urolithiasis, which may precede arthritis or punctuate the course of gout; and nephropathy, which, although common among patients with gout, is usually due to comorbid causes.
Hyperuricemia is appropriately defined as serum urate concentrations exceeding 7.0 mg/dl in men and 6.0 mg/dl in women, employing enzyme-based (uricase) methods of measurement. Serum urate concentrations exceeding 7.0 mg/dl are associated with increased risk for gouty arthritis and uric acid urolithiasis, and the prevalence of these manifestations correlates strongly with the magnitude of hyperuricemia in population studies.
Serum urate values vary considerably among populations sampled and are influenced by many factors, including ethnic background, age, sex, body weight, and body surface area. Renal function, blood pressure, and use of ethanol and a variety of pharmacologic agents are important determinants of urate levels in many individuals.
Hyperuricemia is a common biochemical aberration and is a necessary but not sufficient precondition for development of the gouty state. The majority of hyperuricemic individuals never manifest the clinical features of gout, and moderate hyperuricemia appears to confer no independent risk for development of functionally significant renal impairment. In addition, there is no evidence that hyperuricemia (or gout) plays a causal role in the important disorders with which it is frequently associated, such as obesity, hyperlipidemia, hypertension, atherosclerosis, and the syndrome of hyperinsulinemia and resistance to insulin action.
Acute gouty arthritis is triggered when monosodium urate crystals initiate an inflammatory response. Multiple factors regulate both urate crystal deposition and the inflammatory response, but direct urate crystal interactions with neutrophils and with inflammatory mediator pathways that potentiate neutrophil activation and entry into the joint are crucial to the induction and perpetuation of the attack.
Uric acid is the end product of human purine metabolism, a complex of interacting biochemical pathways whereby (1) purine nucleotides are synthesized either from nonpurine precursors (purine synthesis de novo) or from dietary purines or products of purine nucleotide interconversion and degradation reactions (purine salvage); (2) purine nucleotides are interconverted to provide adequate supplies of adenylates and guanylates for nucleic acid synthesis and for the additional essential roles of purine compounds in differentiated cell activation, cellular energy metabolism, and nonpurine biosynthetic and catabolic pathways; and (3) purines are degraded to uric acid in a series of catabolic reactions. These pathways are regulated and integrated at several levels.
Uric acid production and excretion are balanced processes in which, under normal circumstances, about two thirds of the uric acid turned over daily is excreted by the kidneys and virtually all the rest is eliminated via intestinal bacterial uricolysis. In renal failure and in many hyperuricemic individuals, extrarenal uric acid disposal is increased.
Serum urate concentration is a function of both synthetic and degradative rates. Hyperuricemia may result from uric acid overproduction or underexcretion or from a combination of both mechanisms. Hyperuricemia may be primary or the secondary result of a concurrent condition. Excessive dietary purine intake is rarely a cause of sustained hyperuricemia.
Primary gout is a biochemically and genetically heterogeneous category, presumably attributable to inborn metabolic errors altering uric acid homeostasis. The biochemical defects in the majority of patients are not yet defined. In most gouty subjects, there is reduced renal fractional clearance of urate, which is most prominent in individuals with normal or reduced daily urinary uric acid excretion. This defect may be the major or sole basis of hyperuricemia.
Three different inherited enzyme defects result in early development of marked hyperuricemia and gout. In glucose-6-phosphatase deficiency (glycogen storage disease type I), hyperuricemia results from both excessive uric acid production and impaired uric acid excretion. In severe and partial deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and in superactivity of 5-phosphoribosyl-1-pyrophosphate synthetase (PRS), the basis of hyperuricemia is purine nucleotide and uric acid overproduction. Accelerated purine synthesis in these two disorders is a consequence of increased intracellular availability of PP-ribose-P, a critical regulatory intermediate in the pathway of purine synthesis de novo. The precise biochemical bases of neurologic manifestations encountered in patients with severe HPRT deficiency or defects in the regulation of PP-ribose-P synthetase (PRS) activity remain unknown.
Both genetic and environmental factors contribute to the high prevalence of hyperuricemia in many populations. Cumulative effects of multiple genes are more prominent when heterogeneous populations are studied. Single gene influences, some autosomal dominantly transmitted and some X-linked, are identifiable in studies of less genetically diverse groups. Glucose-6-phosphatase deficiency is an autosomal recessive trait. Both HPRT deficiency and PRS superactivity are X-linked traits.
Although accelerated PP-ribose-P and purine nucleotide synthesis characterize all instances of PRS superactivity, the kinetic mechanisms and genetic defects underlying this disorder are heterogeneous. Point mutations in PRPS1, one of two X-linked genes encoding highly homologous PRS isoforms, result in mutant PRS1 enzymes with defective allosteric properties and account for PRS superactivity with resistance to inhibition of enzyme activity by purine nucleotides. In contrast, PRS1 structure and regulation of PRS activity are normal in another form of PRS overactivity (“catalytic superactivity”), but the PRS1 isoform is overexpressed as a consequence of selectively accelerated transcription of PRPS1.
Specific and effective pharmacologic therapy for gout is available. Anti-inflammatory drugs and colchicine are used to treat and prevent acute gouty attacks. Two classes of antihyperuricemic agents are available to lower serum urate levels into the normal range, thus reducing the frequency of acute gouty arthritis, tophus formation, and urolithiasis. Uricosuric agents inhibit renal tubular postsecretory reabsorption of uric acid, promoting renal uric acid excretion. Uric acid production is decreased by administration of allopurinol, a purine base analogue that inhibits xanthine oxidase.