TY - CHAP M1 - Book, Section TI - Hyperuricemia and Gout A1 - Dalbeth, Nicola A1 - Merriman, Tony A2 - Valle, David L. A2 - Antonarakis, Stylianos A2 - Ballabio, Andrea A2 - Beaudet, Arthur L. A2 - Mitchell, Grant A. Y1 - 2019 N1 - 10.1036/ommbid.134 T2 - The Online Metabolic and Molecular Bases of Inherited Disease AB - The clinical features of gout occur due to the host response to monosodium urate (MSU) crystal deposition. Gout (urate crystal deposition disease) is characterized by hyperuricemia and manifested by recurrent attacks of acute gouty arthritis, tophaceous disease, and chronic gouty arthropathy.Definitions of hyperuricemia vary; most often hyperuricemia is 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.Serum urate concentrations 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. It 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.Acute gouty arthritis is triggered when monosodium urate crystals initiate an inflammatory response. Activation of the NLRP1 inflammasome by MSU crystals and release of mature IL-1β are key mediators in the initiation phase of the acute gout flare. Multiple additional factors regulate both urate crystal deposition and the inflammatory response.Uric acid is the end product of human purine metabolism, a complex of interacting biochemical pathways whereby (1) purine nucleotides are synthesized either from non-purine 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 non-purine 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. Hyperuricemia results from a combination of uric acid over-production, renal under-excretion or gut under-excretion. Over-production resulting from dietary factors is rarely a cause of sustained hyperuricemia.Primary gout is a biochemically and genetically heterogeneous condition. The biochemical basis of common gout is being 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. Reduced renal clearance is a major basis of hyperuricemia. Renally expressed uric acid transport molecules are being identified (URAT1, SLC2A9, NPT1, and OAT4 are prominent). The ATP-dependent ABCG2 molecule is important in extra-renal excretion.Both genetic and environmental factors contribute to hyperuricemia and gout. Established risk factors are dietary purines from red meat, alcohol and sugar-sweetened soft drink consumption. Genome-wide scanning studies have shown that the cumulative effects of multiple genes explain an appreciable proportion of variance in serum ... SN - PB - McGraw-Hill Education CY - New York, NY M3 - doi: 10.1036/ommbid.134 Y2 - 2024/04/19 UR - ommbid.mhmedical.com/content.aspx?aid=1181440444 ER -