Introduction to Gout
Gout is a disorder that is related to excess production and deposition of uric acid crystals. Uric acid is the byproduct of purine nucleotide catabolism. The root cause of gout is hyperuricemia and it is characterized by recurrent attacks of acute inflammatory arthritis. The formation of urate crystals leads to the formation of tophaceous deposits (sandy, gritty, nodular masses of urate crystals), particularly in the joints which precipitates the episodes of gouty arthritis. Gouty arthritis is the most painful manifestation of gout and is caused when urate crystals interact with neutrophils triggering an inflammatory response.
Gout does not occur in the absence of hyperuricemia. Hyperuricemia is defined as a serum urate concentration exceeding 6.8mg/dL in both men and women. However, it should be noted that serum urate concentrations vary markedly among different populations and the values are influenced by such things as age, sex, ethnicity, body weight, and the surface area of the body. Hyperuricemia can result from either excess uric acid production or reduced excretion or a combination of both mechanisms. Primary gout is a biochemically and genetically heterogeneous disorder resulting from inborn metabolic errors that alter uric acid homeostasis.
Genetic and Biochemical Basis of Hyperuricemia
There are at least three different inherited defects that lead to early development of severe hyperuricemia and gout: glucose-6-phosphatase (gene symbol: G6PT) deficiency; severe and partial hypoxanthine-guanine phosphoribosyltransferase (HGPRT, gene symbol: HPRT) deficiency; and elevated 5′-phosphoribosyl-1′-pyrophosphate synthetase (PRPP synthetase) activity.
The familial association of gout was recognized hundreds of years ago but defining the exact genetic mechanisms wasn’t possible until the advent of modern genetic tools. Gout was included as an inherited disorder in the seminal work of Archibald E. Garrod in his 1931 publication on inborn errors in metabolism. Garrod considered gout to be a dominantly inherited trait. However, we now know that G6PT deficiencies are inherited as autosomal recessive traits and HPRT and PRPS defects are X-linked recessive traits.
PRPP synthetase is the enzyme responsible for the synthesis of the activated ribose (5′-phosphoribosyl-1′-pyrophosphate, PRPP) necessary for the de novo synthesis of purine and pyrimidine nucleotides. Regulation of PRPP synthesis is effected through complex allosteric regulation of PRPP synthetase. At least three different enzymes with PRPP synthetase activity have been identified which are encoded by three distinct genes. These genes are identified as PRPS1, PRPS2, and PRPS1L1. The PRPS1 and PRPS2 genes are both located on the X chromosome, PRPS1 is on the q arm (Xq22.3) and PRPS2 is on the p arm (Xp22.2). The PRPS1 gene is composed of 7 exons that generate two alternatively spliced mRNAs encoding isoform 1 (318 amino acids) and isoform 2 (114 amino acids). Mutations in the PRPS1 gene are those that are associated with PRPP synthetase superactivity. In addition, mutations in the PRPS1 gene are associated with Arts syndrome and Charcot-Marie-Tooth disease X-linked recessive type 5. The PRPS2 gene is also composed of 7 exons that generate two alternatively spliced mRNAs encoding isoform 1 (321 amino acids) and isoform 2 (318 amino acids). The PRPS1L1 gene is an intronless gene located on chromosome 7p21.1 that encodes a protein of 318 amino acids. The PRPS1L1 gene is expressed exclusively in the testes and translation of the resulting mRNA begins at a non-AUG codon (ACG). Although ACG normally codes for threonine, in the PRPS1L1 mRNA this alternative start codon directs the initiator methionine for the encoded protein.
All three PRPP synthetase isoforms differ in kinetic and physical characteristics such as isoelectric points (pI), pH optima, activators and inhibitors. Mutations in the PRPS genes that result in superactivity lead to enhanced production of PRPP. Increased levels of PRPP, in turn, drive enhanced de novo synthesis of purine nucleotides in excess of the needs of the body. Thus, the excess purine nucleotides are catabolized resulting in elevated production of uric acid and consequent hyperuricemia and gout.
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme involved in the salvage of purine nucleotides. HGPRT catalyzes the following two interconversions:
hypoxanthine + PRPP ↔ IMP + PPi
guanine + PRPP ↔ GMP + PPi
A complete or virtually complete loss of HGPRT activity results in the severe disorder, Lesch-Nyhan syndrome. Although Lesch-Nyhan syndrome is known more for the associated bizarre emotional behaviors, there is also overproduction and excretion of uric acid and gouty manifestation. Less dramatic reductions in HGPRT activity do cause hyperuricemia and gout due to the reduced salvage of hypoxanthine and guanine leading to increased uric acid production.
Deficiencies in glucose-6-phosphatase result in type I glycogen storage disease (von Gierke disease). However, associated with this defect is increased uric acid production and symptoms of gout. The inability to dephosphorylate glucose 6-phosphate leads to an increase in the diversion of this sugar into the pentose phosphate pathway (PPP). One major product of the PPP is ribose 5-phosphate. An increase in the production of ribose 5-phosphate results in substrate-level activation of PRPP synthetase. Increased activity of PRPP synthetase, in this circumstance, has the same consequences as defects in the PRPS gene that lead to superactivity of PRPP synthetase described above.
Clinical Features of Gout
Hyperuricemia does not always lead to the typical clinical manifestations of gout. These symptoms usually only appear in a person suffering with hyperuricemia for 20 to 30 years. The normal course of untreated hyperuricemia, leading to progressive urate crystal deposition, begins with uric acid urolithiasis (urate kidney stones) and progresses to acute gouty arthritis, then intercritical gout and chronic tophaceous gout. Intercritical gout refers to the period between gouty attacks. Diagnosis of gout during these periods is difficult but analysis for urate crystals in the synovial fluids of a previously affected joint can establish a correct diagnosis. Numerous circumstances can precipitate gouty attacks such as trauma, surgery, excessive alcohol consumption, administration of certain drugs and the ingestion of purine-rich foods.
Acute gouty arthritis consists of painful episodes of inflammatory arthritis and represents the most common manifestation of gout. Typical descriptions of this symptom include a patient who goes to bed and awakens by severe pain in the big toe but may also be experienced in the heel, instep or ankle. The pain is described as that of a dislocated joint and is often accompanied or preceded by chills and a slight fever. The pain progresses and is often described as if a dog were gnawing on the limb. The pain can become so severe that the simple act of cloth touching the area in unbearable. Gouty arthritis attacks usually dissipate within several hours but can also last for several weeks. The inflammatory processes initiated in gouty arthritis are the result of neutrophil ingestion (phagocytosis) of urate crystals and the subsequent release of numerous inflammatory mediators. Gouty arthritis usually develops in males in the fourth to sixth decade of life and in the sixth to eight decade in women. Episodes of gouty arthritis that occur in childhood, in early adults or in pre-menopausal women should suggest an underlying inherited enzyme defect or the ingestion of some agent that interferes with uric acid metabolism.
Chronic tophaceous gout results after a number of years in an untreated individual. Episodes of acute gouty arthritis become more frequent and severe and the intercritical period may disappear completely. This stage of the disease is characterized by the deposition of solid urate (tophi) in the articular (cartilage covering the bony ends of the articulating joints) and other connective tissues. The continued development of tophi results in destructive arthropathy (disease of a joint).
Aside from gouty arthritis and tophus formation, renal disease is the most frequent complication of hyperuricemia. Kidney disease in patients with gout is of numerous types. Urate nephropathy is the result of the deposition of monosodium urate crystals in the renal interstitial tissue. Uric acid nephropathy is caused by the deposition of uric acid crystals in the collecting tubules, renal pelvis or the ureter and results in impaired urine flow. Calcium oxalate urolithiasis also occurs in hyperuricemic patients. Uric acid urolithiasis (uric acid kidney stones) accounts for approximately 10% of all urinary calculi (stones) in the US.
Additional renal effects of hyperuricemia include metabolic acidosis caused by defective lactic acid excretion which in turn exacerbates the hyperuricemia due to reduced urate excretion. The major renal urate-anion exchanger is encoded by the solute carrier gene, SLC22A12 (originally identified as the urate transporter 1, URAT1 protein). Expression of SLC22A12 is very high in the epithelial cells of the proximal tubule of the renal cortex but is not expressed in the distal tubules. The SLC22A12 transporter co-transports urate along with chloride and iodine anions. Transport of urate via SLC22A12 is selectively inhibited by lactate, succinate, β-hydroxybutyrate, and acetoacetate. Urate reabsorption is coupled to renal lactate reabsorption at the apical membrane of the proximal tubule cell via interactions between SLC22A12 and the lactate transporters SLC5A8 and SCL5A12. Due to this interaction lactic acidemia impairs urate reabsorption and excretion while hyperuricemia results in impaired lactate excretion and reabsorption.
Therapeutic Treatment of Hyperuricemia and Gout
Treatments aimed at lowering serum urate levels in hyperuricemic patients are usually only a consideration in the context of gout. Because acute gouty arthritis is an inflammatory event, treatment with anti-inflammatory drugs is often successful in reducing the symptoms. The inflammation caused by acute attacks of hyperuricemia can be treated with the use of colchicine. Colchicine is a microtubule polymerization inhibitor that functions by binding to tubulin. Failure to form functional microtubule filaments results in inhibition of immune cell (B and T cell) division as well as inhibition of phagocytosis of urate crystals by monocytes/macrophages. The overall effect of colchicine is a reduction in inflammatory processes.
Treatments for chronic hyperuricemia and the resultant gout include the use of uricosuric drugs and drugs that inhibit the production of uric acid. The commonly prescribed uricosuric drug in the US is probenecid. The use of two additional uricosurics, sulfinpyrazone and lesinurad, has been discontinued in the US. These uricosuric drugs function, at high doses, by competing for urate reuptake from the glomerular filtrate via SLC22A12 and, therefore, reduce renal reabsorption of uric acid allowing for increased excretion in the urine. However, it is important to be careful with the initial dosing of probenecid (and was also the case for sulfinpyrazone) due to the fact that at the initial low circulating levels of the drug it actually acts to inhibit urate excretion resulting in transient increases in serum urate.
The most commonly prescribed drug for reducing the production of uric acid is the xanthine oxidase inhibitor, allopurinol. Allopurinol is a purine analog that is a structural isomer of hypoxanthine. Another xanthine oxidase inhibitor that was often used if allopurinol failed to lower serum uric acid levels is benzbromarone. However, benzbromarone is no longer used in the US, having been withdrawn from this market by its manufacturer in 2003. A more recent xanthine oxidase inhibitor is febuxostat, approved in the US in 2009. Febuxostat is a non-purine analog that functions as a selective non-competitive inhibitor of the active site of xanthine oxidase. Febuxostat is generally only prescribed for patients who do not tolerate allopurinol.