Hyperuricemia associated with gout
HYPERURICEMIA ASSOCIATED WITH GOUT 11
A metabolic disorder is an interruption of one’s normal metabolicprocess by chemicals or any other body component2. Thisinterferes with the natural substancequantity levels in the body resulting in either too much of the foodsubstances or too little1.Hyperuricemia as a medical condition is effectedby excessive production of uric acid in the body2. Theseabnormal uric acid quantity levels are caused by a component referredto as purine forming the primary cause of the hyperuricemiacondition1. Hyperuricemia can still generate from anotherdisease with the body, such as gout1. Extended periodswith recurrent forms of Hyperuricemia can lead to gout4.Gout is closely related to hyperuricemia as causedby the formation of crystals formed fromprolonged retention of uric acid in the body4. Medicalexperts recommend that uric levels in the body must, at all times, bemaintained at 7mg/dl as a tactic of keeping gout at bay2.Hyperuricemia is, in its only form, not adisease2. However, the main genesis of gout ascrystallized forms of uric acid directlylead to a gout condition in the body2. Essentially, uricacid is dissolved in the body and excreted from the system as urine7.If a body metabolizestoo much, releasing excess amounts of uric acid, crystals can beformed7. The excessquantities first create the disorder that is Hyperuricemia9.Subsequently, crystals form. This is,precisely, how Hyperuricemia leads to gout. The disorder comes first,and gout follows6. Gout mostly affects individuals in the35-55 age group5. It has about four phases that will bedeveloped in the course of this research paper5.This paper will focus on the relation heldby hyperuricemia as a causal agent of gout6.
The most interesting fact abouthyperuricemia associated with gout is that purinesprimarily cause it. Purines are naturally occurring chemicalspresent in everybody1.Thus, everyone, at one point or the other, is always at risk ofcontracting Hyperuricemia and by extension, gout4. Theorigin of gout, as the end disease condition, can be traced to thedietary lifestyles led by individuals2. Common foodstuffssuch as red meat, alcohol and all items bearing a relatively highconcentration of sugar syrups pose a significantrisk in the contraction of gout6. Supplementary healthconditions that can arouse hyperuricemia and gout include obesity6,abnormal levels of blood pressure and cholesterol6. Allthese items result in very high uric quantities setting the stage forthe development of gout5. Evensustained emotional set-ups such as stress can form the precursorfor the formation of this disorder5. It is, therefore,necessary, even at this point that an individual has their bodychecked or scanned10. This reality isbecause has so many originatingpoints10.One may lead a very healthy dietarylifestyle only to contract the disorder from such illnesses as kidneyinfections10. Even social habits do lead to hyperuricemiaand gout complications2.
A number of biomedicalprocesses have been identified in theinterrogation of causal agents of gout3. Primarily, goutis a resultant condition of hyperuricemia3. In thespecific actions taking place in the body, the metabolism of purinesin a process called nucleic catabolism takes place3. Uriccrystals are then formed3.These make sand-like deposits stored invarious body joints in the body9. These areidentified as chemical deposits and precipitate arthritis. Atthis point, severe pain permeates throughout the entire bodyoriginating from the joints8. When crystals meet up withneutrophils, the resulting reactions packaged as response effect thephysical pain felt in the body2. It should be notable thatgout in all its occurring form will not occur without hyperuricemia7.It is a secondary disorder caused by erratic extraction and disposalmechanisms of uric acid7. This reality guides thedevelopment of this paper into a scrutiny exercise on the bio-medicalessence and basis of hyperuricemia21,2.
Hyperuricemia as a reference point for gout can occur from somegenetic defects paving the way forsubstantiation of inheritance it developing its production cycle6.A body deficit of glucose and specifically the GPT-6 containingphosphate elements5. If this deficiency is prominent in agiven family cycle, transfer of it, genetically, will lead to thedistribution of hyperuricemia in that family5.
So far two pathways that lead to gout in hyperuricemia have beenconfirmed7. Gut and renal excretion of uric acid togetherwith glycolysis now firmly implicated the major urateloci are ABCG2 and SLC2A97. Recent studies have shown thatSC2A9 in very much involved in the gut andrenal uric acid excretion and this is implicatedin defense of antioxidant7. Itis very clear that generic complexity exists at SLC2A9 locus20,having multiple statistically variables that are independent (localepistatic interactions and genetic variables) although etiologicalvariants at SLC2A9 are to be identified20.The implicated genetic variants’ positions within the chromatinregions involved in transcription control suggest the importance ofthis mechanism in the regulation of SLC2A9activity rather that the structural changes that SLC2A9 undergoes21.The initial involvement of ABCG2 is inextra-renal uric acid underexcretion23with an etiological variant that influencesexpression. Probable genes that cause goutat the other 26 loci can be identified atPDZK1, INHBB and SLC22A11, with the 10th loci havingstrong candidates23. The confirmation of the gene thatcauses gout will require a combination of trans-ancestralmapping, correlation of data from genetic association with expressiondata and re-sequencing23.
There exist genetic markers involved with hyperuricemia24.The majority of the novel genes have shownassociation with hyperuricemia or gout in GWAS encode proteins24participating in the transport system ofthe renal urinate. Studies have shown that 90% of disorderunsurprisingly are caused by reduced renal excretion of the urate24.The variation in SLC2A9 statistically is the genetic determinant ofthe serum urate6. The loss of mutations in functioning inthe SLC2A9 gene causes renal hyperuricemia.
There exist three different inherited defects that lead to thedevelopment of severe hyperuricemia duringearly stages associated with gout: deficiency of glucose-6-phosphate(G6PT)10, partial and severe hypoxanthine-guaninephosphoribosyltransferase (HGPRT) deficiency and the elevatedactivity of 5’-phosphoribosyl-1’-pyrophosphate synthetase(PRPP)10. PRPP synthetase enzyme is involved in thesynthesis of the activated ribose PRPP required for de novo synthesisof purine and pyridine nucleotides19. Synthesis of PRPP isaffected by the complex allostericregulation of PRPP synthetase19. Three different enzymeshave been identified with PRPP synthetaseactivity encoded by three distinct genes. The genes are PRPS1, PRPS2and PRPS1L117. The PRPS2 and PRPS1 genes arelocated on the X chromosome, with PRPS2 on the p arm (Xp22.22)and PRPS1 gene on the q arm (Xq22.3)17. Seven exons arefound in the PRPS1 gene that generatestwo alternative spliced mRNAs encodingisoform 1 (318 amino acids) and isoform 2 (114 amino acids)17.PRPP synthetase superactivity isassociated with the mutation in the PRPS1 gene. Furthermore,Arts syndrome and Charcot-Marie-Tooth Disease X-linked recessive type5 are also associated with mutations in thePRPS1 gene21.
HGPRT enzyme has involved the salvage ofthe purine nucleotides, and it catalyzesthe following interconversions21:
Hypoxanthine+ PRPP IMP + PPi21
Guanine+ PRPPGMP + PPi21
Virtual or complete loss of HGPRT activity causes a severedisorder known as Lesch-Nyhan syndrome16.Due to the reduced salvage of guanine and hypoxanthine, less dramaticreductions in the activity of HGPRT causes gout and hyperuricemia15.Glucose-6-phosphatase causes type Iglycogen storage disease known as von Gierke disease associatedwith increased production of uric acid and gout symptoms18.
MSU crystals are present in the individuals that suffer from bothchronic tophaceous gout and gouty attacks, in both asymptomatic andsymptomatic joint fluid and tissue3. Major shifts in thelevels of serum uric acid levels lead to reabsorption of the MSUcrystals that occurs after urate-loweringtherapy (ULT) 22. In response to MSU crystals, it is nowclear that the cells that initiate inflammatory cascade in the jointsare macrophages11 these cells release chemoattractantsand phagocytose MSU crystals, that recruit neutrophils to the site16.Neutrophils phagocytose MSU crystals once recruited to the joint andcontribute further to inflammation that characterizesacute gout attacks4.
Studies have been done for many years to determine the mechanismsthrough which cells take up MSU crystals and activation of theinflammatory cascade14. Somemechanisms have been investigated and proposed to explain the uptakeof MSU crystals by leukocytes3.
The only considerations in the context of gout are treatments aimedat lowering serum urate levels in patientswith hyperuricemia. Since acute arthritis is an inflammatorydisorder, it is often successful to use anti-inflammatory drugs inreducing the symptoms18. Colchicine can be used to treatthe inflammation that is caused by theacute attacks of hyperuricemia18. Colchicine is amicrotubule polymerization inhibitor7. The inhibitorfunctions by binding to tubulin18. Inhibition of theimmune cell (B and T cell) occurs from failure to form activemicrotubule filaments as well as well as inhibition of phagocytosisof the urate crystals by macrophages or monocytes18.Reduction in inflammatory process is the overall effect ofcolchicine24.
The use of drugs that inhibit the production of uric acid anduricosuric drugs are treatments for severe hyperuricemia and gout24.The common uricosuric drugs are sulfinpyrazone and probenecid,although the use of sulfinpyrazone has beenstopped in the US24,18. Both of these drugs competefor urate transport through SLC2A12 at high doses and18,hence, allows increased excretion in urine and reduces renalreabsorption of uric acid. Initial low circulating of probenecid andsulfinpyrazone act to inhibit excretion causing a transientincrease in serum urate18.
The most common prescribed drug for decreasing uric acid productionis xanthine oxidase inhibitor, allopurinol24. Febuxostat(Uloric) is an example of a recent xanthineoxidase inhibitor. The drug acts as a noncompetitive inhibitor ofthe xanthine oxidase active site24.
Uric acid has been identified as a markerfor some hemodynamic and metabolicabnormalities. In humans, uric acid is a poorly soluble purine endproduct, unlike in lower animals where allantoin is the moresoluble end product of metabolism18.
The prevalence of metabolic syndrome and gout is very high inhyperuricemic patients. The view thatasymptomatic hyperuricemia in patients has beenshown in recent studies15. The studies have shownthat low cardiovascular risk can result from reduced renal uric acidclearance5.For long, hyperuricemia has been established as major etiologicalgout factor. Urate crystals deposition in the joints triggersinflammatory state7.Hyperuricemia displays additional pathophysiological consequencesthat lead to inflammation of tissue in the vascular bundle20.In the past, therapeutic strategies used to treat hyperuricemia havebeen focused on the limit of acute episodes6.Chronic urate deposition, therefore, requires a right treatment notrestricted to acute episodes based on the modulation of key enzymeactivity involved in excretion and metabolism of urate includingURAT1 and xanthine oxidoreductase(XO)14.Prevention and scavenging of oxygen radical accumulation generated byXO emerge as a treatment option to counteract tissue damages inducedby uric acid21.
1Abeles, A. (2015). Hyperuricemia, Gout, andCardiovascular Disease: An Update. Current Rheumatology Reports,17(3). http://dx.doi.org/10.1007/s11926-015-0495-2
2Ackermann, P., & Hart, D. Metabolic influences onrisk for tendon disorders (1st ed.).
3Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI(n.d). Gastrointestinal damage associated with theuse of nonsteroidal anti-inflammatorydrugs. N Engl J Med327:749–54.
3Bakris, G. L., Doghramji, P. P., Keenan, R. T., &Silber, S. H. (2014). CaseBook Challenges: Managing Gout,Hyperuricemia and Comorbidities—Dialogue with the Experts. TheAmerican Journal of Medicine, 127(1).doi:10.1016/j.amjmed.2013.11.001
5B.N. Cronstein, P. Sunkureddi Mechanistic aspects ofinflammation and clinical management of inflammation in acute goutyarthritis J. Clin. Rheumatol., 19 (2013), pp. 19–29
6Bolzetta, F., Veronese, N., Manzato, E., & Sergi, G.(2013). Chronic gout in the elderly. AgingClinical And Experimental Research, 25(2), 129-137.http://dx.doi.org/10.1007/s40520-013-0031-z
7Coelho C,Mahro M, Trincão J, Carvalho AT, Ramos MJ, Terao M, Garattini E,Leimkühler S, Romão MJ (2012) J Biol Chem 287:40690–40702.doi:10.1074/jbc.M112.390419
8Coleman, L. (2008). Nutrition and rheumatic disease(1st ed.). Totowa, NJ: Humana Press.
9Chen Z, TaoH, Liao L, Zhang Z, Wang Z (2014) J Sep Sci 37:2253–2259.doi:10.1002/jssc.201400342
10Dalbeth, N. (2013). Pathologicalbasis of hyperuricemia and gout. Gout, 24-37.doi:10.2217/ebo.13.105
11D.B. Crittenden, M.H. Pillinger New therapies for goutAnnu. Rev. Med., 64 (2013), pp. 325–337
12D. Grassi, L. Ferri, G. Desideri, P. Di Giosia,P. Cheli, R. Del Pinto, et al.Chronic hyperuricemia, uric aciddeposit and cardiovascular riskCurr. Pharm. Des., 19 (2013), pp.2432–2438
13Dalbeth, N., House, M., Gamble, G., Pool, B., Horne, A.,& Purvis, L. et al. (2014). Influence of the ABCG2 gout risk141 K allele on urate metabolism during a fructose challenge.Arthritis Research & Therapy, 16(1), R34.http://dx.doi.org/10.1186/ar4463
14Ding, X., Zeng, C., Wei, J., Li, H., Yang, T., &Zhang, Y. Et al. (2016). The associationsof serum uric acid level and hyperuricemia with knee osteoarthritis.Rheumatology International, 36(4), 567-573.http://dx.doi.org/10.1007/s00296-015-3418-7
15E. Suresh, P. Das Recent advances in management of goutQ. J. Med., 105 (2012), pp. 407–417
16Fatima, T., Altaf, S., Phipps-Green, A., Topless, R.,Flynn, T., & Stamp, L. et al. (2015). Association analysis of thebeta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urateand gout. Rheumatology International, 36(2), 255-261.http://dx.doi.org/10.1007/s00296-015-3370-6
17Ferreira, J., Detoni, S., Oliveira, S., & Televisan,G. (2016). Living Reference Work Entry. In Encyclopediaof Inflammatory Diseases. Basel: Springer Basel.
18Gaffo, A., & Saag, K. (2012). DrugTreatment of Hyperuricemia to Prevent Cardiovascular Outcomes.American Journal Cardiovascular Drugs, 12(1), 1-6.http://dx.doi.org/10.2165/11594580-000000000-00000
Gout. (2013) (1st ed.). London.
19Grassi, D., Desideri, G., Di Giacomantonio, A., DiGiosia, P., & Ferri, C. (2014). Hyperuricemia and cardiovascularrisk. High Blood Pressure & Cardiovascular Prevention,21(4), 235-242. http://dx.doi.org/10.1007/s40292-014-0046-3
20GarattiniE, Terao M (2013) Expert Opin Drug Discov 8:641–654.doi:10.1517/17460441.2013.788497
21Gresser, U. The Clinical Aspects of Hyperuricemia andGout. Molecular Genetics, Biochemistry AndClinical Aspects Of Inherited Disorders Of Purine And PyrimidineMetabolism, 63-68.http://dx.doi.org/10.1007/978-3-642-84962-6_9
22Hall J,Reschke S, Cao H, Leimkuhler S, Hille R (2014) J Biol Chem.doi:10.1074/jbc.M114.603456
23Hille R,Hall J, Basu P (2014) Chem Rev 114:3963–4038. doi:10.1021/cr400443z
24Hosoya, T., Kimura, K., Itoh, S., Inaba, M., Uchida, S.,& Tomino, Y. Et al. (2014). Theeffect of febuxostat to prevent a further reduction in renal functionof patients with hyperuricemia who have never had gout and arecomplicated by chronic kidney disease stage 3: study protocol for amulticenter randomized controlled study. Trials,15(1), 26. http://dx.doi.org/10.1186/1745-6215-15-26
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