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This content does not have an English version. This content does not have an Arabic version. Hyperuricaemia induced by cytotoxic drugs is the most serious type of drug-induced hyperuricaemia.
It usually develops 48—72 h after cytotoxic therapy. TLS induces a higher mortality rate, probably because of delayed presentation and delayed recognition.
TLS is often associated with cytotoxic chemotherapy. However, it may also occur after treatment with dexamethasone, zoledronic acid, thalidomide and newer chemotherapeutic agents including bortezomib, rituximab and ibrutinib [ 56 ]. The glucose substitutes used in total parenteral nutrition are fructose, glycerol, sorbitol and xylitol. The parenteral infusion of these substrates has several advantages such as a rapid metabolism and a smaller effect on blood glucose concentration as compared with glucose infusions.
Intravenous fructose administration or high fructose oral intake over several days is associated with increased uric acid concentration. Fructose is strongly associated with hyperuricaemia and an increased risk of gout in both genders [ 57 , 58 ]. The hyperuricaemic effect of fructose seems to be dose-related [ 59 ]. Renal transplant recipients treated with both calcineurin inhibitors ciclosporin or tacrolimus are at similar risk of hyperuricaemia induced by fructose consumption [ 61 ].
Different alleles influence serum urate responses to fructose. Furthermore, genetic variation in SLC17A1 , which encodes the human inorganic phosphate transporter NPT1, an anion exchanger that secretes uric acid into the urine, has also been associated with hyperuricaemia and gout. In European people, variation in SLC17A1 influences serum urate and fractional excretion of uric acid throughout a fructose load [ 65 ]. Glycerol consumption is also linked to an increase in serum urate concentration [ 66 ].
Glycerol stimulates uric acid production, lowers cell ATP and increases glycerol 3-phosphate [ 67 ]. Uric acid production correlates inversely with ATP. Xylitol is a five-carbon sugar alcohol. It is used as a glucose substitute in total parenteral nutrition for diabetic patients. Infusion of xylitol leads to reduced gluconeogenesis, increased protein and muscle RNA content and improved nitrogen balance [ 68 ].
It may increase the plasma concentrations of uric acid, hypoxanthine and xanthine by enhancing purine degradation. The increase in purine degradation by xylitol may be due to the impairment of glycolysis in erythrocytes [ 69 ].
In addition, administration of large amounts of xylitol can produce lactic acidosis [ 68 ]. Sorbitol is converted to fructose when metabolized in the liver and produces biochemical effects similar to those of fructose on hepatic adenosine phosphate levels in humans, and can therefore increase uric acid production [ 70 ].
Hyperuricaemia has been reported in a case of sorbitol overdose [ 71 ]. Sodium lactate solution has many advantages and appears promising for resuscitation of critically ill patients [ 72 ]. However, high dose lactate infusion may induce hyperuricaemia by decreasing urinary excretion and the fractional clearance of uric acid [ 73 ].
Lactate interacts with URAT1 [ 25 ]. This latter is an important transporter of urate reabsorption in exchange for lactate at the apical membrane of the proximal tubules.
Therefore, lactate stimulates urate uptake, leading to hyperuricaemia. Testosterone replacement therapy TRT , used for patients with female to male gender identity disorder, increases uric acid level in a dose-dependent manner.
In a recent study, the rates of serum uric acid increase after 3 months of TRT intramuscular injection of testosterone enanthate were 29 and Testosterone-induced gout has also been reported [ 76 ]. Testosterone treatment leads to increased serum uric acid levels and reduced renal excretion of uric acid [ 77 ]. The serum uric acid elevation may be also, at least partially, attributed to an increase in muscle mass during the early phase of TRT [ 75 ].
In addition to the drugs listed above, many miscellaneous agents may induce hyperuricaemia and gout Table 2 [ 79—88 ]. T able 2 Miscellaneous drugs inducing hyperuricaemia and their suggested mechanism. Although, there are no published guidelines on how to prevent drug-induced hyperuricaemia, patients receiving drugs known to induce hyperuricaemia should be encouraged to maintain adequate hydration and have their uric acid levels routinely monitored.
These patients should also be monitored for symptoms that might precede the onset of gout. Approximately two out of three patients with drug-induced hyperuricaemia will remain asymptomatic [ 24 ]. In drug-induced asymptomatic hyperuricaemia, especially with diuretics, treatment to control serum uric acid levels is rarely required.
However, gouty episodes in patients with a personal or family history of established gout may be aggravated by diuretic therapy in hypertensive patients. When gout develops the decision to continue therapy needs to be individualized, and so too does a decision to initiate allopurinol or a uricosuric drug [ 7 ]. In drug-induced symptomatic hyperuricaemia and gout, management includes the identification of offending drugs and the institution of appropriate anti-hyperuricaemic agents.
Withdrawal of the offending drug should be based on an assessment of the benefit—risk ratio. When alternative therapy is available, the offending drug may be replaced by a drug that does not cause hyperuricaemia. However, in certain cases, the offending drug is necessary.
For example, the use of low-dose aspirin for prevention of cardiovascular disease should not be suspended for patients with gout. Close monitoring of serum uric acid when an individual is taking low-dose aspirin may help to avoid the risk of gout attacks.
However, allopurinol or uricosuric agents may be necessary in some cases of aspirin-induced gout [ 54 ]. In hypertensive patients controlled on one or two medications with acute thiazide-induced gout, the reduction of the dose of thiazide rather than its discontinuation is an appropriate option because drug-induced hyperuricaemia is dose-related [ 8 ].
In hypertensive patients controlled on three or more medications thiazide continuation with dose reduction or pharmacological anti-hyperuricaemic therapy, that is, allopurinol, should be considered. Treatment of ciclosporin-induced acute attacks may be difficult since interactions with NSAIDs may lead to enhanced renal toxicity. Colchicine, if prescribed in these acute attacks, should also be used cautiously and the dose reduced. Corticosteroids are an effective alternative to colchicine.
In patients who develop ciclosporin-induced hyperuricaemia and gouty arthritis with tophi, benzbromarone, a uricosuric agent, may be useful.
It should be initiated at a low dose and gradually increased, and liver function should be monitored closely. Allopurinol is also a useful alternative in these patients. Interestingly, the normalization of uric acid levels by allopurinol or benzbromarone reduced the tubulointerstitial disease and arteriolar hyalinosis induced by ciclosporin [ 89 ]. Ciclosporin and tacrolimus withdrawal may be considered for transplant patients with recurrent, severe gout that cannot be managed safely or effectively [ 90 ].
The cornerstone management of TLS is prevention. Prevention strategies may also include hydration plus allopurinol or rasburicase for intermediate-risk patients, and close monitoring for low-risk patients [ 91 ]. For nicotinic acid-induced hyperuricaemia, allopurinol is usually used when therapy is indicated. Nicotinic acid inhibits the effect of uricosuric drugs such as sulfinpyrazone and the latter should be avoided.
Pyrazinamide-induced hyperuricaemia can be managed by observation and does not require withdrawal of treatment. It can be also controlled with allopurinol. However, paradoxical increase in uric acid level with allopurinol use in pyrazinamide-induced hyperuricaemia has been reported [ 92 ]. Allopurinol was shown to increase plasma concentrations of pyrazinoic acid, which is directly responsible for the inhibition of renal urate secretion [ 92 , 93 ]. Aspirin may prevent hyperuricaemia and the arthralgia associated with pyrazinamide therapy.
Hyperuricaemia due to ethambutol was reversed with probenicid, sulfinpyrazone or allopurinol. The latter, increases the serum level of theophylline and therefore the serum level of theophylline should be carefully monitored when allopurinol is added to a hyperuricaemic patient who is under this treatment [ 94 ]. However, benzbromarone and probenecid do not seem to interfere with the theophylline serum level.
In conclusion, drug-induced hyperuricaemia and gout present an emergent and increasingly prevalent problem in clinical practice. Drugs raise serum uric acid level by various mechanisms. Patients receiving these drugs should be encouraged to maintain adequate hydration and have their uric acid levels monitored. Funding : No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement : The authors have declared no conflicts of interest. Epidemiology of hyperuricemia and gout. Google Scholar. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality. Arthritis Rheum ; 61 : — Sugar, uric acid, and the etiology of diabetes and obesity.
Diabetes ; 62 : — Clinical significance of hyperuricemia in routinely screened hospitalized men. JAMA ; : — Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ ; : d Use of diuretics and risk of incident gout: a population-based case-control study. Arthritis Rheumatol ; 66 : — Palmer BF.
Metabolic complications associated with use of diuretics. Semin Nephrol ; 31 : — Handler J. Managing hypertensive patients with gout who take thiazide. J Clin Hypertens ; 12 : — 5. Reyes AJ. Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther ; 17 : — Predicting acute gout in diuretic-treated hypertensive patients. J Hum Hypertens ; 3 : — Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study.
J Rheumatol ; 33 : — 5. Comparison of new-onset gout in adults prescribed chlorthalidone vs. J Clin Hypertens ; 16 : — 8. Apical voltage-driven urate efflux transporter NPT4 in renal proximal tubule. Nucleosides Nucleotides Nucleic Acids ; 30 : — Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol ; 18 : — 9. A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study.
Ann Rheum Dis ; 72 : — 6. Ann Rheum Dis ; 74 : — 8. Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4.
Br J Pharmacol ; : — Steele TH. Evidence for altered renal urate reabsorption during changes in volume of the extracellular fluid. J Lab Clin Med ; 74 : — Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricemia. Curr Pharm Des ; 11 : — Kelley WN. Effects of drugs on uric acid in man. Annu Rev Pharmacol ; 15 : — Falch DK , Schreiner A. The effect of spironolactone on lipid, glucose and uric acid levels in blood during long-term administration to hypertensives.
Acta Med Scand ; : 27 — Spironolactone increases serum uric acid levels in patients with chronic kidney disease. J Hum Hypertens ; 28 : — 1. Changes in intrarenal uric acid handling during chronic spironolactone treatment in patients with essential hypertension.
Nephron ; 32 : — Pyrazinamide-induced hyperuricemia. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature ; : — The molecular physiology of uric acid homeostasis. Annu Rev Physiol ; 77 : — Biol Pharm Bull ; 33 : — J Biol Chem ; : — Hyperuricemia and arthralgias during pyrazinamide therapy in patients with pulmonary tuberculosis. Lab Med ; 38 : — 7.
Shapiro M , Hyde L. Hyperuricemia due to pyrazinamide. Hyperuricemia induced by ethambutol. Br J Dis Chest ; 77 : — 6. Khanna BK. Acute gouty arthritis following ethambutol therapy. Br J Dis Chest ; 74 : — Ethambutol-induced hyperuricaemia. Tubercle ; 65 : — 9. Hyperuricemia due to ethambutol. Studies on the mechanism of ethambutol-induced hyperuricemia. Arthritis Rheum ; 15 : — 9. In another population-based study, thiazide diuretic use was associated with a 1.
They also concluded that the longitudinal change in SUA levels was 0. The Systolic Hypertension in the Elderly Program also concluded that in thiazide-using patients, the three-year increase in the SUA level was 0. On the other hand, in a case-control study, there was a statistically significant association between the use of diuretics and development of gout which was nullified after adjusting for HTN as a confounding variable [ 11 ]. We controlled confounding bias in this study by only recruiting hypertensive patients who were never diagnosed with gout before.
Previously, a study was conducted in Pakistan which reported both HTN and the use of thiazide diuretics as independent risk factors of gout. However, this study was conducted in the general population and not particularly hypertensive patients; hence, the confounding bias remains [ 7 ]. There have been discrepancies in the results of different observational studies. In a retrospective inception cohort, there were no significant differences in the target SUA levels of gout patients who used diuretics as compared to those who did not use diuretics [ 12 ].
However, in another population-based, retrospective, case-control analysis, the odds ratio for incidence of gout in patients taking loop diuretics was 2. Vandell et al. In conclusion, there are strong evidences to support both results - diuretics increase SUA levels and do not have an impact on SUA levels.
This sheds lights on the urgent need to design robust prospective, longitudinal case-control trials to establish concrete evidence regarding this correlation.
Retrospective analysis with heterogeneous populations and uncontrolled confounding factors should be interpreted with caution by the clinicians. Thiazide diuretics are very commonly prescribed to hypertensive patients.
HTN itself is an independent risk factor of gout, which in turn is an independent risk factor of cardiovascular and neurovascular diseases. Men on thiazide diuretics reported a higher mean SUA level than non-thiazide users. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes.
Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.
The authors have declared that no competing interests exist. Consent was obtained by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.
National Center for Biotechnology Information , U. Journal List Cureus v. Published online Aug Author information Article notes Copyright and License information Disclaimer. Corresponding author. Alina Sehar moc. Received Aug 5; Accepted Aug This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article has been cited by other articles in PMC. Abstract Introduction Thiazide diuretics are essential first-line anti-hypertensive drugs which not only maintain blood pressure but also reduce stroke and congestive heart failure associated with morbidity and mortality in hypertensive patients. Methods In this cross-sectional, prospective study, adult hypertensive patients were recruited. Results In the thiazide group, Conclusion Hyperuricemia is a more common occurrence in thiazide diuretic users as compared to non-users.
Keywords: pakistan, hypertension, thiazide, serum uric acid levels, hyperuricemia, anti-hypertensive drugs, diuretics. Introduction In almost all patients with hypertension HTN , renal sodium retention is the primary pathology contributing to elevated blood pressures BP.
Materials and methods A cross-sectional, prospective study was conducted in the outpatient department OPD of a public hospital in Pakistan. Results The study was completed by participants in the thiazide group and in the non-thiazide group. Open in a separate window. Table 4 Duration of thiazide diuretic use and incidence of hyperuricemia.
Discussion In this study, individuals were significantly more hyperuricemic and the mean SUA levels were significantly higher in the thiazide group.
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