Kyselina močová (UA) se převážně tvoří v játrech, střevech a cévním endotelu jako konečný produkt metabolismu purinů získaných exogenně z potravy a endogenně z poškozených nebo mrtvých buněk. Ledviny hrají hlavní roli ve vylučování UA, eliminují asi 70 % denní produkce. Zbytek (přibližně 30 %) je vylučován střevem. Pokud tvorba UA překračuje její vylučování, vzniká hyperurikemie. Hyperurikemie je silně spojena s rozvojem a závažností metabolického syndromu. Nadměrná exprese urátového transportéru 1 (URAT1) a glukózového transportéru 9 (GLUT9) a narušení glykolýzy kvůli inzulinové rezistenci mohou souviset s rozvojem hyperurikemie u metabolického syndromu. Dříve se hyperurikemie po- važovala pouze za hlavní příčinu dny a dnavé artritidy. Také se předpokládalo, že hyperurikemie u pacientů s renálními onemocněními je důsledkem nedostatečného vylučování UA kvůli ledvinnému selhání, a proto nebyla cílem intenzivní léčby. Základní vědecké poznatky nyní naznačují, že hyperurikemie hraje patogenní roli při vzniku chronického onemocnění ledvin a kardiovaskulárních onemocnění, protože způsobuje endoteliální dysfunkci, proliferaci cévních hladkých svalových buněk a aktivaci renin-angiotenzinového systému. Další nashromážděné údaje naznačují, že léčba snižující hladinu UA zpomaluje progresi těchto onemocnění. Snížení hladiny UA je účinnou metodou pro zlepšení stavu, ale ne všechny látky snižující hladinu UA fungují stejně. V klinické praxi je třeba tyto látky používat s opatrností.
Uric acid (UA) is predominantly formed in the liver, intestine and vascular endothelium as an end product of the metabolism of purines derived from food and endogenously from damaged or dead cells. The kidneys play a major role in the excretion of UA, eliminating about 70 % of the daily production. The remainder (approximately 30 %) is excreted by the intestine. If the production of UA exceeds the capacity of its excretion, hyperuricaemia results. Overexpression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and impaired glycolysis due to insulin resistance may be related to the development of hyperuricaemia in metabolic syndrome. Hyperuricemia is associated with the development and severity of metabolic syndrome. Previously, hyperuricaemia was thought to be the main cause of gout and gouty arthritis only. It was also assumed that hyperuricemia in patients with renal disease was a consequence of inadequate UA excretion due to renal failure and therefore was not a target for intensive treatment. Basic scientific evidence now suggests that hyperuricemia plays a pathogenic role in the development of chronic kidney disease and cardiovascular disease by causing endothelial dysfunction, vascular smooth muscle cell proliferation, and activation of the renin- angiotensin system. Lowering UA levels is an effective method for improving the condition, but not all UA lowering agents work the same. In clinical practice, these agents should be used with caution. Further accumulating data suggest that UA-lowering therapy slows the progression of these diseases.
- MeSH
- Allopurinol administration & dosage therapeutic use MeSH
- Gout Suppressants antagonists & inhibitors pharmacology therapeutic use MeSH
- Febuxostat administration & dosage therapeutic use MeSH
- Hyperuricemia drug therapy complications MeSH
- Cardiovascular Diseases prevention & control MeSH
- Uric Acid blood MeSH
- Humans MeSH
- Metabolic Syndrome * diagnosis etiology therapy MeSH
- Check Tag
- Humans MeSH
Předložený text stručně charakterizuje základní možnosti farmakoterapeutického ovlivnění hyperurikemie. Stále nejčastěji využívanou léčivou látkou v dané indikaci je alopurinol působící jako kompetitivní inhibitor xanthinoxidázy s potenciálem využití přesahujícím rámec pouhého ovlivnění urikemie. Stručně zmíněny jsou rovněž další látky, jakkoliv mnohé z nich nejsou aktuálně v ČR dostupné.
The presented text briefly characterizes the basic possibilities of pharmacotherapeutic treatment of hyperuricemia. Allopurinol acting as a competitive xanthine oxidase inhibitor with a potential for use beyond the mere influence of uricemia is still the most commonly used active substance in this indication. Other substances are also briefly mentioned, although many of them are not currently available in the Czech Republic.
- MeSH
- Allopurinol administration & dosage pharmacology adverse effects MeSH
- Gout Suppressants * administration & dosage pharmacology adverse effects MeSH
- Febuxostat administration & dosage pharmacology adverse effects MeSH
- Hyperuricemia drug therapy MeSH
- Uric Acid MeSH
- Humans MeSH
- Uricosuric Agents MeSH
- Check Tag
- Humans MeSH
BACKGROUND: Xanthine oxidase (XO) generates reactive oxygen species during uric acid production. Therefore, XO inhibitors, which suppress oxidative stress, may effectively treat non-alcoholic steatohepatitis (NASH) and atherosclerosis via uric acid reduction. In this study, we examined the antioxidant effect of the XO inhibitor febuxostat on NASH and atherosclerosis in stroke-prone spontaneously hypertensive 5 (SHRSP5/Dmcr) rats. METHODS: SHRSP5/Dmcr rats were divided into three groups: SHRSP5/Dmcr + high-fat and high-cholesterol (HFC) diet [control group, n = 5], SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) [fructose group, n = 5], and SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) + febuxostat (1.0 mg/kg/day) [febuxostat group, n = 5]. Glucose and insulin resistance, blood biochemistry, histopathological staining, endothelial function, and oxidative stress markers were evaluated. RESULTS: Febuxostat reduced the plasma uric acid levels. Oxidative stress-related genes were downregulated, whereas antioxidant factor-related genes were upregulated in the febuxostat group compared with those in the fructose group. Febuxostat also ameliorated inflammation, fibrosis, and lipid accumulation in the liver. Mesenteric lipid deposition decreased in the arteries, and aortic endothelial function improved in the febuxostat group. CONCLUSIONS: Overall, the XO inhibitor febuxostat exerted protective effects against NASH and atherosclerosis in SHRSP5/Dmcr rats.
- MeSH
- Antioxidants pharmacology therapeutic use MeSH
- Atherosclerosis * drug therapy MeSH
- Diet, High-Fat MeSH
- Febuxostat pharmacology therapeutic use MeSH
- Enzyme Inhibitors MeSH
- Rats MeSH
- Uric Acid MeSH
- Lipids MeSH
- Non-alcoholic Fatty Liver Disease * drug therapy pathology MeSH
- Rats, Inbred SHR MeSH
- Xanthine Oxidase MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Hyperurikemie, patologické zvýšení hladin kyseliny močové v séru, je nejvýznamnějším ovlivnitelným rizikovým faktorem vývoje dny. Prevalence hyperurikemie v populaci v posledních desetiletích narůstá. Riziko vývoje manifestní dny významně roste s výší urikemie. Pacienti s asymptomatickou hyperurikemií a dnou mají zvýšené riziko rozvoje komorbidit, zejména hypertenze, chronického onemocnění ledvin a metabolického syndromu. Asymptomatická hyperurikemie a dna je spojena se zvýšenou celkovou a kardiovaskulární mortalitou. Základem úspěšné léčby hyperurikemie je poučení pacienta o podstatě onemocnění, o principech a cílech léčby i o jejích možných komplikacích. Léčba asymptomatické hyperurikemie by měla vždy zahrnovat režimová a dietní opatření, léčbu komorbidit, racionalizaci farmakoterapie a u některých pacientů rovněž hypourikemickou léčbu. U pacientů s manifestní dnou by hypourikemická léčba měla být zvažována již od prvních projevů. Léčba musí směřovat k dlouhodobému udržení urikemie nižší než 360 μmol/l. Důležitou součástí hypourikemické léčby by měla být i profylaktická léčba dnavých záchvatů. Účinnost a bezpečnost hypourikemické léčby je nutné monitorovat a na nesplnění cílů léčby reagovat změnou léčebné strategie.
Hyperuricaemia, a pathological increase in serum uric acid levels, is the most significant modifiable risk factor for the development of gout. The prevalence of hyperuricaemia in the population has been increasing during recent decades. The risk of developing gout increases significantly with the increase in uricaemia. Patients with asymptomatic hyperuricaemia and gout have an increased risk of developing comorbidities, especially hypertension, chronic kidney disease, and metabolic syndrome. Asymptomatic hyperuricaemia and gout are associated with increased overall and cardiovascular mortality. The basis of successful treatment of hypeuricaemia is the patient's awareness of the nature of the disease, the principles and objectives of the treatment, and its possible complications. The management of asymptomatic hyperuricaemia should include lifestyle and dietary measures, treatment of comorbidities, rationalization of pharmacotherapy and, in some patients, urate-lowering therapy as well. In patients with gout, hypouricaemic treatment should be considered since the first manifestations. Urate-lowering therapy should be aimed at long-term maintenance of uricaemia below 360 μmol/l. Prophylactic treatment of gout attacks should also be an important part of urate-lowering therapy. The efficacy and safety of hypouricaemic treatment should be monitored and responded to by changing the treatment strategy in the case of failure to meet treatment objectives.
- MeSH
- Allopurinol administration & dosage adverse effects therapeutic use MeSH
- Anti-Inflammatory Agents, Non-Steroidal therapeutic use MeSH
- Gout Suppressants pharmacology therapeutic use MeSH
- Renal Insufficiency, Chronic ethnology physiopathology prevention & control MeSH
- Gout * diagnosis drug therapy physiopathology MeSH
- Arthritis, Gouty drug therapy physiopathology MeSH
- Febuxostat administration & dosage adverse effects therapeutic use MeSH
- Hyperuricemia * diagnosis drug therapy physiopathology MeSH
- Uric Acid blood metabolism adverse effects MeSH
- Humans MeSH
- Primary Health Care MeSH
- Practice Guidelines as Topic MeSH
- Urate Oxidase therapeutic use MeSH
- Uricosuric Agents administration & dosage adverse effects therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Allopurinol therapeutic use MeSH
- Gout Suppressants therapeutic use MeSH
- Gout * epidemiology drug therapy complications MeSH
- Febuxostat therapeutic use MeSH
- Hyperuricemia epidemiology drug therapy complications MeSH
- Comorbidity MeSH
- Humans MeSH
- Observational Studies as Topic MeSH
- Symptom Flare Up MeSH
- Check Tag
- Humans MeSH
Hyperurikemie je dána nerovnováhou mezi tvorbou a vylučováním kyseliny močové. Nejčastější příčinou hyperurikemie je snížené vylučování kyseliny močové, které zprostředkovávají urátové transportéry, především reabsorpční transportéry urátu URAT1 a glukózy GLUT9 a sekreční transportér ABC (ATP-binding casette) podtřídy G2 (ABCG2) v renálních proximálních tubulech a v případě ABCG2 i v gastrointestinálním traktu. Bylo identifikováno více než 30 genetických lokusů asociovaných s hyperurikemií a dnou, z nichž třetinu tvoří geny pro urátové transportéry. Z farmakologických možností ovlivnění hyperurikemie zůstávají řadu let zlatým standardem inhibitory xanthinoxidázy, které blokují konečnou fázi enzymatické degradace purinů na kyselinu močovou. Pozornost se znovu obrací také na urikosurika. Reabsorpční urátové transportéry v renálních proximálních tubulech jsou cílem vývoje řady nových urikosurik.
Hyperuricemia is caused by an imbalance between endogenous production and excretion of urate. The most common cause of hyperuricemia is decreased excretion of urate. Urate transport is mediated by several transmembrane proteins responsible for reabsorption (mainly URAT1 and GLUT9) and secretion ATP-binding cassette G2 (ABCG2) on the apical and basolateral membranes of the proximal tubules and in the case of ABCG2 also in the gastrointestinal tract. More than 30 genetic loci associated with hyperuricemia and gout have been identified, a third of which are genes for urate transporters. Xanthine oxidase inhibitors, which block the last enzyme involved in the uric acid synthesis pathway, are the most widely used drugs for hyperuricemia. Uricosuric agents experience renewed interest. Urate transporters responsible for the reabsorption of uric acid in renal proximal tubule are the target of the development of several novel uricosurics.
- MeSH
- Allopurinol therapeutic use MeSH
- Febuxostat administration & dosage therapeutic use MeSH
- Hyperuricemia * drug therapy genetics MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Allopurinol administration & dosage MeSH
- Gout drug therapy MeSH
- Arthritis, Gouty drug therapy MeSH
- Febuxostat * administration & dosage chemistry pharmacokinetics metabolism adverse effects MeSH
- Hyperuricemia drug therapy MeSH
- Clinical Trials, Phase III as Topic MeSH
- Uric Acid blood MeSH
- Humans MeSH
- Statistics as Topic MeSH
- Check Tag
- Humans MeSH
Hyperurikemie, patologické zvýšení hladin kyseliny močové v séru, je nejvýznamnějším ovlivnitelným rizikovým faktorem vývoje dny. Prevalence hyperurikemie v populaci v posledních desetiletích narůstá. Riziko vývoje manifestní dny významně roste s výší urikemie. Pacienti s asymptomatickou hyperurikemií a dnou mají zvýšené riziko rozvoje komorbidit, zejména hypertenze, chronického onemocnění ledvin a metabolického syndromu. Asymptomatická hyperurikemie a dna je spojena se zvýšenou celkovou a kardiovaskulární mortalitou. Základem úspěšné léčby hyperurikemie je poučení pacienta o podstatě onemocnění, o principech a cílech léčby i o jejích možných komplikacích. Léčba asymptomatické hyperurikemie by měla vždy zahrnovat režimová a dietní opatření, léčbu komorbidit, racionalizaci farmakoterapie a u některých pacientů rovněž hypourikemickou léčbu. U pacientů s manifestní dnou by hypourikemická léčba měla být zvažována již od prvních projevů. Léčba musí směřovat k dlouhodobému udržení urikemie nižší než 360 µmol/l. Důležitou součástí hypourikemické léčby by měla být i profylaktická léčba dnavých záchvatů. Účinnost a bezpečnost hypourikemické léčby je nutné monitorovat a na nesplnění cílů léčby reagovat změnou léčebné strategie.
Hyperuricaemia, a pathological increase in serum uric acid levels, is the most significant modifiable risk factor for the development of gout. The prevalence of hyperuricaemia in the population has been increasing during recent decades. The risk of developing gout increases significantly with the increase in uricaemia. Patients with asymptomatic hyperuricaemia and gout have an increased risk of developing comorbidities, especially hypertension, chronic kidney disease, and metabolic syndrome. Asymptomatic hyperuricaemia and gout are associated with increased overall and cardiovascular mortality. The basis of successful treatment of hypeuricaemia is the patient's awareness of the nature of the disease, the principles and objectives of the treatment, and its possible complications. The management of asymptomatic hyperuricaemia should include lifestyle and dietary measures, treatment of comorbidities, rationalization of pharmacotherapy and, in some patients, urate-lowering therapy as well. In patients with gout, hypouricaemic treatment should be considered since the first manifestations. Urate-lowering therapy should be aimed at long-term maintenance of uricaemia below 360 μmol/l. Prophylactic treatment of gout attacks should also be an important part of urate-lowering therapy. The efficacy and safety of hypouricaemic treatment should be monitored and responded to by changing the treatment strategy in the case of failure to meet treatment objectives.
- MeSH
- Allopurinol administration & dosage adverse effects therapeutic use MeSH
- Anti-Inflammatory Agents, Non-Steroidal therapeutic use MeSH
- Gout Suppressants pharmacology therapeutic use MeSH
- Renal Insufficiency, Chronic ethnology physiopathology prevention & control MeSH
- Gout * diagnosis drug therapy physiopathology MeSH
- Arthritis, Gouty drug therapy physiopathology MeSH
- Febuxostat administration & dosage adverse effects therapeutic use MeSH
- Hyperuricemia * diagnosis drug therapy physiopathology MeSH
- Uric Acid blood metabolism adverse effects MeSH
- Humans MeSH
- Primary Health Care MeSH
- Practice Guidelines as Topic MeSH
- Urate Oxidase therapeutic use MeSH
- Uricosuric Agents administration & dosage adverse effects therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Allopurinol administration & dosage MeSH
- Gout * diagnostic imaging drug therapy physiopathology MeSH
- Febuxostat * administration & dosage MeSH
- Hyperuricemia etiology drug therapy prevention & control MeSH
- Humans MeSH
- Risk Factors MeSH
- Treatment Outcome MeSH
- Seizures epidemiology MeSH
- Check Tag
- Humans MeSH
BACKGROUND: ABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate underexcretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age. METHOD: The cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31, 17 hyperuricemia/14 gouts); 115 normouricemic controls were used for comparison. We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions. RESULTS: In the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P < 0.0001), and to the European population MAF 9.4% (OR = 5.7, P < 0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Most (74%) of the pediatric-onset patients had affected family members (61% were first-degree relatives). CONCLUSION: Our results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics MeSH
- Allopurinol therapeutic use MeSH
- Gout Suppressants therapeutic use MeSH
- Child MeSH
- Gout diagnosis drug therapy genetics MeSH
- Adult MeSH
- Febuxostat therapeutic use MeSH
- Gene Frequency MeSH
- Genetic Predisposition to Disease genetics MeSH
- Genotype MeSH
- Hyperuricemia diagnosis drug therapy genetics MeSH
- Polymorphism, Single Nucleotide * MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
