Author: Gao Lili This article is authorized by the author to be published by Yimaitong, please do not reprint without authorization.
Hyperuricemia (HUA) and gout are common in clinical practice, and HUA is a metabolic syndrome caused by purine metabolism disorders, which can cause gout and uric acid nephropathy; Gout is a crystal-related arthropathy caused by monosodium urate deposition in the joints, which is associated with HUA and can be seen in children and adolescents. Compared with adult HUA, it is more likely to develop gout and renal insufficiency, which is closely related to hyperlipidemia, hypertension, insulin resistance, etc., which can increase the risk of cardiovascular disease, and may continue to adulthood, causing a serious decline in the quality of life in early adulthood.
HUA is a normal purine diet, and the fasting blood uric acid level in adults twice a day is > 420 μmol/L. The definition of HUA in children and adolescents has not yet reached an agreement, and the cut-off value of Mayo Clinic is mostly used, which is related to congenital and acquired factors, such as genetic variation, glycogen storage disease, malignant tumors, tissue hypoxia, bone marrow transplantation, chronic kidney disease, obesity, etc., and can be divided into poor uric acid excretion type, uric acid hypergenesis type, mixed type, or asymptomatic HUA, symptomatic HUA (such as gouty arthritis, uric acid nephropathy).
Urate-lowering drugs for the treatment of HUA and gout can control blood uric acid levels and avoid urate deposition. According to the "Evaluation and Nutritional Management of Obesity and Hyperuricemia in Children and Adolescents" (2023), it is recommended to add urate-lowering drugs for patients with serum uric acid > 540-600μmol/L after strict nutritional intervention. The recommended target serum uric acid level for adults < 360 μmol/L, and the uric acid level for adolescents is higher than that for adults, and the target uric acid level can be controlled within the reference value range for the same age and sex, but not more than 540 μmol/L.
At present, commonly used urate-lowering drugs include xanthine oxidase inhibitors, drugs that inhibit uric acid synthesis, drugs that promote uric acid excretion, and urate oxidase. Drugs to promote uric acid excretion are suitable for the type of poor uric acid excretion, drugs to inhibit uric acid synthesis are used for the type of excessive uric acid production, and combined drugs are often required for the mixed type.
1. Xanthine oxidase inhibitors
For example, allopurinol and febuxostat can reduce the synthesis of uric acid by inhibiting the activity of xanthine oxidase, thereby reducing the level of blood uric acid, which can be used as a first-line drug for lowering uric acid, and can be used for the treatment of hyperuricemia and gout.
(1) Allopurinol
Hypoxanthine analogues, which can competitively inhibit xanthine oxidase and block the production of uric acid, have a good uric acid-lowering effect, and only have an inhibitory effect on reduced xanthine oxidase, which is ineffective for the formed hyperuricemia, especially suitable for those with hyperuricemia, and is also used for the prevention of hyperuricemia or the treatment of mild hyperuricemia, or obvious hyperuricemia with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
According to the Guidelines for the Rational Use of Drugs in Gout Primary (2021), children < 6 years old 50mg/time, 1-3 times/day; 6-10 years old: 100 mg/time, 1-3 times/day. Dosage can be adjusted as appropriate. According to the Guidelines for the Diagnosis and Treatment of Tumor Lysis Syndrome in Children (2021), allopurinol is mainly used to prevent hyperuricemia, and the recommended oral dose is 200-300mg/(m2·d), ≤ 600mg/d, once every 8 hours; < 10 kg of infants is recommended 10 mg/kg per day, once every 8 hours. Medication 12 to 24 hours before chemotherapy/treatment can be more effective in preventing elevated serum uric acid.
Notes:
➤ It can cause an increase in the serum levels of hypoxanthine and xanthine, the precursors of allopurinol, and in order to prevent acute kidney injury caused by hypoxanthine and xanthine deposition in the renal tubules, hydration and monitoring should be strengthened.
➤ It can cause hypersensitivity reactions such as vasculitis, Steven-Johnson syndrome, and is contraindicated in patients with positive HLA-B*5801 gene. It is recommended that HLA-B*5801 gene testing be performed before treatment is permitted.
➤别嘌醇由肾脏排泄，eGFR<15ml/min禁用。
➤ It can cause liver damage, and it is forbidden for severe liver insufficiency.
➤ It can cause bone marrow suppression, and it is forbidden for patients with obvious low blood cells.
➤ Those who are using iron, azathioprine, and 6-mercaptopurine should avoid combining allopurinol.
➤ Combined with cyclophosphamide, the inhibitory effect of bone marrow can be more obvious. Combined with ampicillin, the incidence of rash can be increased.
(2) Febuxostat
Potent and selective xanthine oxidase inhibitor, with good uric acid-lowering effect, acid suppression and acid reduction are more powerful and durable, can inhibit oxidative and reduced xanthine oxidase, do not need to consider the influence of antacids and food when administering, and it is excreted through the dual channels of kidney and intestine, and the protective effect of the kidney is better, especially suitable for patients with chronic renal insufficiency and HLA-B*5801 gene positive.
According to the "Evaluation and Nutritional Management of Obesity and Hyperuricemia in Children and Adolescents" (2023), febuxostat can be the preferred urate-lowering drug for adolescents, and the starting dose for adults can be 40mg/day and 80mg/day according to the severity of clinical manifestations, and children can start smaller.
Notes:
➤ It can cause liver damage, tubulointerstitial nephritis, rhabdomyolysis, mental abnormalities, etc.
➤ Those who are using 6-mercaptopurine, azathioprine, and chotheophylline are prohibited.
➤ It is not recommended for patients with a history of intracranial venous thrombosis (CVT) or a recent CVT because it may increase the risk of death from cardiovascular disease. Use with caution in patients with a history of cardiovascular disease or new cardiovascular disease.
2. Drugs to promote uric acid excretion
For example, benzbromarone can inhibit the reabsorption of uric acid, promote uric acid excretion, and reduce blood uric acid levels, especially suitable for patients with hyperuricemia and gout with reduced renal uric acid excretion. It is necessary to drink plenty of water to avoid excessive uric acid excretion and the formation of uric acid stones in the urinary system.
According to the Guidelines for the Rational Use of Gout Primary Medication (2021), the initial oral dose is recommended to be 25 mg/d for adolescents over 14 years old, and for those whose blood uric acid level does not meet the target after 2-4 weeks, it will be increased by 25 mg/d, with a maximum dose of 100 mg/d. Oral sodium bicarbonate is decided based on urine pH.
Not recommended for children.
Notes:
➤ It can cause kidney damage, renal colic, kidney stones, eGFR <20ml/min, patients with a high risk of kidney stones, urinary uric acid stones, dialysis, and patients with acute uric acid nephropathy are prohibited.
➤ It can cause liver damage, and there are reports of explosive liver necrosis in Caucasians, and it is contraindicated in patients with severe liver damage. Use with caution in patients with chronic liver disease. If the aminotransferase exceeds 2 times the normal value during the medication, the drug needs to be stopped.
➤ Not recommended for those with increased uric acid synthesis. It is forbidden for those whose uric acid excretion has increased in 24 hours (>3.54mmol).
➤ It can enhance the effect of oral anticoagulants and non-steroidal anti-inflammatory drugs (such as indomethacin, naproxen, etc.).
3. Urate oxidase
Reducing serum uric acid by degrading uric acid into water-soluble allantoin and hydrogen peroxide can be used in patients with significant hyperuricemia, and can also be considered for patients with refractory gout, chemoradiotherapy, or acute elevated serum uric acid caused by hematologic malignancies.
According to the "Evaluation and Nutritional Management of Obesity and Hyperuricemia in Children and Adolescents" (2023), urate oxidase is the first choice for patients with tumor lysis syndrome (TLS) who have obvious hyperuricemia, and the recommended dose is 0.1-0.2mg/kg + NS 50ml each time, intravenous infusion within 0.5h, and the specific dose and number of medications can be determined according to the results of clinical monitoring and evaluation. Combination of allopurinol is not recommended.
Notes:
It can cause fever, nausea and vomiting, diarrhea, headache, rash, allergies, etc. Because it can cause hemolysis in patients with G-6-PD deficiency, it should be avoided in patients with G-6-PD deficiency.
References:1. Assessment and nutritional management of obesity complicated with hyperuricemia in children and adolescents[J].Chinese Journal of Practical Pediatrics,2023,38(10):735-7402.) Chinese Journal of Internal Medicine,2023,62(9):1068-10743. Guidelines for primary diagnosis and treatment of gout and hyperuricemia (2019)[J].Chinese Journal of General Practice,2020,19(4):293-3004.) Chinese Journal of Endocrinology and Metabolism,2020,36(1):1-135. Chinese Journal of General Practice,2021,20(6):631-6376. Chinese Journal of Nephrology,2017,33(6):464-4667. Guidelines for the diagnosis and treatment of tumor lysis syndrome in children[J].Chinese Journal of Practical Pediatrics,2021,36(12):890-895.)