Chinese Multidisciplinary Expert Consensus on the Diagnosis and Treatment of Hyperuricemia and Related Diseases

INTRODUCTION The prevalence of hyperuricemia (HUA) has increased in China in the recent years in relation to socioeconomic developments and changing lifestyles and diets, with a trend toward onset at younger age. HUA has become the second most common metabolic disease after diabetes mellitus. Like gout, HUA is also associated with the occurrence and progression of disorders of the urinary, endocrine, metabolic, cardio-cerebrovascular, and other systems. Different expert panels have developed guidelines and consensuses on HUA and gout in their respective fields. This consensus has been formulated in accordance with a systematic medical model by a task force including rheumatologists, nephrologists, endocrinologists, cardiologists, neurologists, urologists, and experts in traditional Chinese medicine. It is the first multidisciplinary expert consensus on HUA and its related diseases in China and is aimed at promoting a multidisciplinary collaboration and providing guidelines for best clinical practices. DEFINITION OF HYPERURICEMIA According to epidemiological data, HUA has previously been defined as a fasting serum urate level >420 μmol/L in males and >360 μmol/L in females measured on two separate days after a normal purine diet. The saturation level of urate is 420 μmol/L (regardless of sex) in blood, so greater serum urate values can cause precipitation of urate crystals, thus resulting in their deposition in joint cavities and other tissues. Therefore, HUA is defined herein as a serum urate level >420 μmol/L (7 mg/dl). EPIDEMIOLOGY OF HYPERURICEMIA The serum urate level is affected by age, sex, race, heredity, food habits, drugs, environment, and other factors. A nationwide epidemiological survey of HUA is still lacking in China. The data from different regions at various times have shown an overall increasing prevalence of HUA in the recent years.12 Epidemiological studies have shown that the prevalence of HUA varies greatly among geographical regions in China over the previous 10 years, ranging from 5.46% to 19.30%, specifically 9.2–26.2% in males and 0.7–10.5% in females.34567 The prevalence of gout varies from 0.86% to 2.20% among geographical regions in China, specifically 1.42–3.58% in males and 0.28–0.90% in females.138 The prevalence of both HUA and gout increases with age and is more prevalent in males than that in females, in cities than that in rural areas, and in coastal than that in inland areas.9 PATHOPHYSIOLOGY OF HYPERURICEMIA-RELATED SYSTEMIC IMPAIRMENT Uric acid is produced in the liver from purine compounds, which may originate from dietary intake or from the breakdown of body cells Supplementary Figure 1.10 Approximately 2/3rd of all uric acid is excreted via the kidneys, and the rest is excreted through the digestive tract. Uric acid undergoes glomerular filtration and renal proximal tubular reabsorption, secretion, and postsecretion reabsorption. The unabsorbed portions are excreted in the urine Supplementary Figure 2.1112 The production and excretion of uric acid are balanced under normal circumstances, but factors that cause overproduction or underexcretion of uric acid can lead to HUA Supplementary Material 1.10 Schematic diagram of uric acid production. (1) PRPP synthetase; (2) amidophosphoribosyltransferase; (3) adenylosuccinate lyase; (4) adenylate deaminase; (5) 5-nucleotidase; (6) adenosine deaminase; (7) purine nucleoside phosphorylase; (8) HPRT; (9) APRT; (10) xanthine oxidase. PRPP: Phosphoribosyl pyrophosphate; HPRT: Hypoxanthine phosphoribosyltransferase; APRT: Adenine phosphoribosyltransferase; AICAR: Aminoimidazole carboxamide ribotide; AMP: Adenosine monophosphate; ATP: Adenosine triphosphate; GMP: Guanylate; IMP: Inosine monophosphate; PNC: Purine nucleotide cycle; SAICAR: Succinylaminoimidazole carboxamide ribotide. Schematic diagram of uric acid metabolism. Classification of hyperuricemia by pathophysiology When the serum urate level exceeds its saturation concentration, the precipitated urate crystals directly attach to and deposit in joints and soft tissues around the joints, renal tubules, blood vessels, and other sites, thus resulting in the chemotaxis of neutrophils and macrophages. The interaction between these cells and the crystals leads to the release of pro-inflammatory factors (interleukin IL-1β, IL-6, etc.), metalloproteinase 9, hydrolase, and other enzymes,131415 which can cause acute and chronic inflammatory injuries of the articular cartilage, bone, kidney, vascular intima, and other tissues.16 The damage to multiple organs caused by HUA, involving the heart, brain, and kidneys, may be due to complex mechanisms, such as increased generation of oxygen-free radicals, which damage vascular endothelial cells,1718192021 and upregulation of endothelin and downregulation of nitric oxide synthase expression, thus resulting in vasomotor dysfunction. These phenomena lead to the oxidative modification of low-density lipoprotein cholesterol and subsequent atherosclerosis,22 which damages mitochondria and lysosomes23 and results in apoptosis of renal tubular epithelial cells and cardiomyocytes. In addition, the renin–angiotensin–aldosterone system is activated, thereby causing vascular remodeling and organ damage,1624 and the inflammatory response is stimulated, thus resulting in platelet aggregation and adhesion.2526 DIAGNOSIS OF HYPERURICEMIA AND GOUT Hyperuricemia A diagnosis of HUA is established when fasting serum urate levels exceed 420 μmol/L after consumption of a normal daily diet on two separate days. Hematological malignancies, chronic renal failure, congenital metabolic abnormalities, poisoning, some drugs, and other factors can elevate serum urate level Supplementary Materials 1 and 2. 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