Elevated blood uric acid levels are associated with abnormal nucleic acid metabolism in the body and reduced renal excretion, with a normal blood urate saturation of 6.7 mg/dl. HUA without an attack of gout is called asymptomatic HUA.
HUA is often associated with traditional metabolic cardiovascular risk factors such as hypertension, hyperlipidemia, type 2 diabetes, obesity, insulin resistance, etc. Therefore, HUA has long been considered only as a marker of metabolic abnormalities. More than 10 prospective large-scale clinical studies with about 100,000 or more observed subjects in the last 20 years have used multifactorial regression analysis to confirm that HUA is an independent risk factor for cardiovascular disease. There is no evidence-based evidence that lowering blood uric acid reduces the risk of cardiovascular events, so the guidelines do not list HUA as an independent risk factor for cardiovascular disease. However, given that high uric acid is closely associated with poor vascular, cardiac, and renal prognosis, uric acid-lowering therapy is expected to be a new avenue for cardiovascular disease prevention and treatment.
In 2002, the Japanese Gout Nucleic Acid Metabolism Association was the first in the world to propose that asymptomatic HUA should be treated in a stratified manner according to cardiovascular risk factors or coexisting cardiovascular diseases. There are a large number of asymptomatic HUA patients with multiple cardiovascular risk factors or ischemic heart disease in China, and clinicians have different views on how to deal with asymptomatic HUA, whether there is a need to treat asymptomatic HUA and how to determine the treatment criteria are the problems that remain to be solved. In this regard, the Cardiovascular Physicians Branch of Chinese Physicians Association organized experts in related fields to discuss the relationship between HUA and cardiovascular disease and the necessity of treatment, and finally reached a Chinese expert consensus on the recommendations for the diagnosis and treatment of asymptomatic hyperuricemia combined with cardiovascular disease.
I. Epidemiology of HUA
From the epidemiological data of developed countries in Europe and America, the prevalence of HUA increases with the improvement of national economic level, and has a similar epidemiological trend with diabetes and hyperlipidemia, suggesting that HUA is closely related to lifestyle. The epidemiological data in China support this inference. In the early 1980s, Fang Qi et al. showed that the prevalence of HUA in China was 1.4% in men and 1.3% in women [1]. After the mid-1990s, the prevalence of HUA in men ranged from 8.2% to 19.8%, and that in women ranged from 5.1% to 7.6% [2], and the prevalence of HUA in China increased by 10 times in 10 years. Moreover, the prevalence of HUA in the southern and economically developed coastal areas is higher than that in other regions of China during the same period [3, 4, 5], which should be related to the rapid improvement of living standards and the consumption of seafood and high-protein and high-cholesterol foods in these areas.
According to the reports on the prevalence of HUA in recent years, it is conservatively estimated that there are about 120 million HUA patients in China, accounting for about 10% of the total population, and the high prevalence age is middle-aged and old men and postmenopausal women, but the trend of youthfulness has increased in recent years.
Second, the metabolism of uric acid
Uric acid is the product of human purine metabolism. There are two sources of purine in the human body: endogenous by its own synthesis or nucleic acid degradation (about 600mg/d), which accounts for about 80% of the total uric acid in the body; exogenous by the intake of purine diet (about 100mg/d), which accounts for about 20% of the total uric acid in the body. In the normal state, the uric acid pool in the body is 1200 mg, producing about 750 mg of uric acid per day and excreting about 800-1000 mg, with 30% excreted from the intestine and biliary tract and 70% excreted via the kidneys. Under normal circumstances, the daily production and excretion of uric acid in human body basically maintain a dynamic balance, all factors affecting the production and (or) excretion of blood uric acid can lead to an increase in blood uric acid level.
Risk factors of HUA
HUA is related to age, gender, regional distribution, race, genetics, and social status. With increasing age, men, first-degree relatives with a history of HUA, sedentary lifestyle and high social status, as well as the presence of cardiovascular risk factors and renal insufficiency patients are prone to HUA.
Consumption of high purine foods such as meat, seafood, animal offal, thick broth, alcohol (beer, liquor) and strenuous physical exercise can increase blood uric acid. The prolonged application of certain drugs can lead to the increase of blood uric acid, such as thiazide diuretics, small doses of aspirin, compound antihypertensive tablets, pyrazinamide, nifedipine, propranolol, etc. all prevent uric acid excretion.
Fourth, the diagnostic criteria of HUA
1.Diagnostic criteria of HUA: under the state of normal purine diet, the fasting blood uric acid level on two non-same days is >420μmol/l (7mg/dl) in men or >357μmol/l (6mg/dl) in women.
2, HUA typing diagnosis: typing diagnosis can help to find the cause of HUA and give targeted treatment. 5 days after low purine diet for HUA patients, 24-hour urine will be taken to detect uric acid level.
(1) Poor uric acid excretion type: uric acid excretion is less than 0.48mg/kg/h, uric acid clearance rate (Cua, uric uric acid x urine volume per minute/blood uric acid) is <6.2ml/min.
(2) Excessive uric acid production type: uric acid excretion is greater than 0.51mg/kg/h, uric acid clearance rate ≥6.2ml/min.
(3) Mixed type: uric acid excretion more than 0.51mg/kg/h, uric acid clearance <6.2ml/min.
Considering the influence of renal function on uric acid excretion, corrected by creatinine clearance (Ccr), HUA is classified according to Cua/Ccr ratio as follows: >10% is excessive uric acid production type, <5% is poor uric acid excretion type, and between 5-10% is mixed type.
V. Epidemiology of the causal relationship between HUA and cardiovascular disease
(A) HUA and cardiovascular risk factors
1. HUA and hypertension
In 1879, MOHAMED first proposed that blood uric acid was involved in the development of hypertension, and in 1889, Haig proposed that a low purine diet could be used as a means to prevent hypertension. 1990, several cardiovascular epidemiological studies consistently confirmed that blood uric acid was an independent risk factor for the development of hypertension [7, 8, 9], and for every 59.5 μmol/l increase in blood uric acid level, the relative risk of hypertension increased by 25%. risk increases by 25%.
Clinical studies have found [6] that 90% of patients with primary hypertension have combined HUA, whereas only 30% of patients with secondary hypertension have combined HUA, suggesting a causal relationship between HUA and primary hypertension. The causal relationship between hyperuric acid and hypertension was confirmed by a classic animal study [10], which increased blood uric acid levels in rats by 1.6 mg/dl over 7 weeks by an inducer, with a subsequent mean increase in systolic blood pressure of 2.2 mm Hg. However, if blood uric acid-lowering drugs such as allopurinol or phenylsulfonate were given concomitantly, blood uric acid was normal and blood pressure was no longer elevated, suggesting that hyperuric acid is associated with increased blood pressure.
2,, HUA and diabetes
Long-term HUA can destroy the function of pancreatic beta cells and induce diabetes. Two studies suggest that long-term HUA has a causal relationship with abnormal glucose tolerance and the development of diabetes. Two prospective clinical studies from Korea and Japan [11, 12] enrolled 2951 middle-aged HUA patients with 6-7 years of follow-up and found that those with baseline blood uric acid levels >398umo/l had a 78% increased risk of developing abnormal long-term glucose tolerance and type 2 diabetes compared to those with <280umo/l.
3.HUA and hypertriglyceridemia
Domestic and international epidemiological data consistently show a correlation between blood uric acid and triglycerides [13, 14, 15]. There is only one prospective cohort study on the relationship between uric acid and triglycerides [16], which was followed for 8 years and found that basal triglycerides were an independent predictor of future HUA.
Animal tests observed that blood triglyceride levels were significantly higher in rats with artificially formed hyperuricemia than in rats with normal blood uric acid [17, 18], suggesting that uric acid has an effect on blood triglyceride metabolism. However, the mechanism of the interaction between uric acid and triglycerides and the causal relationship between uric acid and triglycerides are not very clear.
4.HUA and metabolic syndrome
The pathophysiological basis of metabolic syndrome is hyperinsulinemia and insulin resistance. Insulin resistance increases the production of blood uric acid during glycolysis and free fatty acid metabolism, and directly leads to hyperuricemia by increasing the reabsorption of uric acid by the kidneys. The inclusion of HUA in the metabolic syndrome was proposed by Professor Reaven, the father of the metabolic syndrome, as 70% of patients with the syndrome also have HUA [19].
HUA is often associated with various indicators of metabolic syndrome, such as hypertension in about 80% of HUA patients, overweight or obesity in 50%-70%, and hyperlipidemia in more than 67%. In a cross-sectional survey of 1600 people in China [20], the prevalence of HUA in the population with metabolic risk factors was 20.58% in men and 30.55% in women, and the proportion of HUA combined with three or more metabolic risk factors (obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, and low HDL) was as high as 76.92% in men and 67.64% in women. and 67.64%.
(B) HUA and cardiovascular diseases
1.HUA and coronary heart disease
(1) Uric acid is an independent risk factor for death from coronary heart disease
The Chicago Heart Study [21], the First National Health and Nutrition Survey (NHANES study) [22] and the MONICA study [23], after correcting for traditional cardiovascular risk factors and diuretic use, found that uric acid was an independent risk factor for all-cause mortality and coronary heart disease death in the general population, regardless of gender. For every 59.5 μmol/l (1 mg/dl) increase in blood uric acid, the risk of death increased by 48% in men and 126% in women. Blood uric acid >357 μmol/l (6 mg/dl) is an independent risk factor for coronary heart disease, and blood uric acid >416.5 μmol/l (7 mg/dl) is an independent risk factor for stroke [24, 25].
For patients with established coronary heart disease, Bickel et al [27] found that the mortality rate in the population with blood uric acid >7.5 mg/dl (433 μmol/l) was five times higher than that in the population with blood uric acid <5 mg/dl (303 μmol/l), and multifactorial analysis confirmed that blood uric acid was an independent risk factor for all-cause mortality and coronary heart disease death in the coronary heart disease population.
(2) Uric acid is an independent risk factor for cardiovascular events
Four large prospective clinical studies: the MRFIT study [28], the PIUMA study [29], the Rotterdam cohort study [30] and the American worksite study [31], all showed that blood uric acid levels were an independent risk factor for acute myocardial infarction, stroke and all cardiovascular events, and the ability of elevated blood uric acid to predict cardiovascular events 86 μmol/l higher than elevated total cholesterol of 1.078 mmol/l and elevated blood pressure of 21.3 mm Hg. However, the MONICA study concluded that blood uric acid did not predict acute myocardial infarction and angina onset.
Recently, Wen-Harn Pan et al. in Taiwan, China, followed 41,879 men and 48,514 women for 8 years and showed that blood uric acid was likewise an independent risk factor for all-cause mortality, total cardiovascular events and ischemic stroke in our general population, low- and high-risk groups [26].
Whether blood uric acid can be used as an independent risk factor for cardiovascular events and whether there are gender differences in the effect of blood uric acid on cardiovascular events deserve further investigation.
2. HUA and renal damage
Uric acid is closely related to renal disease. In addition to the deposition of uric acid crystals, which leads to the increase of renal damage due to small renal arteries and chronic interstitial inflammation, many epidemiological surveys and animal studies have shown that uric acid can directly cause microangiopathy in the small glomerular arteries, leading to chronic kidney disease.
Two large-scale prospective studies in Japan confirmed the association of uric acid with the development of renal lesions. The risk of renal failure was found to be 8-fold higher in those with blood uric acid >8.5 mg/dl (476 μmol/l) compared to those with uric acid in the range of 5.0-6.4 mg/dl (298 μmol/l- 381 μmol/l) [32]. The risk of end-stage renal disease is increased 4-fold and 9-fold for men with blood uric acid ≥7.0 mg/dl (420 μmol/l) and women ≥6.0 mg/dl (357 μmol /l), respectively [33].
Two recent large-scale prospective long-term follow-up studies further confirmed that each 1 mg/dl increase in blood uric acid was associated with a 71% increased risk of kidney disease and a 14% increased risk of deteriorating renal function (GFR decline of 3 ml/min/1.73 ml/year) [34]. Compared to people with normal blood uric acid, those with blood uric acid in the range of 7.0-8.9 mg/dl had a 2-fold increased risk of new kidney disease, and those with ≥9 mg/dl had a 3-fold increased risk of new kidney disease [35].
In a small randomized controlled clinical study investigating the effect of uric acid-lowering therapy on delaying renal disease, application of allopurinol 100-300 mg/d for one year resulted in a 50% reduction in blood creatinine growth rate compared to the unmedicated group. Indirectly, it is suggested that hyperuricemia is associated with the progression of renal impairment [36].
3. HUA and heart failure
Two prospective studies have shown that HUA can be an independent predictor of death in acute and chronic heart failure [37, 38], but it is unclear whether it can be used as a direct indicator or only an indirect indicator.
In summary, hyperuricemia is associated with the following cardiovascular risk factors, subclinical damage to target organs, and clinical disease.
VI. Clinical studies related to pharmacological treatment of asymptomatic HUA
There is no consensus on whether to give uric acid-lowering therapy for asymptomatic HUA in combination with multiple cardiovascular risk factors or cardiovascular disease. There is a lack of high-quality evidence-based evidence on whether uric acid-lowering therapy can be an effective measure to reduce cardiovascular endpoint events, and the limited studies available are as follows.
The LIFE study and the GREACE study indirectly suggest the effect of pharmacological reduction of blood UA levels on cardiovascular endpoint events. However, neither the LIFE nor GREACE studies specifically evaluated the impact of lowering blood UA levels on cardiovascular disease prognosis.
A randomized controlled study of allopurinol intervention [39], enrolling 169 patients undergoing coronary artery bypass grafting to investigate the effect of preoperative treatment with allopurinol on the prognosis of the procedure, showed improved postoperative cardiac function and reduced mortality but increased nonfatal complications in the allopurinol group compared with no allopurinol application.
Kanby et al. enrolled 48 HUA patients with normal renal function and 21 with normal uric acid, and those with HUA were given allopurinol 300 mg/d for 3 months, showing significant improvements in blood pressure, blood uric acid and creatinine clearance in the allopurinol application group [40].
In a randomized double-blind placebo-controlled crossover study, 30 adolescent patients with newly diagnosed class I hypertension combined with mild HUA were crossed over to allopurinol and placebo 400 mg/d for four weeks and showed that allopurinol treatment significantly lowered blood pressure compared to placebo (6.3 vs 0.8 mmHg systolic and 4.6 vs 0.3 mmHg diastolic), and 2/3 of patients treated with allopurinol 2/3 of patients treated with allopurinol returned to normal blood pressure [41].
Whether uric acid-lowering drugs can be used clinically as a new antihypertensive drug needs to be confirmed in large-scale clinical studies, and whether they are suitable for patients with long-term hypertension combined with HUA still needs to be further explored. For long-term HUA, atherosclerosis has occurred in the vessel wall and formed hypertension, which has become non-uric acid-dependent at this time, and even if uric acid-lowering drugs are applied, they will not produce significant antihypertensive effects. Therefore, HUA should be detected early and intervene early.
VII. Suggestions for the treatment of asymptomatic hyperuricemia
1. Improvement of lifestyle
In the 2006 European League Against Rheumatism (EULAR) recommendations on gout prevention and treatment, lifestyle changes are emphasized as the core of treatment for HUA, including healthy diet, smoking cessation, adherence to exercise and weight control.
a) Healthy diet. For people with existing gout, HUA, metabolic cardiovascular risk factors and middle-aged and elderly people, diet should be based on low purine foods (Table 1), strictly control the intake of C foods such as meat, seafood and animal offal, reduce the intake of B foods in moderate amounts and eat mainly A foods.
b) Drink more water and quit smoking and drinking. Drink more than 1500ml of water daily, quit smoking, ban beer and white wine, red wine in moderation.
c) Insist on exercise and weight control. Daily moderate intensity exercise for more than 30 minutes. Obese people should lose weight so that the weight is controlled in the normal range (BMI<24kg/m2).
2. Actively treat metabolic risk factors associated with elevated blood uric acid
In 2006, the European League Against Rheumatism (EULAR) recommendations on gout prevention and treatment emphasized that active control of cardiovascular risk factors associated with HUA, such as hyperlipidemia, hypertension, hyperglycemia, obesity and smoking, should be an important part of HUA treatment.
3, HUA patients should avoid the application of drugs that raise blood uric acid
Such as diuretics (especially thiazides), corticosteroids, insulin, cycloheximide, tacrolimus, nicotine, pyrazinamide, niacin, etc. For patients who need diuretics and have combined HUA, non-thiazide diuretics are preferred, along with alkalinizing urine and drinking more water to keep the daily urine volume above 2000ml. For patients with hypertension combined with HUA, antihypertensive drugs other than thiazide diuretics are preferred. Patients with HUA who have conquered with small doses of aspirin are recommended to alkalize urine and drink more water.
4. Drugs to reduce blood uric acid
4.1 Drugs that increase uric acid excretion
4.1.1 Inhibit the active reabsorption of uric acid by the kidney, including benzbromarone (Ligurian), propofol, sulfopyrone, etc. Propofol and sulfopyrone can only be used for HUA patients with normal renal function, and benzbromarone can be used for renal insufficiency patients with Ccr>20ml/min. The representative drug is benzbromarone (Ligarginum).
Dosage: The starting dose for adults is 50mg (1 tablet) once daily, and after 1-3 weeks the dose is adjusted to 50 or 100mg/d after breakfast according to the blood uric acid level. In the presence of renal insufficiency (Ccr<60ml/min) the recommended dose is 50mg/day once.
Precautions.
a. The application must alkalize the urine, especially with existing renal insufficiency, pay attention to regular monitoring of the first urine PH in the early morning to maintain the urine PH between 6.2-6.9. Also ensure that the daily water intake is more than 1500ml.
b. Pay attention to monitoring liver and kidney function.
c. These drugs may cause urate crystals to be deposited in the urinary tract due to the promotion of uric acid excretion, and patients with uric acid stones are relative contraindications.
Efficacy: Usually, the blood uric acid value reaches about 357μmol/l (6mg/dl) in 6-8 days after taking benzbromarone, and the normal blood uric acid level can be maintained in the body by adhering to it.
Benzbromarone does not interfere with nucleic acid metabolism and protein synthesis in the body, and long-term administration has no effect on blood cells.
4.1.2 Alkalinization of urine Sodium bicarbonate has the effect of alkalinizing urine, increasing uric acid excretion and reducing blood uric acid. Sodium bicarbonate can be used 3-6g/d, divided into 3 oral doses, to maintain the urinary PH in the range of 6.2-6.9 is most appropriate, which is conducive to the dissolution of uric acid crystals and their excretion from the urine, urinary PH over 7.0 is prone to the formation of calcium oxalate and other types of stones.
4.2 Inhibition of uric acid synthesis The representative drug is allopurinol.
The initial dose for adults is 50mg once, 1~2 times a day, and the dose can be increased by 50~100mg per week to 200~300mg per day, divided into 2~3 doses, and the maximum amount should not be more than 600mg per day. If it is still high, the dose can be increased until the blood uric acid returns to 357μmol/l (6mg/dl), then gradually reduce the dose and maintain it for a long time with the minimum effective amount. If Ccr<60ml/min, the recommended dose of allopurinol is 50mg-100mg/day and Ccr<15ml/min is prohibited. Common dosage for children with secondary hyperuricemia: 50mg once, 1 to 3 times a day up to 6 years of age; 100mg once, 1 to 3 times a day from 6 to 10 years of age. The dose can be adjusted as appropriate. Again, more water is needed to alkalize the urine.
Precautions: A common adverse reaction to allopurinol is hypersensitivity. Mild hypersensitivity (e.g., rash) can be treated with desensitization; severe hypersensitivity (delayed vasculitis, exfoliative dermatitis) is often fatal and prohibited. Renal insufficiency increases the risk of severe allergy and should be monitored during application. Check liver and kidney function and blood count regularly during administration; discontinue use if liver and kidney function and blood cells decline progressively. Severe hepatic insufficiency and obvious low blood cells are prohibited.
5. In 2006, the European League Against Rheumatism recommended the prevention and treatment of gout, it is pointed out that patients with HUA should be actively treated with anti-inflammatory and analgesic drugs if they have an attack of gout, but it is not necessary to stop the original uric acid-lowering drugs.
In summary, the “Chinese Expert Consensus on Recommendations for the Combined Diagnosis and Treatment of Asymptomatic Hyperuricemia with Cardiovascular Disease” proposes the following treatment recommendations.
1, HUA treatment target value: blood uric acid <357μmol/l (6mg/dl).
2.Blood uric acid test is routinely performed during physical examination to detect asymptomatic HUA as early as possible.
3.All asymptomatic HUA patients need to make therapeutic lifestyle changes; avoid applying drugs that raise blood uric acid as much as possible.
4.If asymptomatic HUA is combined with cardiovascular risk factors or cardiovascular diseases (including hypertension, abnormal glucose tolerance or diabetes, hyperlipidemia, coronary heart disease, stroke, heart failure or renal abnormalities), drug treatment should be given for blood uric acid value >8mg/dl; for HUA without cardiovascular risk factors or cardiovascular diseases, drug treatment should be given for blood uric acid value >9mg/dl.
5.Actively control the co-existing cardiovascular risk factors in asymptomatic HUA patients.
Asymptomatic hyperuricemia combined with cardiovascular disease treatment flow chart
Life guidance includes lifestyle changes and risk factor control.
Cardiovascular risk factors and cardiovascular diseases include: hypertension, abnormal glucose tolerance or diabetes mellitus, hyperlipidemia, coronary heart disease, stroke, heart failure, abnormal renal function.