Hyperuricemia (HUA), a disorder of purine metabolism in the body, can be caused by any factor that affects the production and/or excretion of uric acid in the blood, leading to an increase in blood uric acid levels. Only 5-12% of people with high blood uric acid levels eventually develop gout, and the rest have no obvious symptoms. Numerous studies have shown that HUA is associated with more traditional cardiovascular disease risk factors such as old age, male, hypertension, diabetes, hypertriglyceridemia, obesity, insulin resistance, etc. Therefore, blood uric acid testing should be routinely performed during physical examinations for early detection and intervention of asymptomatic HUA.
Diagnosis: Typing helps to detect the cause
Uric acid is a product of endogenous and exogenous purine metabolism in the body. Under normal conditions, the body’s uric acid pool is 1200 mg, producing about 750 mg of uric acid and excreting 800-1000 mg per day. under normal conditions, the blood urate saturation is 6.7 mg/dl, and elevated blood uric acid levels are associated with abnormal nucleic acid metabolism in the body or reduced renal excretion.
The kidneys are an important organ for uric acid excretion, with 70% of uric acid excreted through the kidneys and the rest from the intestine and bile duct. HUA can be caused if the renal creatinine clearance (Ccr) decreases by 5%-25%, and the blood uric acid level can be increased by eating high purine food, performing strenuous physical activities and taking certain drugs for a long time.
The international diagnostic criteria for HUA are defined as blood uric acid levels >420 μmol/L (7 mg/dl) in men and >357 μmol/L (6 mg/dl) in women, and HUA without gout attacks is called asymptomatic HUA. HUA is related to age, gender, geography, race, genetics and social status. Epidemiological data show that obesity, hypertension, hypertriglyceridemia, and excessive alcohol intake are all risk factors for the development of HUA.
The staging diagnosis (see table) helps to detect the etiology of HUA. Usually, after having HUA patients on a low purine diet for 5 days, 24 h urine is retained to test urinary uric acid levels and uric acid excretion, uric acid clearance (Cua) is calculated.
Considering the influence of renal function on uric acid excretion, Ccr correction can be used. HUA is classified according to Cua/Ccr ratio as follows: >10% is excessive uric acid production type, <5% is poor uric acid excretion type, 5%~10% is mixed type.
Hazards: closely related to cardiovascular, cerebrovascular and renal diseases
HUA and cardiovascular disease
Although Gertler et al. first suggested a possible complex interaction between uric acid and coronary heart disease in 1951, it has not received much attention until recent years.
The Chicago Heart Study, the NHANES Study and the MONICA Study, 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. 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.
For patients with established coronary heart disease, Bickel et al. found that mortality was 5 times higher in those with blood uric acid >7.5 mg/dl (433 μmol/L) than in those 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.
In addition, large prospective clinical studies such as the MRFIT study, the PIUMA study, the Rotterdam cohort study, and the worksite study have shown that blood uric acid levels are an independent risk factor for acute myocardial infarction, stroke, and all cardiovascular events, and that elevated blood uric acid of 86 μmol/L is a better predictor of cardiovascular events than elevated total cholesterol of 1.078 mmol /However, the MONICA study concluded that blood uric acid was not predictive of acute myocardial infarction and angina pectoris development.
In 1879, MOHAMED first suggested the involvement of blood uric acid in the development of hypertension, and in 1889, Haig suggested a low purine diet as a means of preventing hypertension, and several studies since 1990 have confirmed that blood uric acid is an independent risk factor for hypertension, with a 25% increase in the relative risk of hypertension for every 59.5 μmol/L increase. Clinical studies have found that 90% of patients with primary hypertension are combined with HUA, while only 30% of patients with secondary hypertension are combined with HUA, suggesting a causal relationship between HUA and primary hypertension.
There are prospective studies showing that HUA can be an independent predictor of death in acute and chronic heart failure, but it is unclear whether it can be used as a direct indicator or only an indirect indicator.
HUA and diabetes and MS
Long-term HUA can disrupt pancreatic β-cell function and induce diabetes mellitus. Many studies have suggested a causal relationship between long-term HUA and the development of abnormal glucose tolerance and diabetes mellitus. A study of middle-aged HUA patients followed for 6-7 years showed that those with baseline blood uric acid levels >398 μmol/L had a 78% increased risk of developing long-term abnormal glucose tolerance and type 2 diabetes compared to those with <280 μmol/L.
The pathophysiological basis of metabolic syndrome (MS) is hyperinsulinemia and insulin resistance. Insulin resistance increases blood uric acid production during glycolysis as well as during free fatty acid metabolism and directly leads to hyperuricemia by increasing uric acid reabsorption by the kidneys. HUA is combined with metabolic syndrome in 70% of patients with metabolic syndrome, and conversely, HUA is often associated with all 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%.
Epidemiological data consistently show a correlation between blood uric acid and triglycerides. One prospective cohort study showed that basal triglycerides were an independent predictor of HUA after 8 years of follow-up.
HUA and renal damage
Uric acid is strongly associated with kidney disease. In addition to renal damage exacerbated by small renal arteries and chronic interstitial inflammation due to uric acid crystalline deposits, many studies have shown that uric acid can directly cause microangiopathy in the small glomerular access arteries, leading to chronic kidney disease.
In a large prospective study in Japan, 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 with those with uric acid in the range of 5.0-6.4 mg/dl (298-381 μmol/L), confirming the association of uric acid with the development of renal pathology. The risk of end-stage renal disease was 4-fold and 9-fold higher in men with blood uric acid ≥7.0 mg/dl (420 μmol/L) and in women ≥6.0 mg/dl (357 μmol/L), respectively. Long-term follow-up studies further confirmed that each 1 mg/dl increase in blood uric acid was associated with a 71% increase in the risk of kidney disease and a 14% increase in the risk of deteriorating renal function (GFR decline of 3 ml/min/1.73 m2/year). Compared with people with normal blood uric acid, the risk of new kidney disease increased 2-fold in people with blood uric acid between 7.0 and 8.9 mg/dl and 3-fold in people with ≥9 mg/dl.
Treatment: Improving lifestyle is the core
The goal of treating HUA is to promote crystal lysis and prevent crystal formation, which requires keeping blood uric acid levels below the saturation point of monosodium urate, which should be <357 μmol/L (6 mg/dl), while long-term or even lifelong use of uric acid-lowering therapy is recommended. The main therapeutic tools are described below.
Lifestyle improvement
Lifestyle changes are central to the treatment of HUA and include a healthy diet, smoking cessation, consistent exercise and weight control. The diet should be based on low purine foods (e.g. various cereal products, fruits, vegetables, milk, dairy products, eggs) and strictly control foods with high purine content (e.g. meat, seafood, animal offal, thick broth, etc.) in the middle-aged and elderly population who already have gout, HUA and metabolic cardiovascular risk factors.
Actively control related risk factors
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. At the same time, drugs that elevate blood uric acid, such as diuretics (especially thiazides), glucocorticoids, insulin, cyclophilin, tacrolimus, nicotine, pyrazinamide, niacin, etc., should be avoided.
For patients who need to take diuretics and have combined HUA, avoid thiazide diuretics, and at the same time alkalize urine, drink more water, and keep the daily urine volume above 2000 ml. For patients with hypertension combined with HUA, antihypertensive drugs other than thiazide diuretics are preferred.
Alkalinization of urine
Sodium bicarbonate has the effect of alkalinizing urine, increasing uric acid excretion and lowering blood uric acid. Sodium bicarbonate can be used 3~6 g/d, divided into 3 oral doses, to maintain urine pH in the range of 6.2~6.9, which is most suitable for the dissolution of uric acid crystals and their excretion from urine. Urine pH over 7.0 is prone to the formation of calcium oxalate and other types of stones.
Drugs to lower blood uric acid
Timing of drug treatment: When 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 >8 mg/dl; for HUA without cardiovascular risk factors or cardiovascular diseases, drug treatment should be given for blood uric acid value >9 mg/dl. HUA patients with gout attacks should be actively treated with anti-inflammatory and analgesic drugs without discontinuing the original uric acid-lowering drugs.
Drugs to increase uric acid excretion: including benzbromarone (Ligurian), propofol, sulfopiridone, etc. The mechanism of action of benzbromarone is to inhibit the uric acid transport protein at the apical brush border of proximal tubular cells, i.e., to inhibit the reabsorption of uric acid by renal tubules, thus reducing the concentration of uric acid in blood, so benzbromarone is a potent drug to promote uric acid excretion.
Benzbromarone can be used in patients with renal insufficiency with Ccr > 20 ml/min. The starting dose of 50 mg once daily in adults is adjusted to 50 or 100 mg/d after 1 to 3 weeks, depending on the blood uric acid level, taken after breakfast. The recommended dose in the presence of renal insufficiency (Ccr <60 ml/min) is 50 mg/d. Probenecid and sulpiride should only be used in patients with HUA with normal renal function.
The urine must be alkalinized during application, especially in the presence of renal insufficiency, and the urine pH should be regularly monitored for the first time in the morning to maintain the urine pH between 6.2 and 6.9. Also ensure that the daily water intake is more than 1500 ml. Pay attention to monitoring liver and kidney function. This class of 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.
Inhibition of uric acid synthesis: The representative drug is allopurinol. The initial dose for adults is 50 mg once, once or twice a day, and may be increased by 50-100 mg per week to 200-300 mg/d, divided into 2-3 doses, with the maximum daily dose not exceeding 600 mg. The blood uric acid level is measured every 2 weeks, and if it has reached a normal level, the dose is not increased; if it is still high, the dose may be increased until the blood uric acid returns to 357 μmol/L (6 mg/dl), and then gradually reduced. If it is still high, the dose can be increased until the blood uric acid returns to 357 μmol/L (6 mg/dl), then gradually reduced and maintained for a longer period of time with the minimum effective amount. In case of decreased renal function, the lowest effective dose tolerated is sufficient, e.g. Ccr < 60 ml/min, the recommended dose of allopurinol is 50-100 mg/d, and Ccr < 15 ml/min is contraindicated. Again, more water is required to alkalize the urine.
A common adverse reaction to allopurinol is hypersensitivity. Mild hypersensitivity (e.g., rash) can be treated with desensitization, while severe hypersensitivity (delayed vasculitis, exfoliative dermatitis) is often fatal and contraindicated. 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 significant blood cell depression are prohibited.
Adjuvant uric acid-lowering drugs: cloxacin is used for hypertension with hyperuricemia, and fenofibrate is used for hypertriglyceridemia with hyperuricemia.
Chinese medicine: such as goutidine, etc., in which cypress can inhibit xanthine oxidase; yanhuosuo, tu fu ling, red peony, gentiana can be anti-inflammatory and analgesic; psyllium, tu fu ling, zedoary can be diuretic; Chuan niu qi can improve immunity.