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.[1
2] 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.[3
4
5
6
7] 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.[1
3
8] 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].[11
12] 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]
Supplementary Figure 1
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.
Click here for additional data file.
Supplementary Figure 2
Schematic diagram of uric acid metabolism.
Click here for additional data file.
Supplementary Material 1
Classification of hyperuricemia by pathophysiology
Click here for additional data file.
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,[13
14
15] 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,[17
18
19
20
21] 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 lysosomes[23] 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,[16
24] and the inflammatory response is stimulated, thus resulting in platelet aggregation
and adhesion.[25
26]
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].
HUA patients younger than 25 years or with a family history of gout must be screened
for hereditary purine metabolism abnormalities.
Supplementary Material 2
Medications affecting uric acid metabolism
Click here for additional data file.
Gout
Gout is defined as the deposition of urate crystals in HUA patients, resulting in
arthritis (gouty arthritis), uric acid nephropathy, and kidney stones. Some authors
consider only gouty arthritis to be gout.
The possibility of gout should be considered when a HUA patient experiences an acute
attack involving a red, tender, hot, and swollen joint, usually the metatarsophalangeal
joint of the first toe, ankle, knee, and other joints. In chronic recurrent attacks
of gout, patients may manifest with affection of the upper limb joints and the formation
of tophi. According to the course of disease, gout is divided into four phases: (1)
asymptomatic HUA, (2) acute attack of gouty arthritis, (3) intercritical gouty arthritis,
and (4) chronic gouty arthritis.[27]
Key points for gout diagnosis
Gouty arthritis: This condition is more common in young and middle-aged men. The initial
onset of gouty arthritis is often in the first metatarsophalangeal joint, ankle, midfoot,
or knee. It develops abruptly and peaks within 24 h. Usually, only one joint is initially
affected. The initial attack may last for several days to several weeks and then resolve
completely and spontaneously. Recurrent attacks affect an increasing number of joints
and are associated with a longer duration of symptoms and a shorter interval between
episodes of arthritis
Tophi: Twenty years after the first onset of symptoms, approximately 70% of untreated
patients develop tophi, which are often found at the metatarsophalangeal joint of
the first toe, the auricle, the extensor side of the forearm, the finger joints, and
the elbow. A tophus can be as small as a sesame seed or even larger than an egg. When
a tophus is extruded, ulceration or fistula may be formed with a white bean curd-like
discharge
Synovial fluid examination: Through polarized light microscopy, birefringent needle-shaped
sodium urate crystals can be observed in symptomatic synovial fluid, which is valuable
for a definite diagnosis
Type-B ultrasonic scan: The typical intra-articular “snow storm sign” and “double-contour
sign” are valuable for diagnosis. Intra-articular hyperechoic spots and a mass with
acoustic shadows are common images indicative of tophi[28]
Dual-energy computed tomography (DECT): This technique can reveal the specific distinction
between tissues and periarticular urate crystals, which is useful for diagnosis[29
30]
X-ray: Swollen soft tissue can be observed in early acute arthritis. Recurrent attacks
may destroy articular cartilage edges, irregular articular surfaces, and stenosis
of the joint space on X-ray films. Patients with tophaceous deposits may have punched-out
osteolytic lesions with a sharp edge. The lesions appear as a semicircle or continuous
arc. Bone hyperplasia reactions can be observed on the bony edge.
In the past, gout was usually diagnosed in accordance with the gout classification
criteria released by the American College of Rheumatology (ACR) in 1977 [Supplementary
Material 3]. If any three items are satisfied, the condition can be classified as
gout.[31] In the recent years, both ultrasonic and DECT have been used widely to examine
the joints. Adopting the gout classification criteria proposed by the ACR/European
League against Rheumatism in 2015 is recommended (a web-based calculator can be accessed
at http://goutclassificationcalculator.auckland.ac.nz, and through the ACR and European
League against Rheumatism websites). A threshold score ≥8 classifies an individual
as having gout. Current studies have shown that the 2015 classification criteria are
more scientific, comprehensive, and systematic, with significantly improved sensitivity
for the diagnosis of gout than previous criteria.[32
33
34
35]
Supplementary Material 3
The American College of Rheumatology criteria for Acute Arthritis of Primary Gout
(1977)
Click here for additional data file.
Complications
Gouty arthritis is the most common manifestation in patients with gout; however, chronic
HUA can cause or aggravate the damage to multiple organs, which may be complicated
by renal disease (acute urate nephropathy, chronic urate nephropathy, and nephrolithiasis),
hyperglycemia, dyslipidemia, hypertension, coronary heart disease, cardiac insufficiency,
and stroke.[36]
PROPHYLAXIS AND TREATMENT OF HYPERURICEMIA
After a diagnosis of HUA and gout is established, patient education and lifestyle
interventions should be instituted immediately. Comprehensive and long-term management
is required for HUA patients. The patients should be stratified and managed when pharmacologic
treatment is initiated, and the appropriate treatment target should be set according
to the serum urate level and concomitant clinical symptoms and/or signs.
Patient management
Patient management is the basis of the prevention and treatment of HUA and gout, and
it should be focused on long-term management. For patients, it is the scientific approach
to fully understand the health hazards of the disease, form, and carry out the regimen
of treatment with the help of physicians. Patients should be referred to a high-level
medical institution promptly when they have severe complications or comorbidities
or experiences of unsatisfactory treatment effects.[37]
Management for hyperuricemic patients
(1) Improve awareness of HUA and relevant knowledge. (2) Provide health guidance regarding
diet, exercise, and other aspects and individualized lifestyle interventions. (3)
Screen for and prevent gout and complications. (4) Cooperate with specialists to develop
multidisciplinary treatment regimens for comorbidities and avoid the use of urate-elevating
drugs as much as possible [Supplementary Material 2]. (5) In addition to lifestyle
intervention, patients with drug therapy must maintain long-term target control of
serum uric acid levels.
Management for patients with gout
(1) Patients with gouty arthritis must follow the principles of HUA management. (2)
Physicians should inform patients to avoid possible risk and inducing factors in daily
life, propose correct preventive measures, and design an individualized emergency
treatment protocol for acute attacks. (3) The initiation of pharmacologic urate-lowering
therapy (ULT) should be considered after relief of acute attacks of gout. The established
pharmacologic ULT should be continued without interruption during an acute attack.
Medicines for preventing acute attacks of gout should be given to the patients during
their initial pharmacologic ULT.
Management for patients with complications
(1) Patients should be screened for complications or comorbidities and administered
a multidisciplinary combination therapy regimen immediately after a diagnosis of HUA
or gout. (2) Drugs with nephrotoxic potential must be avoided in patients with acute
or chronic urate nephropathy, renal function must be monitored to guide the selection
of drugs, and glucocorticoids may be used as the first choice treatment during the
acute phase of gout for patients with moderate-to-severe renal insufficiency. (3)
The urine must be alkalized in patients with nephrolithiasis, and stone-dissolving
therapy or surgery should be provided if necessary. (4) Hypoglycemic, lipid-lowering,
and antihypertensive treatments should be given actively to patients with comorbidities
of hyperglycemia, dyslipidemia, and hypertension, for which it would be better to
use a drug that facilitates excretion of uric acid. (5) Cyclooxygenase (COX)-2 inhibitors
should be avoided during an acute attack of gouty arthritis in patients with myocardial
infarction or cardiac dysfunction.
Management for high-risk population
High-risk populations include individuals with a first-degree relative with HUA or
gout, individuals with an unhealthy sedentary lifestyle and a purine-rich or high-fat
diet, and individuals with obesity, metabolic abnormalities (e.g., abnormal glucose
tolerance or diabetes, dyslipidemia, and nonalcoholic fatty liver), cardio-cerebrovascular
diseases (e.g., hypertension, coronary heart disease, heart failure, and stroke),
or chronic kidney disease [Supplementary Material 4 for definition and staging]. A
regular screening program should be established for these high-risk populations. Education
should be emphasized to disseminate the knowledge of HUA and gout and improve the
awareness of HUA prophylaxis and treatment. Serum urate levels should be monitored
regularly to identify and manage HUA or gout as early as possible.
Supplementary Material 4
Definition and classification of chronic kidney disease
Click here for additional data file.
Nonpharmacological treatments
Encouraging a balanced diet, limiting total daily caloric intake, and controlling
purine content in the diet are recommended. A low purine diet is encouraged [Table
1], but the intake of animal offal, seafood, meat, and other purine-rich foods should
be strictly limited. Purine-rich vegetables (such as lettuce, spinach, mushrooms,
and cauliflower), beans, and bean products are not significantly associated with HUA
and gout attacks. Patients are encouraged to consume more fresh vegetables and appropriately
consume beans and bean products (patients with renal insufficiency must consume such
foods under the guidance of a specialist).[38]
Table 1
Dietary recommendations for hyperuricemic patients
Diet recommendation
Food type
Encourage
Vegetables; low-fat and nonfat milk and milk products; eggs
Limit
Beef, lamb, pork, and purine-rich sea food; table sugar, desserts, table salt (including
sauces and gravies), red wine, and fruit wine
Avoid
High-fructose beverages; animal offal; yellow rice wine, beer, and spirits
Drinking large amounts of water can shorten the duration of a gout attack and relieve
symptoms. Adequate body water should be maintained for patients with normal heart
and kidney functions by frequently drinking water to maintain a daily urine output
of 2000–3000 ml. Milk and dairy products (especially nonfat milk and low-calorie yogurt)
can be consumed. The consumption of cola, orange juice, apple juice, and other fructose-containing
beverages and sugar-containing soft drinks should be avoided. The relationship between
coffee and HUA and gout is inconclusive. Studies have shown that drinking coffee does
not increase the risk of HUA but may decrease the risk of gout.[39
40]
Fruits are rich in potassium and Vitamin C, which can decrease the risk of gout attacks.[41]
HUA patients can consume fruits with low fructose contents, such as cherries, strawberries,
pineapple, watermelons, and peaches.
Alcohol intake can increase the risk of gout attacks in HUA patients,[42] and there
is a dose–response relationship between alcohol intake and the risk of gout onset.[43]
Alcohol intake should be limited, and yellow rice wine, beer, and spirits should be
avoided by HUA patients. Whether the consumption of red wine can increase serum uric
acid levels remains controversial.[44
45]
Obesity can increase the risk of gout in HUA patients.[46] Weight loss can effectively
decrease serum urate levels.[47
48] It is recommended that HUA patients should keep their body weight within a normal
range (body mass index: 18.5–23.9 kg/m2).
Regular physical activity can decrease the number of gout attacks and the HUA-related
mortality.[49] HUA patients should be encouraged to adhere to appropriate exercise
programs. Moderate aerobic exercise for at least 150 min every week is recommended
(30 min/d, 5 d/week) to keep the heart rate within the range ([220 − age] × [50–70%])
during exercise. Strenuous activity or suddenly becoming cold should be avoided because
both might trigger gout attacks.
Smoking and passive smoking increase the risk of HUA and gout. Smoking should be ceased,
and passive smoking should be avoided.
Pharmacologic treatments
Pharmacologic treatments should be adopted to address HUA when the effect of nonpharmacological
intervention is poor. The treatment regimen should be individualized and stratified,
and treat-to-target therapy should be adopted; moreover, the regimen should be appropriate
for long-term management. The dose should be titrated gradually. Excessive fluctuations
of serum urate levels over a short duration might induce an acute attack of gout,
which should be avoided.
Urate-lowering therapies
The commonly used urate-lowering agents in clinical practice include two classes:
urate production inhibitors and uricosuric agents. The pharmacologic ULT should be
selected according to the cause of disease, comorbidities, and hepatic and renal functions.
The principles of pharmacologic treatments are shown in Table 2.[37
50
51]
Table 2
Principles of pharmacologic urate-lowering therapy
Clinical manifestations
Timing of ULT initiation
Therapeutic target
(1) ≥2 attacks of gouty arthritis or (2) one attack of gouty arthritis concomitant
with any of the following: age <40 years, evidence of tophi or urate deposition in
the joint cavity, uric acid nephrolithiasis or renal impairment (GFR categories ≥
G2), hypertension, impaired glucose tolerance or diabetes mellitus, dyslipidemia,
obesity, coronary heart disease, stroke, or cardiac insufficiency
Start of treatment
SUA <360 µmol/L; SUA <300 µmol/L in patients with tophi, chronic gouty arthritis,
or frequent attacks of gouty arthritis; decrease in SUA to below 180 µmol/L is not
recommended
(1) one attack of gouty arthritis or (2) no gout attack but having any of the following:
uric acid nephrolithiasis or renal impairment (GFR categories ≥ G2), hypertension,
impaired glucose tolerance or diabetes mellitus, dyslipidemia, obesity, coronary heart
disease, stroke, or cardiac insufficiency
SUA >480 µmol/L
The same as above
None
SUA >540 μmol/L
SUA <420 µmol/L; decrease in SUA to below 180 µmol/L is not recommended
Renal impairment (GFR categories G2) is defined as an eGFR of 60–89 ml·min−1·1.73
m−2. Frequent attacks of gouty arthritis indicate an occurrence of two or more episodes
per year. GFR: Glomerular filtration rate; eGFR: Estimated glomerular filtration rate;
SUA: Serum uric acid; ULT: Urate-lowering therapy.
Urate production inhibitors
Xanthine oxidase inhibitor decreases the synthesis of uric acid by inhibiting the
activity of xanthine oxidase. Commonly used drugs include allopurinol and febuxostat.
Allopurinol
In adults, the starting dose is 50–100 mg/d. The serum urate level should be monitored
every 2–5 weeks. The dose can be increased by 50–100 mg increments to a maximum dose
of 600 mg/d in patients if the serum uric acid target is not reached. The starting
dose should not exceed 1.5 mg/estimated glomerular filtration rate (eGFR) per day
in patients with renal insufficiency,[52] and the recommended dose is 50–100 mg/d
for GFR categories G3–G4. Allopurinol is contraindicated in patients with GFR category
G5. Allopurinol can cause skin allergic reactions and hepatic and renal injury. Fatal
exfoliative dermatitis and other hypersensitivity syndromes might develop in severe
cases. Human leukocyte antigen (HLA)-B*5801 allele positivity, usage of thiazide diuretics,
and renal insufficiency are risk factors for the development of adverse reactions
to allopurinol. The prevalence of the HLA-B*5801 allele in Korean and Thai populations
of Han Chinese is significantly higher than that in Caucasian. Screening for this
gene has been before initiating allopurinol treatment.[50
53] Allopurinol is contraindicated in HLA-B*5801 allele-positive patients.
Febuxostat
This drug is a novel selective inhibitor of xanthine oxidase. The initial dose is
20–40 mg/d, which can be titrated gradually to a maximum of 80 mg/d if the serum uric
acid target is not reached after 2–5 weeks. Febuxostat has a better safety profile
in patients with renal insufficiency and renal transplantation because it is cleared
mainly via the liver. No dose adjustment is needed in patients with mild-to-moderate
renal insufficiency (GFR categories G1-3). However, this drug should be used with
caution in patients with severe renal insufficiency (GFR categories G4–G5). Adverse
reactions to febuxostat include hepatic impairment, nausea, and rash.[54
55]
Uricosuric drugs
Benzbromarone increases urinary excretion of uric acid and therefore lowers serum
urate levels by suppressing renal tubular reabsorption of uric acid by inhibiting
urate transporter 1 (URAT1).
Benzbromarone
The starting dose of benzbromarone is 25–50 mg/d in adults taken orally after breakfast,
which should be adjusted to 75 mg/d or 100 mg/d 2–5 weeks later, according to the
serum urate level. Benzbromarone can be used in patients with mild-to-moderate renal
dysfunction or renal transplantation. The recommended dose is 50 mg/d in patients
with an eGFR of 20–60 ml·min−1·1.73 m−2.[56
57
58] Benzbromarone is contraindicated in patients with an eGFR <20 ml·min−1·1.73 m−2
or uric acid nephrolithiasis. Urine must be alkalized in patients taking benzbromarone
to adjust the urine pH to 6.2–6.9. The daily urine output should be maintained above
2000 ml in patients with normal heart and renal functions. Adverse reactions of benzbromarone
include gastrointestinal discomfort, diarrhea, rash, and hepatic impairment.[59
60]
Novel urate-lowering drugs
These drugs include uricases and selective uric acid reabsorption inhibitors.
Uricases
Uricases are enzymes, including rasburicase and pegloticase, which decompose uric
acid into soluble products for excretion. Rasburicase is a recombinant urate oxidase
that is used primarily for the prevention and treatment of acute HUA in patients with
hematological malignancies, especially HUA caused by radiochemotherapy. Rasburicase
can induce antibody production and thereby decrease its efficacy.[61] Pegloticase
is an apegylated recombinant urate oxidase that is indicated for the majority of refractory
gout. It can be used in adult patients with refractory gout for whom other drugs are
ineffective or contraindicated. The main adverse reactions associated with pegloticase
include serious cardiovascular events and infusion and immunogenic reactions.[62]
Selective uric acid reabsorption inhibitors
RDEA594 (lesinurad) acts by inhibiting URAT1 and the organic anion transporter 4.
It is indicated for gout patients who are unable to achieve the target serum urate
level with a xanthine oxidase inhibitor alone at an adequate dose. It can also be
used in combination with a xanthine oxidase inhibitor. Hydration should be increased
during lesinurad treatment, and renal function should be assessed before the initiation
of lesinurad treatment. Lesinurad is not recommended for patients with GFR categories
G3b-5.[63]
Urine alkalization
This treatment is recommended to maintain urine pH of 6.2–6.9 in patients receiving
urate-lowering drugs, especially uricosuric drugs, and in patients with uric acid
nephrolithiasis to increase the solubility of uric acid in urine. A high urine pH
might increase the risk of calcium phosphate, calcium carbonate, and other stone formation.
Sodium bicarbonate
This treatment is indicated for patients with chronic renal insufficiency and concomitant
HUA and/or gout. The starting dose is 0.5–1g, orally, three times daily. Sodium bicarbonate
should be given in an interval of 1–2 h with other drugs. The main adverse reactions
include flatulence and gastrointestinal discomfort. Attention should be paid to sodium
overload and hypertension in patients who are treated for a long time.
Citrate preparations
These preparations include potassium sodium hydrogen citrate, potassium citrate, and
sodium citrate. Potassium sodium hydrogen citrate is the most commonly used preparation.
Citrate is the strongest endogenous inhibitor of stone formation in urine, and it
alkalizes the urine, thereby increasing the solubility of uric acid, dissolving uric
acid stones, and preventing the formation of new stones. The starting dose of potassium
sodium hydrogen citrate is 2.5–5.0 g/d. Urine pH should be monitored to adjust its
dose accordingly. Potassium sodium hydrogen citrate is contraindicated in patients
with acute renal injury or chronic renal failure (GFR categories G4–G5), severe acid–base
disorder, or hepatic insufficiency.[64]
Pharmacologic therapy for acute gout attacks
The goal of treatment for an acute attack is to quickly control the symptoms of arthritis.
Bed rest is required for patients during an acute attack. The affected limb should
be raised, and a local cold compress can be applied. Drugs should be administered
as soon as possible to control the acute attack. The earlier the therapy is initiated,
the better the efficacy. Colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs)
are the first-line options for the treatment of acute arthritis attacks. If patients
have contraindications or respond poorly to these drugs, corticosteroids are an option
for controlling inflammation. For patients with one or two large joints involved,
an intra-articular injection of short-acting corticosteroids can be considered when
they respond poorly to systemic treatment. However, repeated injections over the short
term should be avoided.
Colchicine
Colchicine exerts its analgesic effect by inhibiting the chemotaxis and phagocytosis
of leukocytes and mitigating inflammatory reactions. Colchicine is recommended to
be administered as soon as possible (within 12 h) after the onset of a gout attack.
The treatment effect is significantly decreased if treatment is initiated 36 h after
the onset. The initial loading dose is 1.0 mg, and this is followed by 0.5 mg 1 h
later and then by 0.5 mg 12 h later, 1–3 times daily. Colchicine should be avoided
in patients receiving cytochrome P450 3A4 or phosphorylated glycoprotein inhibitors
(such as cyclosporine A, clarithromycin, verapamil, and ketoconazole). Adverse reactions
related to colchicine increase with the dosage. Common adverse reactions include nausea,
vomiting, diarrhea, abdominal pain, and other gastrointestinal effects. Colchicine
should be discontinued immediately if adverse reaction symptoms are observed. Abnormal
liver function and elevated transaminases might be observed in a few patients. Colchicine
should be discontinued if the liver function test value exceeds two times the upper
limit of normal. Hematuria, oliguria, and abnormal renal function suggest renal impairment
in patients. In such cases, the dosage of colchicine should be decreased accordingly.
The maximum dosage is 0.5 mg daily in patients with an eGFR 35–49 ml·min−1·1.73 m−2
and 0.5 mg once every other day in patients with an eGFR 10–34 ml·min−1·1.73 m−2.
Colchicine is contraindicated with an eGFR <10 ml·min−1·1.73 m−2 or when the patient
is on dialysis. Colchicine can cause bone marrow suppression, and routine blood tests
should be performed for monitoring during treatment.
Nonsteroidal anti-inflammatory drugs
NSAIDs include nonselective COX and COX-2 inhibitors. Full-dose treatment with fast-acting
NSAIDs is recommended at an early stage if there are no contraindications. The main
adverse reactions of nonselective COX inhibitors are gastrointestinal ulcer or perforation,
upper gastrointestinal bleeding, and other gastrointestinal adverse reactions. If
patients are intolerant to nonselective COX inhibitors, COX-2 inhibitors should be
considered, which decrease gastrointestinal adverse reactions by 50%. However, all
NSAIDs are contraindicated in patients with active gastrointestinal ulcer or bleeding
or prior recurrent gastrointestinal ulcer or bleeding.[65] COX-2 inhibitors should
be avoided in patients with concomitant myocardial infarction and cardiac insufficiency
because they may increase the risk of cardiovascular events. Renal function should
be monitored during NSAID treatment. The use of NSAIDs is not recommended in nondialysis
patients with severe chronic kidney diseases (GFR categories G4–G5).
Glucocorticoids
These drugs are primarily used for patients with severe acute gout attack and serious
systemic symptoms, with contraindications or a poor response to colchicine and NSAIDs,
or with renal insufficiency. When administered systemically, oral prednisone is administered
at a dosage of 0.5 mg·kg−1·d−1 continuously for 5–10 d, and is then discontinued;
alternately, it can be administered at a dosage of 0.5 mg·kg−1·d−1 for 2–5 d, then
tapered off until discontinuation, with a total course of 7–10 d.[37
50] Intravenous glucocorticoids might be considered if oral administration is inappropriate.
Attention should be paid to the adverse reactions to glucocorticoids, such as hypertension,
diabetes mellitus, water and sodium retention, and infections. The use of long-acting
glucocorticoids should be avoided. For patients with one or two large joints involved,
an intra-articular injection of short-acting corticosteroids can be considered if
the patient responds poorly to systemic treatment. However, repeated injections over
the short term should be avoided.
Treatment with a new drug
An IL-1 receptor antagonist can be considered for the treatment of refractory acute
gout when NSAIDs, colchicine, or corticosteroids are ineffective or when patients
have contraindications to these drugs.[37
66
67]
Prevention of acute attacks of gout during initial urate-lowering therapy
Acute attacks of gout are easily induced by fluctuations in serum urate levels. Patients
with gout should receive prophylaxis to prevent gout attacks during the first 3–6
months of ULT. Oral low-dose colchicine is preferred. The recommended dosage is 0.5–1
mg/d. No dose adjustment is needed for patients with mild renal insufficiency, but
renal function should be monitored regularly. The dosage should be decreased by half,
0.5 mg orally once every other day, or tapered as appropriate for patients with moderate
renal insufficiency. The use of colchicine should be avoided in patients with severe
renal insufficiency or who are on dialysis. NSAIDs can be used when colchicine is
ineffective, but attention should be paid to the occurrence of adverse reactions such
as those related to the gastrointestinal tract and cardiovascular system as well as
renal impairment. NSAIDs should be used with caution in patients with coronary heart
disease and other chronic cardiovascular diseases. Alternatively, low-dose prednisone
or prednisolone (≤10 mg/d) can be used when patients respond poorly or have contraindications
to colchicine and NSAIDs. In such cases, osteoporosis and other adverse reactions
should be monitored and prevented. The prophylactic treatment should be maintained
for 3–6 months and tailored as appropriate depending on the attack of gouty arthritis.[37
50]
Prophylactic drugs are not recommended for HUA patients without prior gout attack
who are receiving ULT, but they should be informed of the risk of gout attacks. Treatment
should be administered in a timely manner after the occurrence of acute gouty arthritis.
Subsequent prophylactic medications should also be considered.
Treatment for tophi
Tophi can be gradually dissolved and decreased in size after active ULT to maintain
the serum urate level below 300 μmol/L for more than 6 months. Surgical treatments
can be considered for larger tophi associated with nerve compression or tophaceous
ulceration or for those patients who cannot be cured after prolonged treatment. However,
the patients still require a standardized comprehensive treatment.[37
50]
Traditional Chinese medicine
Traditional Chinese medicine interventions for this disease emphasize the principles
of simultaneous recuperation, combination treatment of the disease and symptoms, and
management according to the disease stage. Patients should choose foods with caution;
abstain from unhealthy choices; avoid drinking alcohol; and avoid overeating fatty,
sweet, and greasy foods. They should adopt long-term dietary therapy to correct their
constitutional imbalance, such as Semen Coicis, Semen Euryales, and Rhizoma Dioscoreae.
Patients should also enhance their physical fitness and promote mental health via
exercises, which are conducive to disease prevention and treatment. For HUA, the basic
treatment is to invigorate the spleen, eliminate toxins, and remove blood stasis,
which are used throughout the course of treatment regardless of the presence of clinical
symptoms. Commonly used medicines include Semen Coicis, Rhizoma Smilacis Glabrae,
Rhizoma Smilacis Chinensis, Rhizoma Dioscoreae Septemlobae, and Rhizoma Polygoni Cuspidati.[68]
If the symptom is related to joints with sudden redness, swelling, and thermalgia,
these symptoms are indicative of acute-stage gout with predominant pathogenic excess.
In such cases, it is better to adopt the strategy of clearing heat and eliminating
dampness, activating meridians, and relieving arthralgia using an agent such as Simiao
Powder or Danggui Niantong Decoction. Commonly used medicines include Cortex Phellodendri,
Rhizoma Atractylodis, Semen Plantaginis, Herba Artemisiae Scopariae, Rhizoma et Radix
Notopterygii, and Feculae Bombycis. If the pain is recurrent and refractory and is
associated with joint deformity or subcutaneous nodules or ulceration, a chronic stage
of gout is indicated, the underlying pathology of which is asthenia complicated with
sthenia. In such cases, it is appropriate to resolve phlegm and remove blood stasis,
relieve arthralgia and dredge collaterals; this strategy should be combined with fortifying
the spleen, invigorating the kidney, and nourishing the liver using, for example,
the upper-middle-lower gout recipe. Commonly used medicines include Radix Clematidis,
Rhizoma Arisaematis, Rhizoma Curcumae Longae, and Ramulus Cinnamomi.
Symptoms in the kidney characterized by sandy urine or oliguria and body edema indicate
gouty nephropathy. It is appropriate to adopt the strategy of fortifying the spleen,
invigorating the kidney, eliminating turbid phlegm, and removing blood stasis. In
addition, treatment should be adjusted on the basis of the syndrome differentiation
in terms of deficiency excess and cold–heat patterns. In addition to turbid phlegm
and blood stasis, excess syndrome is mostly caused by dampness-heat and stone obstruction.
Patients with dampness-heat might suffer from frequent and dripping urination with
burning pain. They should be treated with medicines to eliminate the heat and promote
diuresis, such as Bazhen Decoction or Bixie Huadu Decoction. Commonly used medicines
include Herba Plantaginis, Herba Polygoni Avicularis, Herba Taraxaci, Fructus Chaenomelis,
and Radix Gentianae Macrophyllae. Patients with stone obstruction might have dysuria,
sudden interruption of urination, or sandy urine. For this symptom, a treatment that
relieves stranguria and expels stones, such as Shiwei Powder, is suggested. Commonly
used medicines include Folium Pyrrosiae, Talcum, and Spora Lygodii. Deficiency syndrome
is mostly attributed to the spleen and kidney. The patient should be treated using
a strategy to warm the yang to resolve fluid retention if the yang deficiency is dominant.
The recommended formula is Wenpi Decoction and Jisheng Shenqi Pills. Commonly used
medicines include Radix Astragali, Radix Codonopsis, Cortex Eucommiae, Rhizoma Cibotii,
Radix Dipsaci, and Radix Aconiti Lateralis Preparata. For patients with yin deficiency,
nourishing yin and enhancing body resistance are the main treatments and include the
recommended formulas of Zuogui Pills or Liuwei Dihuang Pills. Commonly used medicines
include Radix Rehmanniae Preparata, Rhizoma Polygonati, Fructus Lycii, and Fructus
Corni.
Modern pharmacological studies are useful for choosing the appropriate medicines or
formulas in addition to the syndrome identification and treatment based on traditional
Chinese medicine. Studies have shown that Rhizoma Smilacis Glabrae,[69
70] Rhizoma Polygoni Cuspidati,[71] Rhizoma Smilacis Chinensis,[72] and Rhizoma Curcumae
Longae[73] can inhibit xanthine oxidase activity and decrease serum urate levels,
whereas Rhizoma Dioscoreae Septemlobae,[74] Fructus Gardeniae,[75] and Herba Plantaginis[76]
can regulate uric acid transporter expression, decrease the reabsorption of uric acid,
and promote the excretion of uric acid.
In addition, local treatment with traditional Chinese medicine by topical application,
steaming, and washing enables medicines to act directly at the lesions and aids in
dispersion of swelling and pain relief. Enemas in traditional Chinese medicines not
only achieve detoxification and purge the internal organs but also facilitate the
absorption of active ingredients via the intestinal tract, so the medicines can act
systemically. Local acupuncture in combination with the stimulation of acupoints along
meridian might simultaneously address the symptoms and cause of the disease.
Multidisciplinary diagnosis and treatment
HUA is often associated with comorbidities of other systems, such as metabolic, renal,
and cardio-cerebrovascular diseases. A multidisciplinary treatment approach is appropriate
for managing HUA patients with such comorbidities.
Hyperuricemia and kidney diseases
The urate deposits in the kidney lead directly to chronic urate nephropathy, acute
uric acid nephropathy, and uric acid nephrolithiasis in HUA patients. In contrast,
renal diseases also affect the excretion of uric acid and induce secondary HUA. The
HUA in turn might lead to or aggravate renal diseases. HUA is an independent risk
factor for chronic kidney diseases.
Chronic urate nephropathy
The pathogenesis of chronic urate nephropathy involves the persistent deposition of
sodium urate crystals in the interstitial tissue of the renal medulla; these crystals
might activate the local renin-angiotensin-aldosterone system; damage endothelial
cells; and cause high glomerular pressure, chronic inflammatory reactions, interstitial
fibrosis, and other pathological changes.[77] If HUA patients develop renal tubular
dysfunction, such as increased nocturia, low specific gravity urine, and low-molecular-weight
proteinuria, chronic urate nephropathy is suspected. The increment of serum urate
levels might not correspond to the degree of renal impairment. Chronic urate nephropathy
can be considered after other chronic kidney diseases are excluded. However, it is
usually difficult to differentiate chronic urate nephropathy from other chronic kidney
diseases with concomitant HUA. Renal biopsy is often required to verify the deposition
of urate crystals in renal tissue to confirm the diagnosis. Late-stage chronic urate
nephropathy can lead to a decreased GFR and chronic renal failure.
Nonpharmacological therapy should be initiated immediately after the diagnosis of
chronic urate nephropathy is confirmed. Pharmacologic therapy should be administered
to patients with poor efficacy on the basis of the serum urate level and comorbidities.
ULT should be initiated to treat to a target serum urate level of <360 μmol/L in patients
with renal impairment (GFR categories ≥G2) or HUA patients (SUA >480 μmol/L) with
uric acid nephrolithiasis. In patients with severe gout (such as tophi, chronic arthritis,
and frequent attacks), the serum urate level should be controlled more strictly with
a target value <300 μmol/L but lowering the level to <180 μmol/L is not recommended.[37
50
51]
Acute uric acid nephropathy
Acute uric acid nephropathy is acute oliguric or anuric renal failure induced by renal
tubular obstruction due to excessive uric acid crystals deposits caused by severe
HUA.[78] It is observed primarily in tumor lysis syndrome.[79] Patients with acute
uric acid nephropathy can develop urinary tract obstruction, low back pain, and either
oliguria or anuria. Acute uric acid nephropathy should be considered when acute renal
injury is complicated by a significant increase of serum urate level (>900 μmol/L
Renal biopsy is required to confirm the diagnosis, but tubulointerstitial nephritis
should be excluded. Renal pathological examination can reveal varying degrees of renal
tubular degeneration and necrosis with concomitant partial tubular atrophy and renal
interstitial fibrosis. There are no obvious lesions or ischemic shrinkage of the capillary
loops in glomeruli. Uric acid crystals deposits can be observed in renal tubular cavities
under a polarized light microscope.[80]
Acute uric acid nephropathy is usually reversible. The focus of management is on its
prevention. Intravenous hydration should be instituted actively in high-risk patients
to maintain a urine output at 80–100 ml·m−2·h−1 if the heart and kidney functions
are adequate. A recombinant uricase or xanthine oxidase inhibitor is preferred to
maintain the serum urate level below 300 μmol/L Emergency management is required for
patients with confirmed acute uric acid nephropathy. Timely and effective treatments
are expected to recover the renal function to a normal level. The treatment measures
are as follows:[81] (1) a strict low purine diet; (2) hydration therapy: daily liquid
intake reaching 3000 ml to maintain the urine output at 80–100 ml·m−2·h−1 if there
are no contraindications; (3) urate-lowering drugs: these drugs should be selected
according to the serum urate level or the risk of tumor lysis syndrome before treatment
(allopurinol is preferred in patients with serum uric acid <480 μmol/L without severe
renal dysfunction, and only a mild-to-moderate risk of tumor lysis syndrome before
treatment; uricase is recommended in patients with increased serum urate before treatment;
and owing to limited clinical data, febuxostat should be used with caution only in
patients who are not able to use uricase and allopurinol); and (4) hemodialysis if
necessary.
Uric acid nephrolithiasis
With improved living standards and changing dietary patterns, the incidence of uric
acid nephrolithiasis is showing an increasing trend. Urate stones account for 8–14%
of the urinary stones in the United States[82] and 5.1% in China,[83] and are second
only to calcium oxalate stones. The decrease in solubility and excess saturation of
uric acid in urine are the premises of urate stone formation. Low back pain and hematuria
are usually characteristic of uric acid nephrolithiasis. When acute obstruction occurs,
it is likely to trigger acute kidney injury, with symptoms of fever, oliguria, anuria,
hydronephrosis, and elevated serum creatinine, among others. Chronic obstruction may
result in hydronephrosis, renal parenchymal atrophy, and even end-stage renal diseases.[84]
The urine pH is often lower than 6.0 in patients with uric acid nephrolithiasis. Urate
crystals can be seen on urine sediment examination. Hyperechoic areas with sound shadows
can be seen in type-B ultrasonic examination of the kidney. Uric acid stones are not
visible on X-ray films (negative stones). Negative stones should be differentiated
from renal xanthine and hypoxanthine stones; the latter two are insoluble in an alkaline
environment. However, calculus shadows with varying densities are observed in mixtures
with calcium oxalate, calcium phosphate, and other ingredients. Intravenous pyelography
can reveal a filling defect. CT is highly useful for the diagnosis of uric acid nephrolithiasis.
For uric acid calculus, the CT values often range from 300 to 400 HU, which is lower
than that of the cystine calculus but higher than that of blood clots and tumors.
The composition of the excreted calculus should be analyzed to confirm the diagnosis.
Uric acid nephrolithiasis can be treated with stone removal therapy, extracorporeal
shock wave lithotripsy (ESWL), and/or surgical treatment.
Stone removal therapy
This therapy applies to patients with small stones (diameter of 0.5–1.0 cm) who lack
symptoms such as urinary tract obstruction, infection, or pain. Such therapies include
general support therapy, traditional Chinese medicine, and litholytic therapy.[85]
General support therapy includes increasing fluid intake, avoiding purine-rich foods,
and exercising appropriately. Among the commonly used traditional Chinese medicines
are Paishi granules (for removing stones) and Niao Shi Tong (for managing urolithiasis).
Oral potassium sodium hydrogen citrate granules are usually used in clinical practice
as a litholytic therapy.
Shock wave lithotripsy
This procedure is indicated for patients with poor outcomes after stone removal therapy
for 1–2 months, such as (1) stones in the renal pelvis, upper and middle calyx (diameter
<2.0 cm); (2) small stones in the lower calyx (diameter <1.0 cm) and larger stones
in the lower calyx (diameter of 1.0–2.0 cm), which should be assessed according to
the presence of adverse factors; and (3) a proportion of staghorn stones (diameter
of 2.0–3.0 cm or surface area <500 mm2). Shock wave lithotripsy is contraindicated
in patients with organic obstruction distal to stones, renal insufficiency, or uncontrolled
urinary tract infection.
Surgical treatment
Surgical treatment is adopted for conditions in which uric acid calculus has resulted
in urinary obstruction, severe infection, or impaired renal functions. It includes
open surgery, percutaneous nephrolithotomy, and retrograde intrarenal surgery. For
kidney calculus larger than 2.0 cm and complicated kidney calculus, percutaneous nephrolithotomy
is recommended. Percutaneous nephrolithotomy is contraindicated in the case of failure
to establish percutaneous access to the kidney due to severe body deformity, extreme
obesity, and other problems. Retrograde intrarenal surgery can be used to remove stones
with a diameter <2.0 cm, which respond poorly to ESWL. For an uncommon uric acid calculus
like a staghorn calculus, the combined application of litholysis therapies, ESWL,
and percutaneous nephrolithotomy can be adopted.
Chronic kidney disease complications in hyperuricemia
Patients with chronic kidney disease should be treated in the same way as chronic
urate nephropathy patients regarding when to initiate therapy and the target value.
The drugs used to treat HUA should be selected according to the primary disease, complications,
and the state of renal function in patients with chronic kidney disease.
The use of NSAIDs is not recommended during acute attack of gout in patients with
chronic kidney disease (GFR categories G4–G5). In such cases, glucocorticoids can
be administered orally for a short term or by intra-articular injection. Alternatively,
low-dose colchicine can be administered as appropriate according to the eGFR (see
“Pharmacologic therapy for acute attacks of gout”).[86
87]
ULT can decrease the uric acid load in the glomeruli and delay the progression of
chronic kidney disease. The treatment for these patients should be individualized
with inhibitors of urate production or uricosuric drugs. Renal impairment may increase
the toxicity of allopurinol. Allopurinol treatment should be initiated at a lower
dose and carefully titrated upward (see “Pharmacologic treatments”).[52
88
89
90
91] No dose adjustment is needed for febuxostat in patients with mild-to-moderate
renal insufficiency (GFR categories G1–G3) and patients with mild-to-moderate hepatic
injury (Child-Pugh class A/B). However, febuxostat should be used with caution in
patients with GFR categories G4–G5. The incidence of hypersensitivity syndrome associated
with febuxostat is lower than that associated with allopurinol.[54
55] The uricosuric drug benzbromarone can be used in patients with mild-to-moderate
renal insufficiency (eGFR: 20–60 ml·min−1·1.73 m−2). The recommended dosage is 50
mg/d. However, benzbromarone is contraindicated in patients with uric acid nephrolithiasis
or severe renal insufficiency (eGFR <20 ml·min−1·1.73 m−2).[56
57
58]
The prophylactic use of colchicine is required in patients with chronic kidney disease
during ULT to prevent ULT-induced gout attacks. However, colchicine is contraindicated
in patients with an eGFR <0 ml·min−1·1.73 m−2 or who are on dialysis, but low-dose
corticosteroids can be considered for short-term use.
Hyperuricemia and metabolic syndrome
Metabolic syndrome is a clinical syndrome that is characterized by the coexistence
of multiple risk factors for cardiovascular diseases, such as obesity, hypertension,
hyperglycemia, and dyslipidemia, in one individual. It is a combination of multiple
metabolically interrelated risk factors. These factors directly contribute to the
occurrence of atherosclerotic cardiovascular diseases and also increase the risk of
type 2 diabetes mellitus.[92] HUA is related to metabolic syndrome closely. Some authors
also consider HUA to be one of the components of metabolic syndrome. Insulin resistance
is the common pathophysiological basis for metabolic syndrome.[93
94
95
96]
Obesity
Obesity, especially abdominal obesity, is closely related to HUA.[97] Obesity-related
mild chronic inflammation and insulin resistance can increase the risk of HUA and
gout. Weight loss, especially a decrease in abdominal circumference, is an effective
way to decrease serum urate levels via a nonpharmacological approach.[98
99]
Hypertension
A large number of studies have shown that HUA is an independent risk factor for hypertension.[100
101] Antihypertensive drugs other than diuretics are preferred for patients with both
HUA and hypertension. Losartan potassium has a uricosuric effect and can decrease
cardiovascular events by 13–29% by lowering serum uric acid.[102
103] Amlodipine is a dihydropyridine calcium antagonist with a uricosuric effect.
It is recommended for use in hypertensive patients with ischemic stroke.[104]
Hyperglycemia
The prevalence of HUA increases in patients with diabetes mellitus.[105] An elevated
serum urate level not only increases the risk of type 2 diabetes mellitus[106] but
also serves as an independent risk factor for the future development of type 2 diabetes
mellitus in the nondiabetic population.[107
108] HUA is also an important predictor of the progression and aggravation of diabetic
nephropathy.[109
110
111
112]
Pharmacologic ULT should be initiated immediately in patients with abnormal glucose
metabolism if their serum urate level exceeds 480 μmol/L The currently available clinical
data do not show that hypoglycemic agents have adverse effects on the serum urate
level. Sulfonylureas can promote the excretion of uric acid.[113] The α-glucosidase
inhibitor acarbose can decrease the elevated serum urate level caused by the decomposition
of sucrose.[114] Thiazolidinediones may decrease the serum urate level by improving
insulin resistance.[115
116] Dapagliflozin, canagliflozin, and other sodium glucose co-transporter 2 inhibitors
can decrease serum urate levels.[117
118]
Dyslipidemia
Dyslipidemia is a common comorbidity of HUA and gout. Hypertriglyceridemia is an independent
predictor of HUA. Atorvastatin is preferred for patients with hypercholesterolemia
or atherosclerosis with HUA.[119] Fenofibrate is preferred for patients with hypertriglyceridemia
and concomitant HUA.[120] Both atorvastatin and fenofibrate have a uricosuric effect.
Hyperuricemia and cardiovascular disease
HUA is an independent risk factor for cardiovascular disease and simultaneously interacts
with many traditional cardiovascular risk factors in contributing to the development,
progression, and outcome of cardiovascular diseases.[121
122] Pharmacologic ULT should be initiated in HUA patients with comorbidities such
as hypertension, coronary heart disease, heart failure, and other cardiovascular diseases,
when the serum urate level exceeds 480 μmol/L. Such ULT can effectively prevent and
treat HUA-related cardiovascular diseases and decrease the incidence of cardiovascular
events.[123
124
125
126
127]
In addition to lowering serum uric acid, xanthine oxidase inhibitors can improve endothelial
function, decrease oxidative stress, regulate myocardial energy metabolism, and thereby
further decrease the incidence of cardiovascular events.[128] NSAIDs are associated
with water and sodium retention and renal impairment, both of which might increase
the risk of aggravation of heart failure and hospitalization for heart failure. Therefore,
the use of such drugs should be avoided as much as possible in patients with acute
or chronic heart failure.
Hyperuricemia and hypertension
There is an independent correlation between HUA and hypertension. The serum urate
level is an independent predictor of the development of long-term blood pressure changes
and the prognosis of hypertension. The risk of hypertension increases by 15–23% for
each additional increase of 60 μmol/L in serum uric acid.[129
130] The antihypertensive options for HUA patients with concomitant hypertension are
detailed in the section titled “HUA and metabolic syndrome.”
Hyperuricemia and coronary heart disease
For each additional increase of 60 μmol/L in serum uric acid, cardiovascular mortality
and ischemic heart disease mortality increase by 26% and 30% in women and by 9% and
17% in men, respectively, and the risk of coronary heart disease increases in women
by 48%.[101
102] HUA is an independent risk factor for all-cause mortality and coronary heart
disease mortality in women. The effects of HUA on the development and prognosis of
coronary heart disease differ between men and women, possibly because of the effects
of estrogen.[131
132]
The effects of aspirin, atorvastatin, and other drugs on serum uric acid levels should
be considered when these agents are used for primary and secondary prevention of coronary
heart disease. Aspirin has a dose-specific effect on the metabolism of uric acid:
high-dose aspirin (>3 g/d) significantly inhibits the reabsorption of uric acid in
renal tubules and promotes the excretion of uric acid. Moderate-dose aspirin (<1–2
g/d) inhibits the excretion of uric acid in renal tubules and thereby increases serum
uric acid.[133] Low-dose aspirin (75–325 mg/d) slightly increases serum uric acid.[134]
However, considering the cardio-cerebrovascular benefits associated with the antiplatelet
effects of using aspirin at 75–325 mg/d, it is not recommended to discontinue aspirin
dosages of 75–325 mg/d in patients with concomitant HUA. In such cases, it is recommended
to concomitantly alkalize the urine, drink more water, and monitor serum urate levels.
Atorvastatin has a weak effect on lowering serum uric acid levels.[119] It is preferred
for the secondary prevention of coronary heart disease with concomitant HUA.
HUA is an independent risk factor for contrast-induced acute kidney injury. It is
recommended to measure serum uric acid, stratify the risk, increase hydration, avoid
the use of hyperosmotic contrast agents, and decrease the doses of contrast agents
when HUA patients undergo coronary CT imaging or coronary angiography.[135]
Hyperuricemia and heart failure
Elevated serum uric acid is associated with the severity of chronic heart failure,
which increases with worsening New York Heart Association functional classification.
Increased serum uric acid is an independent predictor of poor outcome in patients
with chronic heart failure.[126
134]
The use of loop diuretics or complication of chronic renal failure may increase the
serum urate level and result in a poor outcome in patients with acute decompensated
heart failure. After controlling for these confounders, HUA is still associated with
a poor short-term outcome (in-hospital death) and poor long-term prognosis (cardiac
death and readmission due to heart failure).[136]
Long-term use of potassium-wasting diuretics (especially thiazide diuretics) might
decrease renal clearance of uric acid and thereby induce or aggravate HUA. Nonthiazide
diuretics are preferred for heart failure patients with concomitant HUA. Moreover,
an adequate amount of water should be consumed, and the urine should be alkalized.
In addition, concomitant use of thiazide diuretics and allopurinol should be avoided
as much as possible because thiazide diuretics might increase the risk of hypersensitivity
reaction to allopurinol.
Hyperuricemia and neurological diseases
HUA is associated with a variety of neurological diseases. HUA contributes to the
occurrence and poor prognosis of ischemic stroke, whereas it has protective effects
in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
The inherent connection between uric acid and neurological diseases remains to be
further investigated.
Hyperuricemia and ischemic stroke
An elevated serum uric acid level, especially above 420 μmol/L is an independent risk
factor for stroke.[137] HUA contributes to the occurrence of stroke[138] and is an
independent risk factor for ischemic stroke in the Chinese population.[19] In addition,
long-term follow-up studies in nonstroke patients have found that an increased serum
urate level may be an important serological marker for asymptomatic cerebral infarction
and possible stroke in female patients,[139] thus suggesting that controlling the
serum urate level may be of greater significance for the prevention of stroke in female
HUA patients.
Higher serum urate levels are positively correlated with the risk of early death after
stroke. An elevated serum urate level may suggest a poor 90-day outcome after stroke.[140]
Increased serum uric acid is an independent risk factor for the recurrence of stroke
in stroke patients.[16] Serum urate levels can be used as an indicator to predict
the risk of death and recurrence of stroke in patients with acute ischemic stroke.
In patients with cerebral infarction undergoing thrombolysis, higher serum uric acid
levels are associated with a smaller cerebral infarction volume and better prognosis
(modified Rankin Scale Score <2 points). Lower serum uric acid levels are associated
with malignant middle cerebral artery infarction and hemorrhagic transformation.[141]
Elevated serum uric acid levels are positively correlated with improved clinical symptoms
in patients receiving thrombolysis. Concomitant alteplase for thrombolysis and intravenous
infusion of uric acid can improve the prognosis of female patients, but it cannot
improve in male patients potentially because the baseline serum uric acid level in
women is lower than that in men.[142
143]
Based on the above studies, long-term management of HUA, which lowers serum uric acid
levels, might help decrease the occurrence and improve the outcome of ischemic stroke.
The initial and final targets of management should refer to relevant sections. It
is only recommended for patients with acute ischemic stroke receiving thrombolytic
therapy to maintain serum uric acid at higher levels only for a short term, which
helps in improving clinical symptoms and outcomes. Pharmacologic therapy should be
considered in HUA patients with stroke and a high risk of possible stroke. The effects
of aspirin, atorvastatin, and other drugs on serum uric acid should be considered
adequately during pharmacologic treatment. Specific details are provided in the relevant
section of pharmacologic therapy for coronary heart disease.
Hyperuricemia and neurodegenerative diseases
Alzheimer's disease is the most common type of dementia. The serum uric acid levels
in patients with mild cognitive dysfunction and Alzheimer's disease are lower than
those in the normal population. A diet high in uric acid can delay the progression
of mild cognitive dysfunction to Alzheimer's disease.[144] An elevated serum uric
acid level helps to decrease the incidence of Alzheimer's disease and protects cognitive
function in patients with Alzheimer's disease.[145
146] A lower serum uric acid level may increase the risk of cognitive impairment in
patients with mild cognitive dysfunction.[147]
Parkinson's disease is a common degenerative disease of the central nervous system
that occurs in the elderly. The risk of Parkinson's disease is lower in the population
with high serum uric acid levels.[148
149] An increased serum uric acid level helps decrease morbidity and delay the progression
of Parkinson's disease.[150
151] The risk of developing Parkinson's disease is relatively low in male patients
with high serum uric acid levels or gout, but no such correlation has been found in
women.[152]
The relationship between the serum urate level and neurological diseases is complex.
HUA might contribute to the occurrence and poor prognosis of ischemic stroke, whereas
the physiological serum urate level has a certain protective effect on the nervous
system. An excessively low serum urate level might increase the risk of developing
neurodegenerative diseases. Therefore, it is helpful for human health to maintain
a serum urate level within a reasonable range.
This is the first multidisciplinary expert consensus on HUA and associated diseases.
This consensus provides comprehensive insights into the diseases from the perspective
of systematic medicine. Experts from various specialties considered the latest results
of domestic and foreign research, the actual situation, and the features of clinical
diagnosis and treatment practices in China. This consensus was reached through a multidisciplinary
collaboration integrating traditional Chinese medicine with Western medicine and both
internal medicine and surgical approaches for consistently, comprehensively, and systematically
managing HUA and associated diseases. The purpose of these efforts was to improve
awareness of HUA and associated diseases in various disciplines in China, to standardize
and guide clinical practice, and eventually to improve patient outcomes. This consensus
adopts unified diagnostic criteria for HUA and proposes individualized, stratified,
and treat-to-target approaches and long-term management. The consensus recommendations
also set the lower limit of the ULT target after considering the physiological role
of uric acid. This consensus emphasizes the importance of patient management and nonpharmacological
therapy. Since relevant research data are lacking in the Chinese population and the
quality of clinical studies remains to be improved, this consensus suggests that multidisciplinary
joint studies should be performed in the future, especially on the following topics:
an epidemiological study of HUA and the influential factors in different regions of
China, a prospective ULT study examining the outcome of the corresponding systemic
impairment, and a study of the safety and efficacy of pharmacologic ULT monotherapy
and combination therapy. These studies should provide a basis for drafting Chinese
guidelines on treating HUA and related diseases.
Consensus panel members
Rheumatology: He-Jian Zou, Huashan Hospital, Fudan University; Hu-Sheng Wu, Beijing
Jishuitan Hospital; Jing-Guo Zhou, Affiliated Hospital of North Sichuan Medical College;
Xue-Jun Zeng, Peking Union Medical College Hospital; Lie Dai, Sun Yat-sen Memorial
Hospital, Sun Yat-sen University; Hua-Xiang Wu, the Second Affiliated Hospital of
Zhejiang University School of Medicine; Xiao-Xia Zhu, Huashan Hospital, Fudan University.
Nephrology: Chang-Lin Mei, Shanghai Changzheng Hospital, the Second Military Medical
University; Chuan-Ming Hao, Huashan Hospital, Fudan University; Nan Chen, Ruijin Hospital,
Shanghai Jiaotong University School of Medicine; Bi-Cheng Liu, Zhongda Hospital of
Southeast University; Jiang-Hua Chen, the First Affiliated Hospital, Zhejiang University
School of Medicine; Li Yang, Peking University First Hospital; Jing Nie, Nanfang Hospital,
Southern Medical University; Chen Yu, Tongji Hospital affiliated to Shanghai Tongji
University; Ai Peng, Shanghai Tenth Peopleai Hospital, Tongji University School of
Medicine; Sheng-Qiang Yu, Shanghai Changzheng Hospital, the Second Military Medical
University; Lin Li, Shanghai Changzheng Hospital, the Second Military Medical University.
Cardiology: Jun-Bo Ge, Zhongshan Hospital, Fudan University; Yong Huo, Peking University
First Hospital; Shu-Yang Zhang, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences and Peking Union Medical College; Yun-Dai Chen, Chinese People's
Liberation Army General Hospital; Yu-Gang Dong, the First Affiliated Hospital, Sun
Yat-sen University; Chun Liang, Shanghai Changzheng Hospital, the Second Military
Medical University; Yu-Xiang Dai, Zhongshan Hospital, Fudan University. Endocrinology:
Xin Gao, Zhongshan Hospital, Fudan University; Chang-Gui Li, the First Affiliated
Hospital of Qingdao University; Jia-Jun Zhao, Shandong Provincial Hospital; Hai-Bing
Chen, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University;
Zhi-Feng Cheng, the Fourth Affiliated Hospital of Harbin Medical University; Huan-Dong
Lin, Zhongshan Hospital, Fudan University. Neurology: Yang-Tai Guan, Renji Hospital,
Shanghai Jiaotong University School of Medicine; Kai Wang, the First Affiliated Hospital
of Anhui Medical University; Ben-Yan Luo, the First Affiliated Hospital, Zhejiang
University School of Medicine; Ruo-Lian Dai, Renji Hospital, Shanghai Jiao Tong University
School of Medicine. Traditional Chinese Medicine: Quan Jiang, Guang’anmen Hospital,
China Academy of Chinese Medical Sciences; Luan Xue, Yueyang Hospital of Integrated
Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese
Medicine. Urology: Chao-Chao Liang, the First Affiliated Hospital of Anhui Medical
University; Ming Chen, Zhongda Hospital of Southeast University; Song Fan, the First
Affiliated Hospital of Anhui Medical University.
Academic secretaries and writers
Lin Li, Xiao-Xia Zhu, Yu-Xiang Dai, Huan-Dong Lin, Ruo-Lian Dai, Luan Xue, Song Fan.
Supplementary information is linked to the online version of the paper on the Chinese
Medical Journal website.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.