|Year : 2014 | Volume
| Issue : 2 | Page : 95-100
To treat or not to treat asymptomatic hyperuricemia
Department of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
|Date of Web Publication||18-Jul-2014|
Department of Medicine, Umm Al-Qura University, P. O. Box 7607, Makkah
Source of Support: None, Conflict of Interest: None
Background: Hyperuricemia is a term given to serum uric acid levels higher than 7.0 mg/dL; asymptomatic hyperuricemia may precede gouty attacks with several years. This progression is variable from a person-to-person and may not even develop. Owing to this, there is a great controversy in whether to treat asymptomatic hyperuricemia or not.
Objective: The objective of the following study is to determine the treatment habits of asymptomatic hyperuricemia in Makkah Region, Kingdom of Saudi Arabia.
Materials and Methods: This survey was carried out using a structured questionnaire that was answered through face-to-face interviews with 104 physicians who diagnose and treat hyperuricemia. The data was collected on the second half of 2012. The specialties included in the study were general practitioners, family physicians, orthopedicians and rheumatologists.
Results: Half of the doctors in our study (50.9%) chose to observe and follow asymptomatic hyperuricemic patients and 84% depend on the serum uric acid levels to help them decide when to start their treatment, 53% asked about co-morbid diseases as renal stones, diabetes mellitus and ischemic heart disease whereas 49% asked about family history. When doctors are to start the treatment, 84.1% will start with allopurinol and 42.5% will advise on the change of dietary and life-style habits.
Conclusions: The results showed that the doctors in Makkah Region depend on the serum uric acid levels to decide when to start the treatment, not abiding by the international guidelines. They still chose the life-style and dietary modification, as well as starting treatment with allopurinol with a starting dose of 100 mg/dL daily.
تعنى هذه الدراسة بارتفاع حمض اليوريك في الدم والذي يسبق ارتفاع حمض اليوريك غير المصحوب بنوبات النقرس بعدة سنوات. ويعتبر هذا التدرج أو التعاقب مختلفا من شخص لآخر ويمكن كذلك عدم تكونه مطلقًا.
وبناءًا على ذلك فهناك جدل كبير فيما إذا كان لابد من علاج زيادة حمض اليوريك غير المصحوب بأعراض من عدمه.
شملت هذه الدراسة الاستطلاعية استبانة في منطقة مكة المكرمة. تمت الإجابة عليها من 104 طبيب ذوي تخصصات مختلفة مثل أطباء الأسرة، وأخصائي العظام وأخصائي أمراض الروماتيزم.
ولقد بينت الدراسة أن الأطباء المتخصصين في علاج مرض النقرس في منطقة مكة المكرمة، يعتمدون على نسبة حمض اليوريك في الدم فقط ولا يلتزمون بالمبادئ التوجيهية الدولية في ذلك.
Keywords: Allopurinol, hyperuricemia, serum uric acid
|How to cite this article:|
Mustafa H. To treat or not to treat asymptomatic hyperuricemia. Saudi J Med Med Sci 2014;2:95-100
| Introduction|| |
Hyperuricemia is defined as a serum uric acid level greater than 7.0 mg/dL in men or greater than 6.0 mg/dL in women as measured by the automated enzymatic (uricase) method. ,,,
Biologically significant hyperuricemia occurs when serum urate levels exceed urate solubility in serum and extracellular spaces such as the joint or soft-tissue, at approximately 6.8 mg/dL at 37°C. ,,, At serum urate levels above this threshold, uric acid precipitates as monosodium urate crystals in these compartments, but for varying reasons, it does not always cause an inflammatory response.  Manifestations of chronic crystal deposition, including gouty arthritis, may occur, although asymptomatic hyperuricemia often persists for many years without progression. 
Stage 1: Asymptomatic hyperuricemia: It is common and does not in itself constitute a disease. During this period, urate deposits may directly contribute to organ damage. This does not occur in everyone, however and at present there is no evidence that treatment is warranted for asymptomatic hyperuricemia. 
Stages 2 and 3: Acute gout and intercritical periods. If sufficient urate deposits develop around joints and if the local milieu or some trauma triggers the release of crystals into the joint space, the patient will suffer from acute attacks of gout. 
Stage 4: Advanced gout. If crystal deposits continue to accumulate, patients may develop chronically stiff and swollen joints. 
The progression from asymptomatic hyperuricemia to advanced gout is quite variable from person-to-person. In most people, it takes many years to progress. 
Hyperuricemia can be caused by overproduction of urate or far more commonly, by inefficient excretion by the kidneys or both  which may affect the management.  Serum uric acid levels may also increase with aging and weight gain. This accounts for >90% of cases. ,
Hyperuricemia, is intricately linked with the metabolic syndrome (hypertension, glucose intolerance, dyslipidemia, truncal obesity, increased risk of cardiovascular disease) and there is mounting evidence that hyperuricemia itself may be an independent risk factor for cardiovascular disease. 
Hyperuricemia is a biochemical entity that is gaining increasing importance as it has been found by some researchers to be not only a cardiovascular risk factor, but also play a role in the development of renal and metabolic diseases. ,,
This study was conducted to evaluate the treatment strategy of physicians in Makkah Region and to determine whether they follow the international guidelines or not in the treatment of asymptomatic hyperuricemia to identify any wrong practices.
| Materials and methods|| |
We conducted a study to find out whether the doctors in the Makkah Region match the international guidelines in the treatment pattern of asymptomatic hyperuricemia. Face-to-face interviews were conducted with 104 physicians; who interfere with the diagnosis and/or treatment of asymptomatic hyperuricemia; in 6 hospitals and 10 primary care centers in Makkah Region between July 2012 and December 2012; interviews were conducted by final year medical students, the time of the interview was 15-20 min, interview transcripts were done by the corresponding author and then statistical analysis was performed on the overall sample.
A sample size of 100 doctors would give a confidence level of 95% and reliability (margin of error) of 5.85% considering population size of 5,000 doctors.
As hyperuricemia is a common disease and different specialties can take part in its treatment, we included different specialties in our study as general practitioners (GP), family physicians, Orthopedicians and Rheumatologists.
| Results|| |
Different physician specialties took part in this study; there were 58 GPs (55.7%), 27 family physicians (25.9%), 13 orthopedicians (12.5%) and 6 rheumatologists (5.7%) respectively.
Out of these physicians; 53 doctors (50.9%) chose to observe and follow the asymptomatic hyperuricemia patients while 18 doctors (17.3%) require further assessment, 17 doctors (16.3%) suggested to refer patients to rheumatologists, 11 doctors (10.5%) wanted to start treatment and only 5 doctors (4.8%) saw that nothing is required.
When doctors were asked about the elements that help in deciding on the treatment strategy, 84 doctors of the sample (84%) chose serum uric acid level while 53 doctors (53%) and 49 doctors (49%) chose the existence of co-morbid disease and family history respectively.
Sixteen doctors (16.8%) do not depend on the serum uric acid level in starting the treatment of asymptomatic hyperuricemia while the level of serum uric acid affects the decision of 79 doctors (83.1%). The level at which these doctors start the treatment is shown in [Table 1].
The comorbid diseases that doctors look for in order to decide whether to start treatment or not are the presence of renal stones, alcohol intake, diabetes mellitus (DM), ischemic heart disease (IHD), thyroid disease and asthma. [Table 2] shows the percentage of each comorbid disease.
For the doctors who will start the treatment of asymptomatic hyperuricemia, 85 doctors (84.1%) will prescribe allopurinol, 49 doctors (48.5%) will change the dietary habits of the patient, 43 doctors (42.5%) prescribe anti-inflammatory drugs, 17 doctors (16.8%) prescribe colchicine and 10 doctors (9.9%) will prescribe uricosurics agents.
|Table 2: Percentage of comorbid diseases asked for by doctors before starting treatment|
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Out of 85 doctors who will prescribe allopurinol, 36 doctors (35.6%) will start with 100 mg dose while 12 doctors (11.8%) will start with 300 mg, only 6 doctors (5.9%) will start with 200 mg and no one will start with 400 mg, 31 doctors (30.6%) refused to recommend a certain dosage as a starting dose as it is case depending.
Allopurinol was prescribed once daily by 38 doctors (37.6%), bis in die (BID) by 16 doctors (15.8%) and ter in die (TID) by 4 doctors (3.9%); while 27 doctors (26.7%) prescribed it according to the case.
The doctors in our study like to order 24 h urine uric acid test, serum creatinine, urinalysis, liver function test, complete blood count, calcium levels and electrocardiogram (ECG). The percentages are shown in [Table 3].
About one-third of our doctors, 39 doctors (39.3%), sometimes refer their patients to a dietitian, 27 doctors (27.2%) always refer the patient to dietitian, 26 doctors (26.2%) range between occasionally and rarely referring and 7 doctors (7.0%) never refer the patient to a dietitian.
| Discussion|| |
Over the years, it has been a conflict on whether to or not to treat asymptomatic hyperuricemia. Almost 10% of adults are documented to have hyperuricemia at least once in their lifetime.  The dilemma is how to predict, who is most likely to benefit from early urate-lowering treatment and who will not. Currently, clinicians have no reliable way of predicting the likelihood of gout development in a given hyperuricemic patient. 
In our study, we found that only 10.5% of our doctors started the treatment directly whereas the rest preferred to follow and observe their patients, asked for further assessments or even referred them to a rheumatologist. Hence, we match the international guidelines in "not starting the treatment of asymptomatic hyperuricemia directly." Most experts recommend no treatment for asymptomatic hyperuricemia. In most of the patients, symptoms do not develop. If gouty arthritis or renal stone occur they can be treated readily. 
Treatment of asymptomatic hyperuricemia is not necessary in most patients, but there are some situations where they should be treated as patients who have very high levels of uric acid or are at risk of complications, such as those with a personal or strong family history of gout, urolithiasis, or uric acid nephropathy, patients starting cancer chemotherapy or radiation therapy. They should be given allopurinol and fluids to prevent acute uric acid renal tubular blockade as this is likely to cause extensive cell lysis. ,
In our study, 84% of doctors implied that the serum uric acid level was a helpful element in deciding the beginning of the treatment as indicates in [Table 1] and 44.2% started treatment if it was more than 7.1 mg/dL, 14.7% started the treatment at 6 mg/dL, 13.8% started it at 8.1 mg/dL and 10.5% started when the serum uric acid Level exceeded 9 mg/dL. There are some practices that start the treatment as low as 8.0 mg/dL or higher as a general indicator, but it should be undertaken with caution.  This is similar to most of the doctors in our study. Although other practices, tend not to treat asymptomatic hyperuricemia unless the uric acid level is at least 10 mg/dL in women or 12 or 13 mg/dL in men. , These practices adopt this to diminish any projected risks of gouty arthritis or renal stones, although there is no conclusive evidence to support it. 
The presence of renal stone is one of the major comorbid diseases asked about in our study, 78.5% of doctors asked about it; this has been proved by other studies to be an indication to start the treatment in asymptomatic hyperuricemic patients. Patients with a history of kidney stones, who are at risk for recurrent uric acid nephrolithiasis, should be considered for long-term allopurinol treatment. 
Nearly 51.0% of the doctors asked about alcohol intake in order to help them decide on whether or not to start treatment.
Hyperuricemia has long been suspected to be a cardiovascular risk factor.  The positive association between serum uric acid and cardiovascular diseases such as stroke or IHD has been recognized since the 1950s and has been confirmed by numerous epidemiological studies since then. 
Although the Framingham Heart study found no independent association between hyperuricemia and increased risk of coronary artery disease, several subsequent studies have found one. A recent review concluded that serum uric acid is a moderate, independent cardiovascular risk factor and appears to be a stronger risk factor in individuals already at high risk for cardiovascular disease than in healthy individuals.  The National Health and Nutrition Examination Survey data followed 5926 patients for an average of 16.4 years found that increased serum uric acid levels were independently and significantly associated with cardiovascular mortality in both men and women. ,
Although these findings suggest a relationship between high serum uric acid levels and coronary artery disease, other studies did not support this conclusion. ,,, Some of our doctors still cared to evaluate it in correspondence to hyperuricemia, 27.5% asked about IHD in the patients they treated and even 8.1% of them ordered ECG.
Elevated serum uric acid levels are commonly seen in association with glucose intolerance, hypertension and dyslipidemia, a cluster of metabolic and hemodynamic disorders which characterize the so-called metabolic syndrome. ,
Hyperuricemia is probably associated with glucose intolerance through multiple mechanisms, but the central one may be related to the ability of insulin to decrease the clearance of uric acid in the renal proximal tubule resulting in an increase in serum uric acid levels. ,
Due to the above we found that 36.7% doctors in the study also asked about DM.
Although treatment of asymptomatic hyperuricemia is not indicated in most of the cases, 85 of the doctors in our study prescribed allopurinol. The benefits of treatment with allopurinol appear questionable in patients with asymptomatic hyperuricemia and do not justify the risks associated with long-term administration. 
In our study, 36 doctors out of the 85 who start treatment with allopurinol gave at 100 mg daily, keeping with the EULAR guidelines. The dose can be increased by 100 mg every 1-4 weeks until a target serum urate level (<6 mg/dL) is achieved or the maximum appropriate allopurinol dose is reached. ,,
Food and Drug Administration approved four doses up to 800 mg daily, this is also reinforced by the EULAR in patients with preserved renal function. ,,,, The most commonly used allopurinol dose is 300 mg/day. , However, patients with tumor lysis syndrome usually require higher doses of allopurinol. 
Allopurinol should be started at a lower dose in elderly patients and those with impaired renal function or heart failure. ,,
The frequency of allopurinol administration has been standardized in being a single daily dose for those patients receiving a total of ≤300 mg/day and two equal doses for daily amounts exceeding a total of 300 mg in order to improve GI tolerance. ,, In our study, 38 doctors gave the allopurinol dose as once daily and 16 doctors as BID, 27 doctors said that it depends on the case and only 4 doctors gave it TID.
Another treatment for asymptomatic hyperuricemia indicated by only 9.9% of our doctors is uricosurics agents. Uricosuric agents are less frequently used primarily because of the need for 3 times daily dosing and the requirement for measuring 24 h urinary uric acid before beginning therapy. 
One of the most ordered tests in our study was the 24 h urine uric acid; this was ordered by 61.2% of the doctors. It helps in determining whether hyperuricemia is caused by overproduction or under excretion particularly in patients with kidney stones, a strong family history of gout or kidney stones, or gout at a young age. 
People with normal renal function excrete <600 mg of uric acid in 24 h on a purine-restricted diet, or less than 1 g on a normal diet.  The 24-h uric acid excretion can play a role in deciding whether to start long-term treatment with allopurinol, which decreases uric acid production in case of overproduction of uric acid.
Diet and life-style modification have achieved an important part of our study as 48.5% of the doctors used it as a method of treatment and 27.2% always refer their patients to a dietitian. Life-style guidance is a non-drug therapy aimed at correcting life-style habits and plays a vital role in treatment regardless of whether or not drug therapy is implemented. 
Life-style guidance is necessary for all hyperuricemia patients and as there is scant evidence regarding treatment for asymptomatic hyperuricemia patients first undergoes life-style guidance and then if serum urate levels remain high, drug therapy is considered. 
Patients should be educated on dietary and life-style modifications. They should attempt to reduce purine-rich foods and avoid alcohol intake, especially beer. Patients should be advised to lose weight if obese and exercise have been shown to have a positive impact on urate reduction. ,,
Although diet has long been recognized as a major causative factor in the pathogenesis of hyperuricemia, dietary restriction or modification as a means of controlling it has been and continues to be largely neglected. 
| Conclusion|| |
Treatment of asymptomatic hyperuricemia to prevent the development of its complications is not generally recommended in the international guidelines. However, our results showed that the doctor's in Makkah Region depend on the serum uric acid levels to decide when to start the treatment, not abiding by the international guidelines. The decision also should be individualized in correspondence with several elements as the presence of strong family history, co-morbid disease, very high serum uric acid and considerable alcohol consumption. These factors also played an important role in whether to start the treatment or not in our study. When the decision of starting treatment is taken, allopurinol was by far the first therapy in choice.
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[Table 1], [Table 2], [Table 3]