今日の臨床サポート

高尿酸血症

著者: 田中隆久 田中内科 大宮糖尿病クリニック

監修: 野田光彦 国際医療福祉大学市川病院 糖尿病・代謝・内分泌内科

著者校正/監修レビュー済:2022/05/25
参考ガイドライン:
  1. 日本痛風・尿酸核酸学会:高尿酸血症・痛風の治療ガイドライン 第3版[2022年追補版]
  1. 米国リウマチ学会:痛風管理ガイドライン2020年版
患者向け説明資料

概要・推奨   

  1. 高尿酸血症では、他の心血管疾患の危険因子のサーベイが強く推奨される(推奨度1)
  1. 高尿酸血症は痛風の最大の危険因子であり、尿酸値が高いほど痛風発作の危険が高まる(推奨度2)
  1. 高尿酸血症は尿路結石のリスクであり、高尿酸血症患者においては尿路結石の既往歴を聞くことや、尿路結石の患者では尿酸をチェックすることが推奨される(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
田中隆久 : 特に申告事項無し[2022年]
監修:野田光彦 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 病期分類に腎外排泄低下型が追加され、尿酸産生過剰型と合わせて腎負荷型が提唱された。
  1. 新規薬剤が上市された。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 男女とも血清尿酸値が7mg/dLを高尿酸血症と定義する。
  1. 成人男性では20%以上が高尿酸血症の基準に当てはまる。それに対し、女性では5%未満である。
  1. 無症状で発見される高尿酸血症は、まず二次性の高尿酸血症の除外が必要である。
  1. 二次性の高尿酸血症、悪性腫瘍の合併や化学療法中の患者では、急性尿酸性腎症および腫瘍融解症候群の緊急の治療を要する場合があることに留意する。
  1. 高尿酸血症では痛風関節炎や尿路結石の予防が重要で、患者から訴えがなくても、関節炎の既往、尿路結石の既往やそれを疑わせるような腹痛発作の既往、健診や偶然見つかった尿検査の異常や腎機能障害について、病歴聴取する。
  1. さらには心血管疾患、腎障害などの合併症の予防が重要で、その患者のベースラインのリスク評価が重要である。
問診・診察のポイント  
  1. 痛風関節炎、尿路結石を疑うエピソードが過去にないかどうか、詳細な病歴聴取が必要である。

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文献 

M Tomita, S Mizuno, H Yamanaka, Y Hosoda, K Sakuma, Y Matuoka, M Odaka, M Yamaguchi, H Yosida, H Morisawa, T Murayama
Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers.
J Epidemiol. 2000 Nov;10(6):403-9.
Abstract/Text A positive association between hyperuricemia and cardiovascular disease has been reported, but no study has evidenced yet the precise role of serum uric acid in the development of cardiovascular disease. In addition, no epidemiological studies have so far documented a decreased risk of cancer among people with hyperuricemia, even though the antioxidant action of uric acid has recently been stressed to inhibit DNA damage. The present prospective cohort study investigates the relationship between hyperuricemia and health hazards in a Japanese working population. The subjects were 49,413 Japanese male railroad workers, aged 25-60 years at enrollment. Serum uric acid and other baseline data were provided by annual health-survey records from 1975 to 1982. The vital status of the subjects was traced until the end of 1985 for those who remained alive. During an average 5.4-year study period, 984 deaths were recorded. Those with serum uric acid over 8.5 mg/dl showed elevated relative risks (RRs) of death in all causes (RR 1.62, p<0.01), coronary heart disease ( RR 1.52), stroke (RR 2.33, p<0.01), hepatic disease (RR 3.58, p<0.01), and renal failure ( RR 8.52, p<0.01), as compared with those with serum uric acid levels of 5.0-6.4mg/dl. The RR of death in all causes still remains statistically significant when adjusted by age and serum total cholesterol (2.00, p<0.01), age and alcohol intake (1.85, p<0.001), age and smoking (1.69, p<0.001), age and gout treatment (1.61, p<0.05), and also age and BMI (1.50, p< 0.05). On the other hand, the RR of all causes decreased but was still above 1.0 when adjusted by age and blood glucose (1.62), age and systolic blood pressure (1.32), age and GOT (1.23), and also age and history of cardiovascular disease (1.17). These results showed that hyperuricemia has a strong association with the RRs of death in all causes, coronary heart disease, stroke, hepatic disease and renal failure, and indicated that serum uric acid seems to be a considerable risk factor for reduced life expectancy.

PMID 11210110
Seo Young Kim, James P Guevara, Kyoung Mi Kim, Hyon K Choi, Daniel F Heitjan, Daniel A Albert
Hyperuricemia and coronary heart disease: a systematic review and meta-analysis.
Arthritis Care Res (Hoboken). 2010 Feb;62(2):170-80. doi: 10.1002/acr.20065.
Abstract/Text OBJECTIVE: The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension.
METHODS: A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults.
RESULTS: Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04).
CONCLUSION: Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.

PMID 20191515
E W Campion, R J Glynn, L O DeLabry
Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study.
Am J Med. 1987 Mar;82(3):421-6.
Abstract/Text To quantify the consequences of asymptomatic hyperuricemia, this study examined rates for a first episode of gouty arthritis based on 30,147 human-years of prospective observation. A cohort of 2,046 initially healthy men in the Normative Aging Study was followed for 14.9 years with serial examinations and measurement of urate levels. With prior serum urate levels of 9 mg/dl or more, the annual incidence rate of gouty arthritis was 4.9 percent, compared with 0.5 percent for urate levels of 7.0 to 8.9 mg/dl and 0.1 percent for urate levels below 7.0 mg/dl. With urate levels of 9 mg/dl or higher, cumulative incidence of gouty arthritis reached 22 percent after five years. Incidence rates were three times higher for hypertensive patients than for normotensive patients (p less than 0.01). The strongest predictors of gout in a proportional hazards model were age, body mass index, hypertension, and cholesterol level, and alcohol intake. When the serum urate level became a factor in the model, none of these variables retained independent predictive power. At the final examination, only 0.7 percent of participants had a serum creatinine level of 2.0 mg/dl or more, with no evidence of renal deterioration attributable to hyperuricemia. These data support conservative management of asymptomatic hyperuricemia.

PMID 3826098
A P Hall, P E Barry, T R Dawber, P M McNamara
Epidemiology of gout and hyperuricemia. A long-term population study.
Am J Med. 1967 Jan;42(1):27-37.
Abstract/Text
PMID 6016478
Takahiro Yasui, Masanori Iguchi, Sadao Suzuki, Kenjiro Kohri
Prevalence and epidemiological characteristics of urolithiasis in Japan: national trends between 1965 and 2005.
Urology. 2008 Feb;71(2):209-13. doi: 10.1016/j.urology.2007.09.034.
Abstract/Text OBJECTIVES: We evaluated the epidemiological details and chronological trends of upper urinary tract stones in Japan using a nationwide survey of urolithiasis.
METHODS: All patient visits to urologists that resulted in a diagnosis of first-episode upper urinary tract stones in 2005 were enumerated irrespective of admission and treatment. The study included all hospitals approved by the Japanese Board of Urology, thus covering nearly all urologists practicing in Japan. We compared the estimated annual incidence according to gender and age with the incidence determined from nationwide surveys between 1965 and 1995.
RESULTS: The estimated annual incidence of first-episode upper urinary tract stones in 2005 was 134.0 per 100,000 (192.0 in men and 79.3 in women). The estimated age-standardized annual incidence of first-episode upper urinary tract stones in 2005 was 114.3 per 100,000 (165.1 for men and 65.1 for women), which represents a steady increase from 54.2 in 1965. The annual incidence has increased in all age groups except during the first 3 decades of life and the peak age for both men and women has also increased.
CONCLUSIONS: The annual incidence of upper urinary tract stones has steadily increased in Japan and this trend will continue in the near future. This probably results from improvements in clinical-diagnostic procedures, changes in nutritional and environmental factors, and general apathy toward metabolic clarification and metaphylaxis.

PMID 18308085
Daniel I Feig
Uric acid: a novel mediator and marker of risk in chronic kidney disease?
Curr Opin Nephrol Hypertens. 2009 Nov;18(6):526-30. doi: 10.1097/MNH.0b013e328330d9d0.
Abstract/Text PURPOSE OF REVIEW: To assess the current data suggesting that uric acid-lowering therapy may be useful in the prevention or mitigation of chronic kidney disease (CKD).
RECENT FINDINGS: Eleven observational studies assessing the potential role of serum uric acid in the prevalence and progression of CKD have been published in the past 2 years. Seven suggest an association, whereas four do not. Recent experimental models and clinical trials have mechanistically linked serum uric acid and hypertension, an established risk factor for CKD.
SUMMARY: Elevated serum uric acid is a marker for decreased renal function, may have a mechanistic role in the incidence and progression of renal functional decline and likely has a causal role in hypertension and vascular disease. Clinical trials are needed to determine whether uric acid-lowering therapy will be effective in preventing CKD.

PMID 19654543
Thomas H Taylor, John N Mecchella, Robin J Larson, Kevin D Kerin, Todd A Mackenzie
Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial.
Am J Med. 2012 Nov;125(11):1126-1134.e7. doi: 10.1016/j.amjmed.2012.05.025.
Abstract/Text OBJECTIVE: Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack.
METHODS: A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30.
RESULTS: On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point.
CONCLUSIONS: Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers.

Published by Elsevier Inc.
PMID 23098865
Jasvinder A Singh, Supriya G Reddy, Joseph Kundukulam
Risk factors for gout and prevention: a systematic review of the literature.
Curr Opin Rheumatol. 2011 Mar;23(2):192-202. doi: 10.1097/BOR.0b013e3283438e13.
Abstract/Text PURPOSE OF REVIEW: Our objective was to perform a systematic review of risk factors and prevention of gout. We searched Medline for fully published reports in English using keywords including but not limited to 'gout', 'epidemiology', 'primary prevention', 'secondary prevention', 'risk factors'. Data from relevant articles meeting inclusion criteria were extracted using standardized forms.
RECENT FINDINGS: Of the 751 titles and abstracts, 53 studies met the criteria and were included in the review. Several risk factors were studied. Alcohol consumption increased the risk of incident gout, especially beer and hard liquor. Several dietary factors increased the risk of incident gout, including meat intake, seafood intake, sugar sweetened soft drinks, and consumption of foods high in fructose. Diary intake, folate intake, and coffee consumption were each associated with a lower risk of incident gout and in some cases a lower rate of gout flares. Thiazide and loop diuretics were associated with higher risk of incident gout and higher rate of gout flares. Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity, and early menopause were each associated with a higher risk of incident gout and/or gout flares.
SUMMARY: Several dietary risk factors for incident gout and gout flares are modifiable. Prevention and optimal management of comorbidities are likely to decreased risk of gout. Research in preventive strategies for the treatment of gout is needed.

PMID 21285714
Abstract/Text OBJECTIVE: To evaluate the proposed relationship between persistent reduction of serum urate into the subsaturating range and reduction in the frequency of acute gouty attacks.
METHODS: We retrospectively examined data derived from 267 patients who had experienced at least 1 gouty attack before their first visit to our clinic. Serum urate concentration, history of recurrent gouty attacks, and information about antihyperuricemic drug use were collected on each visit for up to 3 years from the first visit of each patient. Data derived from visits >1 year after study entry were subjected to statistical analysis.
RESULTS: When adjusted for baseline serum urate level and the number of gouty attacks prior to study entry, reduction of followup serum urate concentration and antihyperuricemic drug use were each significantly associated with a reduced risk of gouty attacks (odds ratio [OR] 0.42, 95% confidence interval [95% CI] 0.31-0.57; OR 0.22, 95% CI 0.10-0.47, respectively).
CONCLUSION: The data indicate that reduction of serum urate concentrations to 6 mg/dl or lower will eventually result in a reduced frequency or prevention of future gouty attacks.

PMID 15188314
H Yamanaka, R Togashi, M Hakoda, C Terai, S Kashiwazaki, T Dan, N Kamatani
Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment.
Adv Exp Med Biol. 1998;431:13-8.
Abstract/Text To find an optimal range of urate concentrations wherein the risk of attacks during the initial 6 months of treatment is minimized, data from 350 gouty patients treated with anti-hyperuricemic drugs were retrospectively analyzed. We determined the optimal range of urate concentrations to be 4.6-6.6 mg/dl. If urate concentrations were within this range, the risk ratio of an attack as opposed to outside of the range was 0.705 (95% confidence interval, 0.629-0.791). The increase (or decrease) in urate concentration in one month associated with minimal risk of gouty attacks was also determined. The lowest risk ratio of attack (0.451) occurred at a range of -0.1 to 0.6 mg/dl/month increase in urate concentrations (95% confidence interval, 0.310-0.655). In conclusion, we propose that urate concentrations during the initial 6 months of anti-hyperuricemic therapy should be maintained within a range of 4.6-6.6 mg/dl, and reduction in the urate concentrations during treatment should be as slow as possible.

PMID 9598023
Gregory C Borstad, Leslie R Bryant, Michael P Abel, Daren A Scroggie, Mark D Harris, Jeff A Alloway
Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis.
J Rheumatol. 2004 Dec;31(12):2429-32.
Abstract/Text OBJECTIVE: The use of colchicine to prevent acute gout flares during initiation of allopurinol therapy is widely practiced despite lack of proven benefit. We investigated if colchicine administration during initiation of allopurinol for chronic gouty arthritis reduces the frequency and/or severity of acute gout flares.
METHODS: Patients starting allopurinol for crystal-proven chronic gouty arthritis were randomized to receive colchicine 0.6 mg po bid or placebo in a randomized, prospective, double blind, placebo controlled trial. Subjects were followed for evidence of acute gout flares and remained on study drug for 3 months beyond attaining a serum urate concentration < 6.5 mg/dl. Treatment arms were analyzed regarding frequency of flares, likelihood of any flare or multiple flares, severity of flares on the visual analog scale (VAS), and length of flares in days.
RESULTS: Forty-three subjects were studied. Subjects treated with colchicine experienced fewer total flares (0.52 vs 2.91, p = 0.008), fewer flares from 0 to 3 months (0.57 vs 1.91, p = 0.022), fewer flares 3-6 months (0 vs 1.05, p = 0.033), less severe flares as reported on VAS (3.64 vs 5.08, p = 0.018), and fewer recurrent gout flares (p = 0.001). Colchicine was well tolerated.
CONCLUSION: Colchicine prophylaxis during initiation of allopurinol for chronic gouty arthritis reduces the frequency and severity of acute flares, and reduces the likelihood of recurrent flares. Treating patients with colchicine during initiation of allopurinol therapy for 6 months is supported by our data.

PMID 15570646
Abstract/Text
PMID 8523332

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