Case 1: A 67-year-old man was referred to our hypertension clinic because of refractory hypertension associated with gout. The onset of hypertension occurred in his 20s. Since his early 30s, he also had recurrent podagra, and at that time was taken off thiazide, but nonetheless continued to experience recurrent gouty episodes every several months. Approximately 1 year prior to his hypertension evaluation, the patient was prescribed allopurinol and last experienced podagra 6 months previously.
Recent blood pressures (BPs) had been 152/78 mm Hg and 175/88 mm Hg and was 162/84 mm Hg when seen in the hypertension clinic. Creatinine was 1.1 mg/dL (normal 0.7–1.3 mg/dL) and uric acid was 4.6 mg/dL (normal 3.4–7.2 mg/dL). Medications included atenolol 50 mg twice a day, allopurinol 200 mg twice a day, amlodipine 10 mg once a day, clonidine 0.1 mg twice a day, losartan 50 mg once a day, and terazosin 6 mg at bedtime. The patient was hesitant to retry a diuretic, but was persuaded to take hydrochlorothiazide 12.5 mg daily, subsequently advanced to 25 mg daily. Follow-up BPs were 128 to 132 mm Hg/66 to 72 mm Hg without recurrence of gout 6 months later.
Case 2: A 43-year-old man was seen in our hypertension clinic because of uncontrolled BP. Antihypertensive medication was introduced to the patient in his 30s, but thiazide had been avoided due to recurrent episodes of gout. Podagra and gouty flares of the right instep occurred once or twice yearly and were almost always preceded by eating mong beans. BP at the time of evaluation was 146/90 mm Hg, with a creatinine value of 1.2 mg/dL and uric acid value of 9.4 mg/dL. His medications included lisinopril 40 mg daily, nifedipine extended-release 90 mg daily, and atenolol 50 mg daily.
Allopurinol 300 mg daily and hydrochlorothiazide 12.5 mg, advancing to 25 mg daily were prescribed, with a follow-up BP of 130/82 mm Hg and a uric acid value of 6.4 mg/dL.
Hypertension and Gout Are Overlapping Diseases
The prevalence of gout has been increasing and the Third National Health and Nutrition Examination Survey (NHANES III) estimated that more than 5 million Americans were affected in 1994.1 The incidence of gout also increases with advancing age similar to the age-related occurrence of hypertension. Hypertension alone is a predictor of gout, along with the additional risk factors of obesity, serum uric acid level, alcohol intake, and the use of thiazide and loop diuretics in additive fashion.2,3 Since gout is a common disease, affecting 1% of men in Western countries,2 its management will occasionally overlap with a primary care practice of patients with hypertension. Although there are many antihypertensive medication classes in addition to diuretics from which to choose, 15% to 20% of hypertension patients will be refractory to 3 drugs. Moreover, the concordant experience of two large university clinics has been that the most common cause of refractory hypertension is the lack of diuretic therapy.4,5 Therefore, as in these two cases, gout will occasionally occur in patients with resistant hypertension who need diuretic therapy.
What Is the Relationship Between Hyperuricemia and Clinical Gout?
Based on 30,147 human years of prospective observation in the Prospective Normative Aging Study,3 incident rates of acute gouty arthropathy were highly related to the most recent serum urate level. However, incident rates were only 7% per year for the highest urate levels ≥9.0 mg/dL, and only 1.8% of all urate levels were ≥9.0 mg/dL (Figure 1). During 5 years of prospective follow-up, 78% of individuals with urate levels ≥9.0 mg/dL remained free of gout. For those participants with urate levels of 7.0 mg/dL to 8.9 mg/dL, the cumulative incidence of gout after 5 years was only 3%. Because all of the participants in this aging study were men, these incidence rates were probably higher than the general population due to the male:female ratio of clinical gout ranging from 7:1 to 9:1.2
What Effect Does Thiazide Have on Uric Acid Levels and Gout?
The Hypertension Detection and Follow-up Program (HDFP) randomized patients to more intensive “stepped care” therapy vs usual or “referred care.” Step 1 of the HDFP drug protocol was chlorthalidone 50 mg daily. Although baseline uric acid levels were related to renal function, increases in uric acid on chlorthalidone were the same with serum creatinine levels <1.5 or ≥1.5 mg/dL.6 Additionally, individuals treated with chlorthalidone in the lowest quartile of baseline uric acid levels experienced a greater rise in uric acid than those in the highest quartile of uric acid. The primary conclusion of this analysis is that discontinuation of chlorthalidone due to clinical gout was rare, occurring in 18 of 3693 patients over 5 years, 0.5%.6
Although infrequent, diuretic use is an important risk factor for gout in observational studies.7–9 However, diuretics may be less important in this regard than other risk factors. In the Health Professionals Follow-up Study,9 the multivariate relative risks of gout were 2.31 for the presence of hypertension, 1.99 for weight gain of ≥30 pounds over 12 years, and 1.77 for diuretic use.9 It is hypothesized that diuretic-induced extracellular volume contraction promotes proximal tubular reabsorption of urate, although decreased renal tubular secretion is probably also a contributing explanation of diuretic-related hyperuricemia.8,10 Gout is more strongly related to loop diuretics than thiazide.7
The expected increase in serum uric acid as a result of thiazide treatment is small and dose related. A dose of ≥50 mg of hydrochlorothiazide or chlorthalidone led to an average increase of 1.53 mg/dL of uric acid in one study, and in several other studies of hydrochlorothiazide 25 mg, an average increase of 0.8 mg/dL was observed.11
How Beneficial Is the Uricosuric Effect of Losartan?
The uricosuric effect of losartan is unique among the angiotensin receptor blockers.12,13 This effect is independent of sodium loading and occurs despite the presence of chronic kidney disease. The uricosuric mechanism has been attributed to inhibition of urate transporter 1, thereby interfering with urate reabsorption across the apical luminal membrane of the proximal renal tubule.14 The short-term time course of <6 hours for the uricosuric effect implies that this property belongs to the parent compound rather than its metabolites.15 Studies examining uric acid lowering related to the dosage of losartan are inconsistent. In one study, decreases in serum uric acid followed a dose-dependent pattern from 0.32 mg/dL to 1.33 mg/dL over a losartan dose range from 25 mg/d to 200 mg/d.15 Another study showed that losartan dose escalation from 50 mg/d to 100 mg/d did not lead to further uric acid lowering.16
Other studies have examined the urate-balancing effects of adding losartan to hydrochlorothiazide.17,18 Uricosuria occurring with losartan in patients treated with hydrochlorothiazide occurs in the absence of risk for precipitating urate nephropathy.17 There is a significant decrease in thiazide-induced hyperuricemia proportional to losartan dosing, but not enough to completely reverse all of the thiazide-related augmentation of serum uric acid (Figure 2).18
It is uncertain whether the modest and transient uric acid–lowering effect of losartan is enough to translate into benefit-reducing gouty attacks, and clinical end point studies are lacking.2 Missing a single daily dose of losartan would lead to a gap in protection. Alhough losartan and probenecid share similar uric acid–lowering mechanisms, losartan is less potent and should not be considered for reliable long-term antihyperuricemic therapy. Other drugs with incidental uricosuric effects include ascorbic acid, calcitonin, and fenofibrate.19
Is Uric Acid a Cardiovascular Risk Factor? Does Reducing Uric Acid Decrease BP in Patients With Hypertension?
Many studies that generally use multivariate analyses have associated a high relative risk of hypertension with hyperuricemia, but whether hyperuricemia is truly an independent risk factor is controversial.20 The Framingham Heart Study concluded that uric acid was not independently associated with cardiovascular risk, and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure did not list uric acid as a cardiovascular risk predictor.21,22 Because of the high correlation of pediatric hyperuricemia with hypertension, it has been hypothesized that uric acid may be one of several triggers for renal vasoconstriction as an initial phase in the development of essential hypertension.23–26 However, prevention of hyperuricemia has not been shown to forestall hypertension.
An analysis of the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study27 found that the attenuation of serum uric rise by losartan accounted for 29% of the beneficial treatment effect. However, a better explanation of the treatment difference between losartan and atenolol favoring losartan in the LIFE trial probably was the lack of comparable reduction of central aortic pressure with atenolol.28 Although a small short-term study showed minimal reduction of BP within the normal range in patients with hyperuricemia treated with allopurinol, treatment of hyperuricemia has not been shown to reduce BP in patients with hypertension.29 Allopurinol is not a very favorable drug outside of its indication for prophylactic antihyperuricemic therapy because, although rare, its toxicities include a severe hypersensitivity syndrome.2
What Are the Options When a Hypertensive Patient Taking Thiazide Develops Gout?
These two cases illustrate that patients with long histories of recurrent gout and hypertension resistant to ≥3 medications tolerated thiazide with allopurinol and experienced significant reductions in BP, which would be expected from adjunctive thiazide therapy, without recurrent gout. Lowering serum uric levels to between 4.6 mg/dL and 6.6 mg/dL with antihyperuricemic agents lowers recurrence of gouty arthropathy in predisposed patients by 30%.2
Another common scenario is a patient with controlled hypertension taking thiazide who has an attack of acute gouty arthritis. Intercritical gout, the term applied to the periods between gouty attacks, may last years. In one series, 62% of patients had recurrences within the first year, 16% had recurrences in 1 to 2 years, 11% in 2 to 5 years, and 4% in 5 to 10 years19; 7% experienced no recurrences in more than 10 years. Because of the long time interval between gouty attacks, which may be mild and readily responsive to therapy, and the fact that maintenance of BP control may not be readily achieved with an antihypertensive drug substitution for thiazide, cessation of thiazide is a consideration but not mandatory depending on the clinical context.
Reduction of the dose of thiazide rather than discontinuation is also an option because drug-related hyperuricemia is dose-related. Spironolactone might be a good add-on in such situations. A small well-done study showed only a modest increase in serum uric acid in patients receiving 100 mg of spironolactone,30 and spironolactone has not been identified as a risk factor for gout. Therefore, in a patient with resistant hypertension in whom a decision to reduce thiazide leads to loss of control, 12.5 mg to 25 mg of spironolactone could be prescribed with a follow-up of serum uric acid.31
A reasonable strategy for dealing with an attack of gout for a patient taking thiazide for hypertension is treatment with 1 or 2 days of a nonsteroidal anti-inflammatory drug or colchicine, while continuing thiazide therapy pending early follow-up. Uric acid level obtained during an acute attack may be spuriously low2 and may mislead therapy. Depending on the severity of the gouty attack, the level of uric acid following resolution of the episode, and the degree of difficulty in achieving BP control, treatment options listed in the Table can be discussed in calmer surroundings outside of the emergency department or urgent care clinic where gouty flares are often evaluated.
Table Table. Management Options for Hypertensive Patients With Acute Gout Taking Thiazide Based on Clinical Context
aLifestyle measures: weight reduction if overweight, alcohol avoidance, low purine diet. bAvoid initiating uric acid–lowering therapy during inflammatory phase of acute gout.
Hypertension controlled on 1 or 2 medications
Attack of gout, 0 or 1 prior attacks in past year
Consider alternative antihypertensive drug if serum uric acid >6 mg/dL
Attack of gout, ≥2 prior attacks in past year
Change to alternative antihypertensive drug
Hypertension controlled on ≥3 medications
Attack of gout, 0 or 1 prior attacks in past year
Thiazide continuation with consideration of dose reduction