why aspirin is contraindicated in acute gout?

Figure 1. Aspirin-mediated inhibition of cyclooxygenase (COX). COX enzymes exist as dimers. In the absence of aspirin (left panel), arachidonic acid (AA) that is formed by phospholipase A2 breakdown of membrane phospholipids gains access to the active site of COX via a hydrophobic channel. Metabolism of AA by COX produces an intermediate prostaglandin PGH2, which in platelets is broken down by tissue isomerases to thromboxane A2. As shown on the right panel, aspirin irreversibly inhibits COX activity by acetylation of a serine residue in the active site for COX (SER 529 in COX-1 & SER 516 in COX-2). This produces a steric hindrance that prevents AA from being metabolized. Aspirin works by the same mechanism to block COX-2 in other tissues. Adapted from Fitzgerald & FitzGerald (2013).

Figure 2. Selective inhibition of platelet COX-1 activity vs monocyte COX-2 activity measured in vitro after the addition of aspirin to whole-blood samples drawn from healthy human subjects. Bars represent Mean ±SD. Modified from Cipollone et al (1997).

Figure 2. Aspirin's bimodal dose-dependent effect on the renal clearance of urate/uric acid (UA). In patients, low doses of aspirin (75 mg-2 gm/day) cause retention of uric acid by inhibiting uric acid secretion. In contrast, high doses (>3 gm/day) increase the excretion of uric acid in the urine by inhibiting its reuptake in the proximal tubule (Yu & Gutman, 1959). While several clinical studies have confirmed the bimodal effect of aspirin on uric acid clearance, the precise transporters involved have not been clearly identified.

Aspirin is not used to treat gout flares because of the paradoxical effects of salicylates on serum urate, resulting from renal uric acid retention at low doses (<2 to 3 g/day) and from uricosuria at higher doses [33-36].

The goal of treatment during an acute gout attack is suppression of inflammation and control of pain. It is important to note, that if a patient is not on uric acid lowering therapy at the time of an acute attack – then this is not the time to initiate such therapy. However, if a patient is on uric acid lowering therapy at the time of an acute attack, it should not be discontinued.

Treatment of pain and inflammation can be achieved with NSAIDs, colchicine, or corticosteroids (systemic or intra-articular). The choice of which treatment is the right one for a particular patient should be made on the basis of the patient’s co-morbid medical conditions, other medications, and side effect profile.

Patients who have multiple episodes of acute gout attacks per year or who have tophi on exam are candidates for uric acid lowering therapy. Use of uric acid lowering agents will reduce the frequency of gout attacks and over time, reduce tophi formation, and diminish the risk of joint destruction. The following are indications for uric acid lowering therapy:

Uric acid is the end product of purine (nucleic acid component of DNA) metabolism and is produced normally by the body during tissue remodeling and breakdown. About 20% of uric acid is derived from purines ingested in food. Causes of hyperuricemia can be divided into two major categories: decreased clearance of uric acid from the kidney and increased synthesis of uric acid.

All patients should be encouraged to modify their lifestyle including limiting alcohol intake, encouraging weight loss where appropriate and decreasing food rich in purines. Co-morbid medical conditions should also be controlled including hypertension, diabetes and hyperlipidemia.

Foods High in Purines

Probenecid may be given to patients with decreased clearance of uric acid by the kidney and normal renal function. In general its use should be limited to patients under the age of 60. Probenecid acts by inhibiting reabsorption of uric acid in the proximal tubules of the kidney. Starting dose is at 500 mg to 1000 mg daily and increased to 1500 mg to 2000 mg as needed. Occasionally higher doses are needed. Probenecid may precipitate renal stone formation and good oral hydration should be encouraged. Probenecid is contraindicated in patients with renal stones (including calcium and uric acid stones) and in patients with urate nephropathy. Probenecid given inappropriately to patients with hyperuricemia due to overproduction of uric acid can cause renal stones and urate nephropathy.

Allopurinol is a well tolerated, inexpensive, and commonly used uric acid lowering agent. Allopurinol can be started at doses as low as 100 mg daily (100 mg qod if creatinine clearance < 10 cc/min) and titrated by 100 mg every 10-14 days to achieve a serum uric acid level of 4-5 mg/dl.  Liver tests, blood counts, and renal function and should be monitored while on therapy. Toxicites include rash, hepatoxicity, bone marrow suppression and severe hypersensitivity reactions. Medication interactions can occur with allopurinol, warfarin, and theophylline and levels should be monitored. Allopurinol should be avoided in patients on azathiprine, 6-mercaptopurine and cyclophosphamide because of risk for bone marrow toxicity.

In 2009, the FDA approved the use of a new xanthine oxidase inhibitor, febuxostat, for the treatment of hyperuricemia in gout. It has demonstrated a dose-dependent decreasee in serum uric acid (daily doses 80mg or 120mg). Its efficacy has been demonstrated in patients with mild or moderate renal impairment and gout. However, it can cause abnormalities in liver function tests and routine monitoring of bloodwork is recommended. Similar to allopurinol, there are interactions of febuxostat with azathioprine, 6MP, and theophylline.

Uricase is an enzyme that converts poorly soluable urate (uric acid) to the more soluable allantoin (excreted in the urine). Uricase is present in most mammals, and these mammals with uricase do not develop gout. However, humans and some primates lack uricase (because of evoluationary gene inactivation) and lack the ability to make uric acid more soluable and hence, have gout. Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who have failed conventional therapy.

Pegloticase is administered  by intravenous infusion every 2 weeks. Patients should be treated prophylactically for allergic reations to the infusion with steroids and anti-histamines and monitored closely for the development of an infusion reaction. Caution should be used in prescribing this treatment in patients with a known cardiac history.

Gout is a metabolic disorder that causes a painful and common type of arthritis. It is caused when there is too much uric acid in the blood. This is called hyperuricemia. Uric acid is a breakdown product of normal metabolism in the body and is normally excreted through urine. Buildup of uric acid results in needlelike crystals forming in the joints, soft tissues, and organs.

Cases of gout have increased in recent years. This increase is likely due to an aging population, dietary and lifestyle changes, the rising incidence of obesity, greater use of medicines, such as diuretics (water pills), all of which can lead to a high uric acid level in the body.

Metabolism of Purines

The process leading to hyperuricemia and gout begins with the metabolism, or breakdown, of purines. Purines are compounds that are important for energy. They are part of the nucleic acids (DNA and RNA) that are present in all cells of the body. Purines can be divided into two types:

The process of breaking down purines results in the formation of uric acid in the body. Most mammals, except humans, have an enzyme called uricase. Uricase breaks down uric acid so it can be easily removed from the body. Because humans lack uricase, uric acid is not easily removed and can build up in body tissues.

Uric Acid and Hyperuricemia

Purines in the liver are converted to uric acid. The uric acid enters the bloodstream. Most of the uric acid goes through the kidneys and is excreted in urine. The remaining uric acid travels through the intestines where bacteria help break it down.

The enzyme responsible for production of uric acid from purines is xanthine oxidase. This enzyme is the target of urate-lowering treatments such as allopurinol.