GOUT

 

Gout is a clinical syndrome caused by a group of heterogeneous diseases characterized by deposition of monosodium urate crystals in synovial fluid and joints with or without hyperuricemia, renal disease, and nephrolithiasis. Classically, the presentation is that of an acute lower extremity peripheral joint inflammatory synovitis. The most commonly affected sites are the first metatarsophalangeal joint and the ankle.

 

Epidemiology

 

Gout affects approximately 5 million Americans and has historically been described as a disease that affects men; however, it also affects women. Recent epidemiologic studies demonstrate that on average, women develop gout a decade later than men, and that female patients with gout are more likely to have renal insufficiency or to be taking diuretics. Obesity has been linked to gout, and both diseases have increased in incidence over the past two decades. Alcohol has long been recognized as a risk factor for gout, but only recently has consumption of purine rich foods such as meat and seafood has been shown to correlate positively with serum urate levels and gout. It has also been shown that eating low fat dairy products may be protective. Gouty attacks in children are so uncommon that this diagnosis should prompt an evaluation for a malignant or genetic cause.

 

Pathogenesis

 

Hyperuricemia is a risk factor for gout, but acute gouty arthritis can occur in patients with normal serum uric acid levels. Patients with serum uric acid levels greater than 7 mg/dL have a 22 percent chance of developing gout over a 5-year period, demonstrating that many patients with elevated serum uric acid levels may never have gouty arthritis.

Uric acid is the end product of purine catabolism. Humans lack the enzyme uricase, which breaks down uric acid into a more water-soluble product. When the plasma monosodium urate level exceeds its limit of solubility, it is more likely to precipitate in tissues. Hyperuricemia results from either overproduction or underexcretion of uric acid. Ninety percent of affected patients are underexcreters.

Table 161-4 presents a classification of hyperuricemia. Less than 10 percent of patients with hyperuricemia or gout excrete excessive quantities of uric acid in a 24-hour urine collection. It is usually in this group that identifiable and inherited derangements in mechanisms regulating protein nucleotide synthesis, specifically a deficiency of hypoxanthine-guanine phosphoribosyltransferase, glucose-6-phosphatase, or fructose-1-phosphatase, either partial or complete, can be found. These are genetically inherited by X-linked and autosomal recessive means (in the latter two); therefore, family history or early presentation may be a clue. The Lesch-Nyhan syndrome, well described but very rare, is an extremely severe form of hypoxanthine-guanine phosphoribosyltransferase deficiency associated with mental retardation, gout, and self-mutilation.

 

 

Uric acid underexcretion is idiopathic in patients with hyperuricemia. The anatomic appearance and physiologic function of the kidney appear normal; however, alteration of renal tubular function in these patients by many drugs can precipitate gouty attacks. These pharmacologic agents include loop diuretics, low-dose cyclosporine, and salicylates.

Precipitating causes of an acute gouty attack are not well understood. Studies have shown the presence of intracellular monosodium urate crystals in synovial fluid of asymptomatic patients, suggesting that inflammation in gout is chronic. There must be an unidentified trigger in the acute attack that incites a more robust inflammatory response. Monocytes are present and secrete cytokines, including TNF-α, interleukin 1, interleukin 6, and interleukin 8. Neutrophils are then attracted to the site as well, ingest the crystals, and release multiple inflammatory mediators, initiating further inflammation and tissue damage.

 

Clinical Manifestations

 

It is felt that gout occurs in four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout (between gouty attacks), and chronic tophaceous gout.

Patients are often asymptomatic for years, requiring no therapeutic intervention in the absence of other evidence of disease (for example, nephrolithiasis or renal insufficiency).

Acute gouty arthritis usually occurs in middle age and primarily affects a single joint in the lower extremities, the first metatarsophalangeal being the most common site of initial involvement (podagra). Clinically, the affected joint is erythematous and exquisitely tender to palpation. This may be confused with a sprain, a septic joint, or cellulites. Cytokine release can lead to fever and systemic symptoms, confounding the picture further. Further differential diagnoses include other forms of arthritis (psoriatic, reactive arthritis osteoarthritis, or RA) and pseudogout (chondrocalcinosis).

Intercritical gout describes the interval that occurs between attacks of gout, an interval of between 6 months to 2 years. As attacks continue, they tend to be polyarticular, more severe, and of longer duration. Chronic tophaceous gout describes gout where patients rarely have asymptomatic periods. Urate crystals may be found in the soft tissues, cartilage, and tendons  They have been reported in a variety of unusual places as well, including the nasal dorsum. They may be confused with rheumatoid nodules, and aspiration or biopsy may prove useful.

Laboratory Presentation and Pathology

Laboratory analysis may reveal elevated uric acid levels, but this finding is not necessary for the diagnosis. Leukocytosis and

elevated sedimentation rate are often seen during acute arthritic attacks. Accurate diagnosis rests on the demonstration of intracellular, negatively birefringent, needleshaped crystals by polarized microscopy. Histopathologic examination of a gouty tophus reveals granulomatous inflammation surrounding yellow-brown urate crystals or needle-like spaces in a radial arrangement, representing crystals dissolved during processing

 

Treatment

 

The goal of therapy in acute gouty attacks is analgesia and reduction in inflammation. The main options to choose from are the nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids. Indomethacin has been shown in randomized controlled trials to decrease pain, as has colchicine; however, the adverse gastrointestinal side effect of colchicine is often a deterrent for its use. Indomethacin can precipitate acute renal failure in patients with underlying renal disease. Corticosteroids, both oral and intra-articular, are also believed to be effective. Because patients with gout are older and often have many co-morbidities, therapy should be individualized. Treatment should continue for 7 to 10 days after the acute attack, and prophylactic therapy may be continued for 3 to 6 months.

In patients with only one gouty attack, a conservative management approach can be used. This includes avoidance of drugs that decrease the excretion of uric acid such as thiazide or loop diuretics, aspirin, pyrazinamide, or niacin. Patients should maintain adequate hydration, lose weight, control hypertension and hyperlipidemia, and make diet adjustments by decreasing purine intake. Effectiveness of limiting cholesterol, fat, meat, and alcohol has never been studied, but should be advocated to avoid the need for lifelong oral therapy.

Uric acid-lowering therapy is probably necessary in patients in whom the diagnosis of gout has been established, and who have had more than one gouty attack or are suffering from chronic tophaceous gout. It is also indicated in patients with history of gout and renal calculi, extremely high values of serum uric acid, high serum uric acid levels in the setting of a known familial history of gout (for example, where there is a known deficiency of one of the relevant enzymes previously described), and prophylaxis for patients receiving acute courses of chemotherapy.

The goal of urate-lowering drugs is to maintain the serum urate level consistently at less than 6 mg/dL. Uricosuric therapy is ideal in younger patients (age less than 60 years) with normal kidneys who are underexcreters of uric acid. Uricosurics include probenecid and sulfinpyrazone. The major risks associated with these medicines include hypersensitivity reactions and increased risk of uric acid nephrolithiasis (avoided by alkalinizing the urine). Unfortunately, most patients with gout do not fit this “ideal” situation.

For all other patients, the xanthine oxidase inhibitor allopurinol is used. It decreases production of uric acid, and is indicated for patients with nephrolithiasis, renal impairment, those who failed uricosuric agents, with myeloproliferative disorders on chemotherapy, and patients with hyperuricemia due to enzyme abnormalities. Dosages must be reduced in patients with renal failure. Twenty percent of patients taking allopurinol report side effects, and 5 percent discontinue medication as a result. Side effects include dyspepsia, headache, diarrhea, a pruritic papular eruption, thrombocytopenia, and hepatic function abnormalities. Allopurinol hypersensitivity syndrome is rare and includes fever, urticaria, leukocytosis, eosinophilia, interstitial nephritis, acute renal failure, granulomatous hepatitis, and toxic epidermal necrolysis.