Hyperuricemia Primer
Serum urate, produced when purines are metabolized, is eliminated from the body in the form of uric acid. Uric acid may have a significant physiological function, acting as an antioxidant, a role in which it is as effective as ascorbate. However, when the balance of purine nucleotide synthesis, breakdown and recycling, and elimination becomes unbalanced, hyperuricemia may result.
Primary Gout
The development of hyperuricemia is straightforward: uric acid builds up in the blood when the body increases its production of uric acid, or the kidneys do not eliminate it efficiently, or both. Overproduction is responsible for 10% of cases of primary gout; underexcretion for 90%.
Production may increase through endogenous (cell turnover and metabolism) and/or exogenous (dietary) factors.
Reduced elimination suggests a renal cause because most uric acid is eliminated via the kidneys. (Enteric elimination is the next most significant means of elimination, and it can increase in response to hyperuricemia.) Genetic factors may play a role for individuals with hyperuricemia and reduced renal clearance of uric acid. Most subjects with gout have lower clearance rates for uric acid, which may be measured directly or as a ratio of urate to inulin clearance (Curate/Cinulin ratio). However, most gout and hyperuricemia patients show no other renal function abnormality.
Though 90% of primary gout cases are triggered by difficulties in urate elimination, the exact mechanism behind lower uric acid clearance rates has not been established. Known factors that may affect urate clearance include the volume of urine flow (excretion is increased by > 25% if urine flow is doubled), the level of estrogens (as evidenced by lower serum uric acid concentrations in women before menopause and in children), surgery, and autonomic nervous system function.
Secondary Gout
Secondary gout can also be attributed to a reduction in the glomerular filtration rate causing a decrease in the excretion of uric acid by the kidney. This can be seen in certain kidney disorders or with medications such as diuretics that interfere with urate excretion.
Pathophysiology of Gout
The serum urate saturation point is approximately 6.8 mg/dL. Although several biochemical factors impact whether an individual experiences a flare at this point. Risk for the development of gout symptoms increases steadily at concentrations higher than 6 mg/dL. In a patient with hyperuricemia, urate can crystallize as monosodium urate monohydrate (MSUM) and may form deposits in the synovial membrane. An acute gout attack can occur when there is a marked inflammatory response to these crystal deposits.
overproduction/underexcretion >> excessive urate >>
urate crystals >> phagocyte activation >> inflammation
In broad terms, gout attacks are symptoms of the inflammatory response to monosodium urate crystal deposition. However, we do not have a complete understanding of the factors that lead to an attack. Supersaturation of serum urate is the underlying cause, but not sufficient in and of itself to cause precipitation. Similarly, the presence of crystals alone may be insufficient to elicit an inflammatory response.
During a recent presentation to primary care physicians, Dr. Ralph Schumacher discussed the pathogenesis of gout. Watch and download Dr. Schumacher’s presentation. Watch Video
Asymptomatic patients may have crystals in the synovial fluid and neutrophils within the synovium—diagnostic clinical signs of gout. Additionally, microtophi have been identified in areas of the synovium during the early stages of gout attacks. These observations are consistent with a continuum of inflammatory response between intercritical periods and acute attacks in chronic gout.
The inflammatory response may be initiated when microcrystals shed from microtophi adjacent to the joint space and enter the synovial fluid. In addition to their location, the size of the crystals may be a significant factor. New microcrystals that form and those that break off from larger crystals appear to be essential to the process. This observation may also explain why aggressive antihyperuricemic therapy may trigger a mobilization flare: it can cause larger crystals to dissolve and release microcrystals. Thus, prophylactic treatment with anti-inflammatory drugs has been recommended for 6 months or longer after the start of antihyperuricemic therapy, while urate levels are in flux.
Many biochemical mediators are involved in the inflammatory response. Monocytes play a large role, releasing proinflammatory cytokines and attracting neutrophils to the site, thus amplifying the response. Phagocytes resident within the synovium may be insufficient to trigger an immune response to microcrystals. However, the entry of new monocytes and neutrophils may shift the immune balance, leading to the gout flare.
Our Gout Multimedia section features a video presentation on the primary issues of hyperuricemia in gout. Learn More