Gout is a disease that results from a derangement in uric acid metabolism, causing elevation of serum uric acid levels and deposition of urate crystals in joints and other tissues. Uric acid is the end product of purine metabolism in humans. At physiological pH, uric acid is 98% ionized and is present mainly as urate ion. In extracellular fluids, uric acid exists as a solution of monosodium urate, which has very low solubility and can precipitate very easily.
Normal uric acid metabolism
Purine nucleotides are components of nucleic acids; they are also intimately involved in energy transformation and phosphorylation reactions and act as second messengers.
There are three sources of purines in man:
- The diet.
- Degradation of endogenous nucleotides.
- De novo synthesis.
Urate is excreted by the kidney and the intestine. In the intestine, urate is metabolized to carbon dioxide and ammonia by bacterial action ("uricolysis").
Urate handling by the kidney is complex. It is filtered by the glomeruli and then almost completely reabsorbed in the proximal tubules; in the distal tubules, both reabsorption and secretion occurs. Net urate clearance is only 10% of the filtered load. If the filtered load is increased in normal subjects, excretion is increased. In patients with renal failure, however, urate excretion decreases with decrease in glomerular filtration rate, and the serum level rises.
Dietary purines account only for 30% of excreted urates.
The metabolic pathways leading to endogenous uric acid synthesysis are mediated by several enzymes in a complex fashion. There is de novo synthesis from ribose-1-phosphate to inosine as well as a secondary "salvage" pathway which leads to the production of uric acid by converting guanine and adenine bases into inosine, which is in the main pathway of xanthine production. Xanthine is oxidized by xanthine oxidase to uric acid.
Uric acid is the last stage in purine degradation in humans, because all primates lack the enzyme (uricase) to convert uric acid into allantoin.
Uric acid in serum
Serum concentrations of uric acid are higher in men than in women (gout is much more common in men), tend to rise with age, and tend to be higher in individuals of higher economic classes and in obese people. There is considerable variation in serum urate concentrations between different ethnic groups.
Although the mechanism of gout has not been completely elucidated, the likelihood of gout increases with increased serum urate levels. However, only a small proportion of individuals with elevated uric acid levels develop gout (in the Western Hemisphere, it is estimated that 10% of the population has high uric acid levels, but only 0.5% develop gout). The solubility of urate decreases with decreasing temperature, explaining the increased incidence of gout in peripheral joints (which are cooler).
Hyperuricemia can be caused by increased formation of uric acid, by reduced excretion by the kidneys, or by a combination of both mechanisms.
Increased formation of uric acid occurs with:
- High dietary intake.
- Increased purine synthesis
- Inherited (several genetic mechanisms have been described)
- Increased nucleic acid turnover
- Myeloproliferative disorders (e.g., leukemias)
- Secondary polycythemia.
- Chronic hemolytic anemias.
- Cytotoxic drugs.
Reduced excretion of uric acid by the kidneys occurs with:
Chronic renal disease
- Increased organic acid concentration in blood
- lactic acid
- acetoacetic acid
Gout may be either primary (unknown cause; "idiopathic"), or secondary (due to a condition known to cause hyperuricemia).
Pathogenesis of gout
- Sodium urate crystals precipitate in tissues (classically within joints) of hyperuricemic patients.
- The crystals exert chemotactic action on neutrophils (PMNs) and are phagocytized by macrophages.
- PMNs are attracted by the crystals. They temporarily phagocytize the crystals, and subsequently release them. (You have to remember that neutrophils are the first cells to respond in the inflammatory process and that they have phagocytic properties)
- The neutrophils are lysed, releasing their lysosomal enzymes, which became activated and produce acute inflammation and tissue injury locally, e.g. within joints.
- Macrophages also phagocytize crystals. They secrete Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a), which release of proteases from the synovial and cartilaginous cells of the joints. The proteases in turn add their deleterious action to the destructive action of the lysosomal enzymes of the neutrophils, resulting in destruction of joint tissue.
Even though this theoretical chain of events appears plausible, certain phenomena remain unexplained in the pathogenesis of gout:
- What initiates crystallization of urates in joints?
- Why are certain peripheral joints preferentially involved?
- Why isn't there a perfect correlation between high levels of uric acid and the occurrence of gouty arthritis?
Anatomic Pathology Changes
Tissue injury is due to the deposition of crystals in joints. The characteristic pathological changes in gout are:
- Acute arthritis: PMN leukocytes phagocytized urate crystals. The synovium is congested and contains histiocytes, lymphocytes and plasma cells. When the crystals resolubilize, the attack remits.
- Chronic tophaceous arthritis: This is the result of repetitive attacks. Tophi (singular "tophus") are the gross morphologic hallmark of gout. A tophus consists of central aggregates of crystals surrounded by macrophages, lymphocytes and giant cells. Tophi can be encountered in joints, in juxta-articular soft tissues, and also within the ear lobes ("pinnae") and kidneys. When they become large, they can produce severe tissue destruction and ulceration of the overlying skin.
The deposition of crystals leads to chronic inflammation in which the synovium becames hyperplastic, fibrotic and thickened. The inflammatory cells form a "pannus" (a membrane of granulation tissue covering a surface), and the enzymes released by the inflammatory cells destroy the cartilage, there are also deposits of crystals inside the bone (bone histology 1 and bone histology 2). This results in juxta-articular bone erosions which may end in ankylosis (fusion of a joint). The end result is the complete loss of joint function.
- Gouty nephropathy, characterized by:
NOTE: The uric acid crystals of gout are dissolved during routine processing, and consequently cannot usually be identified in routinely-stained tissue sections. Rather, the space previously occupied by the crystals is seen, with its collar of cells. (Special precautions have to be taken in the processing of specimens if preservation of crystals is desired.)
Acute gouty arthritis:
- Excruciating pain
- sudden onset
- lower extremity, peripheral joints
- 50% in great toe
- Joints are red, swollen and tender (mimicking suppurative/infectious arthritis).
- Frequently, there is some stress prior to attack: dietary overindulgencence, excessive alcohol intake, physical or emotional fatigue.
- Pain subsides with therapy or spontaneously after a couple of days.
- The disease may relapse even after years of quiescence.
Chronic gouty arthritis:
- Follows multiple attacks of acute gout.
- Occurs in only 10-15% of patients.
- Tophi appear in subcutaneous tissues around joints.
- Limitation of motion ranges from mild to severe.
- The soft tissue tophi are painless and nontender.
- 90% of patients develop some form of renal function impairment:
- Acute tubular necrosis.
- Patients are also prone to develop arteriosclerosis and diabetes mellitus.
- Characteristic clinical presentation.
- Elevated serum urate level.
- Microscopy of joint fluid: long needle crystals show strong negative birefrigence when examined under the polarizing microscope.