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Tufts OpenCourseware
Author: Ronenn Roubenoff, M.D.

1. Introduction

Most patients with gout present with intermittent attacks of acute, intense monarthritis, usually of the great toe. Gout, the most common inflammatory arthritis in men, is caused by uric acid (monosodium urate) crystals deposited in the joint. Other inorganic crystals, such as calcium pyrophosphate dihydrate, can cause a monarthritis that mimics gout and is known as "pseudogout."

Gout has fascinated healers since antiquity. The ancients marveled at gout's explosive onset and the bacchanalian habits of some of its victims. Investigators in the 19th century explained gout's proclivity for certain people (see "Clinical Features" below), and made gout one of the few rheumatic diseases whose pathogenesis is now almost fully understood. Current knowledge allows the physician to recognize when a patient with monarthritis has gout and not some other condition, to identify the few patients with gout who have an important underlying metabolic disorder, and to treat effectively this disabling and very painful arthritis. The physician should also be aware that more than one third of patients with gout have hypertension, and that men with gout have a high prevalence of vascular disease.

1.1. Learning Objectives

  1. Describe the two main metabolic abnormalities that lead to hyperuricemia
  2. List at least 3 risk factors for gouty arthritis
  3. Describe the various stages of gout, and explain how treatment varies by each stage of disease
  4. Describe the pathogenesis of pseudogout and its clinical manifestations

2. Clinical Features

Gout is typically an episodic monarthritis, although about 10% of patients have polyarticular gout, with three or more joints involved. Men are affected eight times as often as premenopausal women, but after menopause women narrow the male:female ratio to 3:1. Gout usually begins after age 30 in men and 45 in women. Onset before these ages should raise suspicion of a primary metabolic disturbance (see "Pathogenesis" below).

The pain of acute gout was perhaps best described by Thomas Sydenham in the 17th century 1:

The victim goes to bed and sleeps in good health. About two o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. This pain is like that of a dislocation....Then follow chills...and a little fever. The pain...becomes more intense...Now it is a violent stretching and tearing of the ligaments now it is a gnawing pain, and now a pressure and tightning. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of the bedclothes nor the jar of a person walking in the room. The night is passed in torture....

1 Thomas Sydenham: The Works of Thomas Sydenham, Translated from Latin by RG Latham, vol II. London, Sydenham Society, 1850, p 124.

Over half of patients present with podagra, an acute inflammation of the first metatarsophalangeal (MTP) joint, and 75 -- 90% of patients eventually develop podagra. The first MTP joint is thought to be most susceptible to gout because this joint is very prone to trauma and to cooling, both of which reduce the solubility of uric acid. After the first MTP, acute gout most commonly involves the ankles, knees, and instep, but it can also affect the wrists, elbows, and small joints of the hands and feet. Large joints such as the hips, shoulders, and vertebral joints are rarely involved. Acute gout can also cause tenosynovitis (inflammation of tendon sheaths) and bursitis. Uric acid crystals can be deposited in the skin; particularly around the foot, these crystals can cause a sterile cellulitis with intense erythema and warmth, even in a person who has no gouty joints.

As Sydenham wrote, gout generally begins explosively, although some patients describe a series of small bouts leading up to a full scale attack. Untreated gouty arthritis lasts from days to weeks; minor bouts can resolve spontaneously in a few hours. Early in the disease course, the only abnormality that joint x-rays show is soft tissue swelling. If left untreated, acute gout can evolve into a deforming, chronic polyarthritis that may be difficult to distinguish from rheumatoid arthritis.

3. Diagnosis of Acute Gout

The three most common causes of monarthritis are infection, trauma, and gout. The hot, red joint looks similar in all three conditions. The way to differentiate them is by analyzing synovial fluid obtained through arthrocentesis. Gout can be documented only when examination of the joint fluid, ideally under a polarizing microscope, shows intracellular or extracellular uric acid crystals. These crystals may be present during the intervals between attacks. They are needle shaped and 3 20 µ long. They are negatively birefringent: They look yellow when lying parallel to the red compensator on a polarizing microscope, and blue when perpendicular. The calcium pyrophosphate crystals of pseudogout are positively birefringent yellow when perpendicular to the axis of the red compensator, and blue when parallel. These light properties are the surest way to distinguish gout from pseudogout. A useful mnemonic for the refringent properties of crystals is that "yellow," "parallel," and "allopurinol" all have two "L's," and all apply to gout.

A first attack of monarthritis is always an indication for arthrocentesis, even if the clinical situation is typical for gout. Synovial fluid obtained by arthrocentesis both confirms gout and allows for cultures to test for infectious arthritis. If there is enough fluid, a cell count is useful, though not mandatory. Most patients with gout have elevated synovial leukocyte counts, but the reported range is wide, from 2,000 to >100,000 cells/cu mm. Gout and infection can co-exist in a joint, and joint infection can precipitate a gout attack. Thus, even if crystals are found, the physician should test for infection. Possible infection is also the only reason to repeat the arthrocentesis if a patient has further gout attacks. Infection should be suspected in patients who have diabetes or a fever or high peripheral white blood cell count.

4. Pathogenesis of Gout and Hyperuricemia

Gout is caused by uric acid crystals deposited in the joint space. Once phagocytosed by polymorphonuclear leukocytes or macrophages, the crystals initiate an immune response, recruiting white blood cells. The white cells release lysosomal enzymes, as well as tumor necrosis factor and interleukin 1, which recruit more white cells. In addition, ingested uric acid kills the phagocytosing cells, leading to release of the uric acid crystals and more proteolytic enzymes, and thus reinforcing the inflammatory condition. The crystals become progressively less inflammatory after several cycles of ingestion and release, and the inflammation relents over 10--14 d. With repeated gout attacks, however, the lysosomal enzymes destroy cartilage and erode the joint.

Hyperuricemia is a serum uric acid level above the saturation point at 37°, about 7.0 mg/dl. People who develop gout have had hyperuricemia for years or decades, and the great majority have elevated uric acid levels at the time of the attack. However, only a fraction of persons with hyperuricemia develop gout. The patients who develop gout may be those whose uric acid solubility in certain joints is reduced by cool temperature (as found in the toe), lead in the synovial fluid, or trauma. The trauma can range from the simple stubbing of a toe to abdominal surgery.

The serum uric acid level is influenced by how much uric acid the body produces, how much uric acid the patient eats, and how much uric acid the kidney excretes. Uric acid can be overproduced in two ways: 1) Uric acid is a metabolic byproduct of purines, which are essential components of DNA synthesis. Psoriasis, lymphoma, polycythemia, and any other disorder that causes rapid cell turnover can produce hyperuricemia and, eventually, gout. 2) Rare patients have intrinsic enzyme defects in purine metabolism, leading to hyperuricemia and gout.

Uric acid, or its precursor purines, are part of a normal diet. Particularly rich in purines are sardines and organ meats like liver, kidney, and sweetbreads. Eating too much of these foods can cause hyperuricemia. Together, overproducing and overeating uric acid account for 15% of cases of gout.

The remaining 85% of cases are caused by too little urinary excretion of uric acid. Most patients with impaired renal clearance of uric acid have no other signs of renal insufficiency. Their serum creatinine and urinalysis are normal. However, patients who have frank renal insufficiency clear uric acid poorly. Renal excretion of uric acid is decreased by drugs, especially thiazide or loop diuretics, or aspirin in doses of <2.5 g/d.

Some factors contribute to gout in more than one way. For example, lead can cause the kidneys to underexcrete uric acid, and can also directly reduce uric acid's solubility in synovial fluid. The gout resulting from lead toxicity is called "saturnine gout." In the past, saturnine gout developed chiefly in people who drank alcohol, especially sherry shipped in lead lined casks. More recently, saturnine gout has been seen in drinkers of illegal "moonshine" whiskey distilled through lead lined stills. By itself, excessive alcohol causes hyperuricemia by both increasing uric acid production and inhibiting renal uric acid excretion.

In trying to understand why a patient has developed gout, the physician should review the patient's medical history (eg, renal failure), diet (eg, alcohol and high purine food intake), medications (eg, aspirin, diuretics, cyclosporine), and exposure history (eg, moonshine). The physical examination may also help identify conditions that overproduce uric acid (eg, polycythemia). The physician should suspect an underlying enzyme defect in purine metabolism if gout begins in someone younger than 30, but most patients with these defects manifest metabolic disorders long before they develop gout. The serum creatinine and complete blood count help identify patients who have occult renal or hematologic disorders.

5. Renal Manifestations of Hyperuricemia

The most common renal consequence of hyperuricemia is formation of kidney stones. About 5 10% of all renal stones are pure uric acid; uric acid can also serve as a nidus around which calcium stones form. Unlike calcium or mixed calcium uric acid stones, pure uric acid stones are radiolucent.

Acute uric acid nephropathy is a consequence of cytotoxic chemotherapy in patients who have leukemia or lymphoma with a large tumor burden. If much of the tumor dies all at once, the load of uric acid overwhelms the renal tubules, causing an acute obstructive uropathy and renal failure. Pre treatment with allopurinol, which inhibits the formation of uric acid, has largely eliminated this problem.

Chronic uric acid nephropathy, resulting from years of uric acid deposition into the kidney, rarely causes progressive renal insufficiency. Hypertension, which occurs in over one third of patients with gout, poses a much greater threat to the kidneys and the vascular system. Therefore, long term management of gout requires at least as much attention to the blood pressure as to the uric acid.

6. Management

Although gout is one of the most treatable of medical conditions, attacks can be provoked or prolonged by incorrect therapies. The single most common mistake that physicians make is failing to separate the treatment of the acute gouty attack from treatment of the hyperuricemia. Treatment of acute gout should focus on eliminating the inflammation rather than lowering the serum uric acid. Paradoxically, drugs that suddenly lower the serum uric acid can actually exacerbate an attack. Therefore, the physician should consider treating hyperuricemia only after the attack has resolved.

6.1. Management of Acute Gout

For most patients with acute gout, the treatment of choice is a nonsteroidal anti inflammatory drug (NSAID). Many nonsteroidals are effective. The one used most often is indomethacin, which usually greatly relieves the discomfort within 2 d and eliminates it by 5--10 d.

If patients cannot tolerate NSAIDs because of hypersensitivity, fluid overload, or pre existing peptic ulcer disease or renal insufficiency, their two alternatives are colchicine and glucocorticoids. Colchicine is effective, but it has been relegated to secondary status by its toxicity. Many patients taking the high oral doses of colchicine needed to abolish an acute gout attack develop unacceptable side effects, particularly nausea and diarrhea. While patients who cannot take oral medications may respond to intravenous colchicine, intravenous administration should be discouraged because it can have life threatening side effects, including renal or bone marrow failure. Patients with pre-existing kidney or liver disease should never be given intravenous colchicine.

Another problem with colchicine is timing. The drug is most effective when given during the first 24--48 h of an attack, presumably because it interferes with leukocyte migration and cytokine production. Colchicine no longer works once the inflammation is fully established. In contrast, NSAIDs often work even when started several days into an attack.

The second alternative to NSAIDs is glucocorticoids, which can be given orally, intravenously, or by intra articular injection. Since gout usually affects one joint, the most effective way to control an attack often within a few hours is to inject a long acting glucocorticoid directly into that joint. A glucocorticoid injection should be given only after the joint fluid has been cultured to exclude septic arthritis masquerading as gout, and patients must be followed carefully for complications such as joint infection. Individuals with multiple inflamed joints should be given a short, generous course of oral glucocorticoids. Patients who cannot take oral medicines may be treated intravenously.

6.2. Management of Hyperuricemia

Once the acute gouty attack has resolved, the physician can consider treating the underlying hyperuricemia. There is no reason to treat hyperuricemia in a person who has no history of gout or uric acid kidney stones. Whether patients with a history of gout should have their hyperuricemia treated depends in large part on their risk of having another attack. Only half of patients who have had one attack of gout will have another within 5 y. Therefore, few patients who have had one attack should be started on life long therapy, particularly if the uric acid is only minimally elevated or the person has other readily modifiable risk factors such as regular use of low dose aspirin. However, treatment is indicated for any patient who has had multiple attacks in the past year, and anyone who has had a uric acid kidney stone. Treatment should be considered after a single attack in a patient who is at high risk for recurrence because of renal insufficiency, congestive heart failure necessitating long term diuretics, or a very high serum uric acid (>12 mg/dl).

Hyperuricemia can be treated by either a uricosuric agent or allopurinol. Uricosuric agents work by enhancing renal excretion of uric acid. The two uricosuric agents available in the United States are probenecid and sulfinpyrazone. (Patients taking these drugs must be urged to drink at least a quart of fluid a day, to prevent the formation of uric acid kidney stones.) Allopurinol works by inhibiting the enzyme xanthine oxidase; this inhibition reduces production of uric acid and increases production of xanthine, which is many times more soluble than uric acid and is readily excreted.

Which drug to give depends largely on whether patients overproduce or underexcrete uric acid. The physician makes this distinction by measuring how much uric acid patients excrete in the urine over 24 h, while eating their usual diet. If the 24 h uric acid excretion is <700 mg, patients are underexcreters and may first be treated with a uricosuric agent. If the excretion is >1,000 mg, patients are overproducers who require allopurinol. Patients who produce 700 to 1,000 mg of uric acid a day are in a "gray zone," and may be treated with either type of drug.

In certain situations, allopurinol should be given regardless of how much uric acid the patient excretes. First, allopurinol is indicated for anyone who has had a uric acid kidney stone. Uricosuric agents should not be given, because they move more uric acid into the kidneys. Second, allopurinol is indicated for patients who have renal insufficiency. Since uricosuric agents work through the kidney, they are not effective in these patients. Third, allopurinol is the choice for patients who have developed tophi (see "Treatment of Chronic Tophaceous Gout" below), because these people have a very high total body uric acid load. Lastly, allopurinol is the alternative when uricosuric agents have not worked.

Allopurinol should be used cautiously, especially in the elderly and in people with reduced renal or hepatic function, because the drug's main metabolite, oxypurinol, has a very long half life. Allopurinol toxicity can cause fever, rash, eosinophilia, and hepatic and renal failure that can, albeit rarely, prove fatal. No one has ever died of gout, but patients have died from complications of allopurinol treatment most often people with renal insufficiency who are receiving full doses. These complications underscore the importance of not treating asymptomatic hyperuricemia.

When used properly, however, allopurinol is usually safe and effective. As with the uricosuric agents, the allopurinol dose should be built up slowly over several weeks. Patients must be warned that if they develop a rash they should stop taking the drug and call their physician immediately. If for any reason the patient's renal function deteriorates, the dose should be reduced. Allopurinol should be used cautiously in patients taking the purine derivative azathioprine, whose action is greatly potentiated when xanthine oxidase is blocked.

Whether patients take a uricosuric agent or allopurinol, they also need small doses of oral colchicine, because treatment that disturbs body uric acid stores paradoxically increases the frequency of gout attacks. After uric acid levels have fallen to normal, the colchicine can be stopped. Colchicine has no effect on serum uric acid levels, but it reduces the chance that uric acid crystals will trigger an attack. Most people can tolerate long term small doses of colchicine. Rarely, however, chronic low dose colchicine causes a myopathy that mimics polymyositis. This complication is limited to patients who are over age 60 and have a serum creatinine >2.0 mg/dl.

6.3. Management of Chronic Tophaceous Gout

Tophaceous gout (a tophus is a subcutaneous deposit of uric acid) develops after an average of 10 years of untreated or inadequately treated gout. Over this time, gout may evolve from an intermittent, intense monarthritis of the foot to a chronic, deforming polyarthritis, often most strikingly affecting the hands. This arthritis can mimic rheumatoid arthritis, although it is usually less symmetric. The radiologic hallmark of tophaceous gout is large, well demarcated erosions without joint space narrowing ("rat bite erosions"). Tophi may be found in and around joints, bursae (especially the olecranon), tendons (especially the Achilles and infrapatellar), and the extensor surfaces of the forearms. Less commonly, tophi arise in the cardiac valves, cornea, sclera, nasal cartilage, and pinna of the ear. The diagnosis is confirmed when needle aspiration or spontaneous rupture of a tophus elicits a white, chalky material that microscopy shows to be full of uric acid crystals. All non allergic patients with tophi should take allopurinol.

7. Calcium Pyrophosphate Dihydrate (CPPD) Deposition Disease

Deposition of calcium pyrophosphate dihydrate (CPPD) crystals in joints can cause four forms of arthritis, which together are known as CPPD deposition disease. One form so closely resembles gout in its intensity and acuteness of onset that it is called "pseudogout". Like gout, pseudogout is often precipitated by surgery. However, the two conditions tend to affect different joints: What the great toe and ankle are to gout, the knee and wrist are to pseudogout. Pseudogout is about half as common as gout, and accounts for up to 20% of CPPD disease. Pseudogout occurs about equally often in men and women, and usually begins after age 65; gout generally begins before 60. Occasionally patients have both gout and pseudogout.

A second, unusual form of CPPD mimics rheumatoid arthritis in that it affects chiefly the wrist and metacarpophalangeal joints, though usually with less striking inflammation than in rheumatoid arthritis. The third and most common form of CPPD mimics osteoarthritis, although unlike osteoarthritis it most often affects the knees and shoulders. The fourth and rarest form produces x-ray changes resembling a Charcot joint, with evidence of bone fragmentation associated with extensive, bizarre hypertrophic bony changes. A true Charcot ("neuropathic") joint develops when neuropathy, usually from diabetes, tabes dorsalis, or syringomyelia, has disrupted position sense and pain sensation, thereby promoting unrecognized repetitive joint trauma.

All forms of CPPD in symptomatic patients are diagnosed by characteristic x-ray findings or demonstration of CPPD crystals in the synovial fluid of involved joints. X-rays of affected joints typically show linear calcifications in the cartilage, called chondrocalcinosis. "Chondrocalcinosis" should not be used interchangeably with "CPPD" since many people, especially the elderly, have the x-ray abnormality but no clinical disease. The most common sites of chondrocalcinosis are the knees, triangular ligament of the wrist, and pubic ramus. X-rays of any of these areas offer the best chance of finding chondrocalcinosis to support a diagnosis of CPPD. The definitive diagnosis of CPPD, like that of gout, rests on arthrocentesis. The joint fluid must contain intracellular or extracellular rhomboidal crystals that are positively birefringent, looking blue when parallel to the axis of the red compensator on a polarizing microscope.

CPPD usually occurs spontaneously, but the physician should be aware of its association with certain metabolic conditions, especially hyperparathyroidism and hemochromatosis. CPPD can also be inherited as an autosomal dominant arthropathy.

The inflammation of CPPD is thought to begin when calcium pyrophosphate crystals are shed from joint cartilage into the synovial fluid. Like the uric acid crystals in gout, CPPD crystals are inflammatory. They are phagocytosed by polymorphonuclear leukocytes, which release lysosomal enzymes that damage the joint, while chemotactic factors recruit more white cells.

All forms of CPPD are treated with a nonsteroidal anti inflammatory drug or colchicine. Intra articular corticosteroids are also useful for managing attacks. Colchicine has been shown to prevent pseudogout attacks and improve the more chronic forms of CPPD. However, there is no way to reduce the pyrophosphate concentration in the joint, in the same way that allopurinol or uricosuric agents remove uric acid from the body. A patient presenting with CPPD should be evaluated for hyperparathyroidism and hemochromatosis.

8. Summary

  • Gout and pseudogout are common causes of acute monarthritis. Gout most often attacks the great toe; pseudogout, the knee or wrist.
  • The diagnosis of gout rests on finding uric acid crystals in the synovial fluid, and that of pseudogout on finding calcium pyrophosphate dihydrate crystals.
  • In a few patients, gout is the first manifestation of a disorder such as polycythemia, and pseudogout is a manifestation of hyperparathyroidism or hemochromatosis.
  • The treatment of acute gout and the treatment of hyperuricemia are completely separate issues. Treatment of hyperuricemia should be considered only after an acute attack has resolved.
  • One third of patients with gout have hypertension, which should be treated whether or not the gout needs treatment.

9. Suggested Reading

  • Choi HK, Mount DB, Reginato, AM: Pathogenesis of Gout. Ann Intern Med 2005;143:499-516.
  • Campion EW, Glynn RJ, DeLabry LO: Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study. Am J Med 1987;82:421.
  • Roubenoff R et al: Incidence and risk factors for gout in white men. JAMA 1991;266:3004.