Gout and Pseudogout

Synonyms and related keywords calcium pyrophosphate disease, CPPD, peripheral arthritis, sodium urate crystals, monosodium urate monohydrate crystals, MSU crystals, calcium pyrophosphate crystals, CPP crystals, podagra, hyperuricemia, primary gout, secondary gout, intermediate gout, late-phase gout, pseudogout, tophi, gouty nephropathy, gouty arthritis, first metatarsophalangeal joint pain, uric acid, increased serum uric acid, arthritis nodosa, arthritis uratica, foot pain, edema of the foot, crystal-induced arthritis, acute arthritis, lysis of polymorphonuclear white blood cells, inflammatory crystalline arthritis,

Background Gout and pseudogout are the 2 most common crystal-induced arthropathies. They are debilitating illnesses in which pain and joint inflammation are caused by the formation of crystals within the joint space. Gout is inflammation caused by monosodium urate monohydrate (MSU) crystals. Pseudogout is inflammation caused by calcium pyrophosphate (CPP) crystals and is sometimes referred to as calcium pyrophosphate disease (CPPD). Gout is the most common crystal-induced arthritis

Pathophysiology Pain and joint edema of acute arthritis in patients with gout and pseudogout are caused by an inflammatory response triggered by the lysis of polymorphonuclear white blood cells that have ingested MSU crystals or CPP crystals. MSU crystals are formed in synovial fluid when the fluid becomes supersaturated with MSU. This supersaturation can result from overproduction or reduced excretion of MSU. Many conditions and drugs have been associated with an increase in plasma (and subsequent synovial) urate levels. A genetic predisposition for the disease exists. CPP crystals are produced by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a catalytic enzyme found in vesicles that develop within osteoarthritic cartilage. A genetic predisposition exists for the condition, but any process that leads to osteoarthritis also can be associated with subsequent pseudogout

Mortality/Morbidity: Pain and edema of inflammatory crystalline arthritis is extremely debilitating. Chronic injury to intra-articular cartilage leaves the joints more susceptible to subsequent joint infections. Race: Limited data suggest an increased prevalence of gout in American blacks compared with whites; however, clinically recognized gout is extremely rare in blacks living in Africa. Diet may be linked to racial prevalence since diet has a large influence on the clinical expression of gout. Sex: For gout, the male-to-female ratio is 9:1. Age: The predominant age range is 30-60 years.

History: The history and physical examination alone cannot reliably determine the cause of new-onset acute monoarticular arthritis. Septic arthritis, gout, and pseudogout can present in very similar ways. The spontaneous onset of pain, edema, and inflammation in the metatarsal-phalangeal joint of the great toe (podagra) is highly suggestive of acute crystal-induced arthritis. This is the most common presentation of gout. Other than the great toe, the most common sites of gouty arthritis are the ankle, wrist, and knee. Consider the diagnosis in any patient with acute monarticular arthritis of any peripheral joint except the glenohumeral joint of the shoulder, in which a crystal-induced arthritis is more likely to be due to pseudogout.

The most common sites of pseudogout arthritis are the knee, wrist, and shoulder. Case reports have documented carpal tunnel syndrome as an initial presentation of pseudogout. Case reports of pseudogout forming masses in the spinal ligamentum flavum have been documented. These have lead to both single and multi-level myelopathy. Crystal-induced arthritis is most commonly monarticular; however, polyarticular acute flares are not rare, and many different joints may be involved simultaneously or in rapid succession. Multiple joints in the same limb often are involved, as when inflammation begins in the great toe and then progresses to involve the midfoot and ankle.

Fever, chills, and malaise do not distinguish cellulitis or septic arthritis from crystal-induced arthritis because all 3 illnesses can produce these signs and symptoms. A careful history may uncover risk factors for cellulitis or septic arthritis, such as possible exposure to gonorrhea, a recent puncture wound over the joint, or systemic signs of disseminated infection. Gout is also associated with hyperlipidemia, hypertension, hypertriglyceridemia, kidney failure, obesity, and insulin resistance. Social factors such as alcohol intake also increase the risk of gout.

Physical: Patients with gout or pseudogout most often present with a single joint that is hot, erythematous, tender, and affected with asymmetric edema. If inflammation is severe, desquamation of overlying skin may be present. Extra-articular deposits of MSU, known as tophi, may be seen along the Achilles tendon or on the ear helix, olecranon bursa, or prepatellar bursa. Migratory polyarthritis is a rare presentation. An inflammatory synovial effusion may be present. Although uncommon, acute gout may present with signs of carpal tunnel syndrome.

Causes: Although the pathophysiology, clinical presentation, and acute-phase treatment of gout and pseudogout are very similar, the underlying causes of the 2 diseases are very different. Acute gouty arthritis results from overproduction or reduced secretion of uric acid. Thiazide diuretics and foods that are rich in purines will increase the frequency of attacks. Many cases of pseudogout are idiopathic, but pseudogout has also been associated with aging, trauma, and many different metabolic abnormalities, the most common of which are hyperparathyroidism and hemochromatosis. Lead poisoning Hemo-proliferative disorders Renal disease

Lab Studies: Diagnostic arthrocentesis is indicated for every patient in whom a diagnosis has never been proven by joint aspiration and for those in whom a possibility of septic arthritis exists. A prior history of gout or pseudogout does not rule out the possibility of acute septic arthritis. In fact, the latter is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly. Irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours. Joint fluid analysis Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light can aid in diagnosis. In gout, crystals of MSU appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence). In pseudogout, CPP crystals appear shorter and often rhomboidal. Under a polarizing filter, CPP crystals do not change color depending upon their alignment relative to the direction of the red compensator. In crystal arthritis, the WBC count in the joint fluid is usually 50,000-100,000.

Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy. Gouty attacks are triggered by crystal formation in synovial fluid. They are not related to serum levels of uric acid. Thus, a normal serum uric acid level does not exclude the diagnosis of acute gout, and an elevated level does not prove the diagnosis. Pseudogout attacks can be triggered by many metabolic abnormalities. Thus, patients who have an initial attack of arthritis with CPP crystals should have a workup including a chemistry screen; magnesium, calcium, and iron levels; and thyroid function tests. WBC count usually is elevated. Erythrocyte sedimentation rate (ESR) usually is elevated during acute attacks. Hyperuricemia may be present but is not diagnostic. Renal uric acid excretion should be obtained in high-risk patients, including those with renal calculi, strong family history of gout, and first attack before age 25 years.

Imaging Studies: Radiographs Plain radiographs of the affected joint or joints are indicated. Radiographic lesions of chronic gout may appear as rat-bitten, sclerotic regions on the joint surfaces, with overhanging margins. Patients with new onset of acute gout usually have no radiographic findings. Patients with pseudogout usually have degenerative joint changes and may have calcifications in the soft tissues, tendons, or bursae. Bone scan reveals increased nuclide concentration at affected sites. MRI MRI is capable of detecting crystal deposits but is not part of any routine evaluation for acute arthritis. MRI can be very useful in determining the extent of the disease and may help in the differential diagnosis. MRI with gadolinium is recommended to evaluate any tendon sheath involvement and when osteomyelitis in the differential diagnosis. Large deposits of crystals may be seen in bursae or ligaments.

Procedures: Aspiration and biopsy Joint aspiration is the principal procedure used to make the diagnosis of crystal-induced arthritis and to rule out septic joint effusion. Biopsy of synovial membrane or subcutaneous nodule includes and examination with polarizing optic

Treatment - Nonsteroidal anti-inflammatory drugs (NSAIDs - Uricosuric agents -- These agents increase renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. Corticosteroids -- - These agents have anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids cause profound and varied metabolic effects Corticotropic hormones -- These agents are used in diagnostic tests to differentiate primary adrenal insufficiency from secondary adrenal insufficiency

Narcotics analgesics -- Anti-inflammatory agents and other drugs that work against the intra-articular inflammatory process may take hours or days to relieve the pain of acute crystal-induced arthritis COX-2 inhibitors -- These are a relatively new type of anti-inflammatory drug that are currently under scrutiny. By inhibition of cyclooxygenase-2, the vicious cycle of inflammation and pain caused by gout is impeded. COX-2 expression in monocytes has been suggested to be induced in response to urate crystals