Pathophysiology
Gout is the most common form of inflammatory joint disease and is associated with crystal formation and inflammatory arthritis. It is one of the oldest diagnoses, leading back to Greek civilization. Today in the United States, approximately 4% of the population suffers from some form of gout.
Uric acid is the end product of purine metabolism and is produced normally by the body during tissue remodeling and breakdown. About 20% of uric acid is derived from purines ingested in food. The pain associated with gout is caused by the production of monosodium urate monohydrate crystals (MSU). Uric acid combines with sodium and water ions to form MSU crystals. The causes of hyperuricemia have been extensively studied, as have the mechanisms by which crystals initiate inflammation. MSU causes needle-like hard crystal deposits in the joints and surrounding tissue causing an inflammatory arthritis. If untreated, this disorder can lead to joint destruction and, in the case of renal uric acid crystals, renal damage. Causes of hyperuricemia can be divided into two major categories: decreased clearance of uric acid from the kidney and increased synthesis of uric acid.
The development of gout though is thought to occur when additional factors push the person over the threshold. Although the presence of hyperuricemia is essential for the formation of crystals, only a fraction of hyperuricemic patients develop gout–ranging from 2 to 36% of patients–suggesting that not all hyperuricemias will develop crystal formation.
Other than the presence of hyperuricemia, some of the risk factors that contributed to the development of gout are:
Stressors – Initial acute onset is frequently seen after trauma, illness or surgery.
Genetic and Familial – Results in primary urate overproduction.
Associated health conditions- Intrinsic renal disease, high cholesterol, high blood pressure, diabetes and heart disease may raise risk by altering renal clearance.
Medications- Diuretics can raise uric acid levels; immunosuppressants taken for rheumatoid arthritis, psoriasis, organ transplant; low dose aspirin use; and cyclosporine all reduce uric acid clearance.
Radiation and chemotherapy – Increases the production of uric acid.
Gender and age- Gout is three times more common in men than women. Estrogen is believed to give some protection to women since it is rare to see in premenopausal women. African American males have the highest incidence.
Lifestyle- Foods high in purines, such as meat and shellfish increase risk. Alcohol, especially beers, and high fructose sodas also increase uric acid synthesis
Obesity- Obese people are at a higher risk for gout, and they tend to develop it at a younger age than people of normal weight. Conversely, those who have undergone gastric bypass surgery have an increased risk.
Stages of Gout
Asymptomatic hyperuricemia usually goes undetected but may be found on routine blood work. This is the period prior to the onset of an acute attack. There are no symptoms, but blood uric acid levels are high and crystals may be forming. This is the best time to encourage diet and lifestyle changes to prevent an acute attack.
Acute gout occurs after a catalyst causes uric acid levels to spike or jostles the crystals already formed in a joint or tissue. The resulting inflammation and pain usually strike at night and intensify over the following eight to 12 hours. The symptoms ease after a few days and usually go away in a week to 10 days. Some people never experience a second attack, but an estimated 60% of people who have an acute gout attack will have a second one within a year. Overall, 84% may have another attack within three years. If the patient is not taking a uric acid lowering medication, it should NOT be started during an acute attack.
Interval or intercritical gout is the time between attacks. Patients are asymptomatic at this interval. Low-level inflammation though will continue to irritate and damage the joint (s) unless medication, diet and life style changes are instituted. Evaluation for secondary causes of hyperuricemia should be instituted during this non-critical time.
Chronic tophaceous gout develops in people with gout whose uric acid levels remain high over a number of years. Chronic gout in older adults may be less painful and can be confused with other forms of arthritis. Attacks become more frequent and the pain may never truly abate. Joint damage and the development of tophi occur, which can lead to a loss of mobility and disfigurement. With proper management and treatment, this stage is preventable.
Clinical presentation
Symptoms of gout include the following:
Severe pain in the large joint of the great toe (podagra) is the initial symptom in 50% of gout cases.
Attacks begin abruptly in the evening or early morning and typically reach maximum intensity within 8-12 hours. Residual discomfort may last from days to weeks.
Nodules (tophi) developing from subcutaneous lumps of crystals in the hands, elbows, knees, toes, or ears may appear without pain and may become disfiguring
Arthritic symptoms in other sites such as the instep, ankle, wrist, finger joints, and knee or elbow.
Many different joints may be involved simultaneously or in rapid succession.
Tenderness to even light touch and swelling of the affected joint. The joint will be warm to the touch.
Low grade fever, chills and headache
Red to purple discoloration of the joint and surrounding tissue.
Decreased range of motion and mobility may occur as the disease progresses.
Itching and peeling of the skin around the joint can occur following an acute attack.
Without treatment, attacks can involve more proximal and upper-extremity joints, occur more often, and last longer.
In some cases, eventual development of chronic polyarticular arthritis that can resemble rheumatoid arthritis.
Diagnosis
Studies that are helpful in the diagnosis of gout include serum uric acid levels, though hyperuricemia is not diagnostic of gout. Although hyperuricemia is not a universally accepted definition, it is generally defined as serum urate concentration in excess of 6.8 mg/dl. Although hyperuricemia is listed as one of the criteria and is a risk factor for developing gout, serum uric acid levels can be normal during an acute flare of gout. Therefore, it is recommended that those levels be drawn again about 2 weeks after the acute attack has subsided.
Joint aspiration and synovial fluid analysis that show uric acid crystals are diagnostic of gout. Cultures of the synovial fluid will be negative for bacterial growth. A complete renal and liver profile including a 24-hour urinary uric acid test needs to be included to insure the proper medication is prescribed. Blood studies, including white blood cells with differential, may show increased neutrophils activated by crystals. Typical inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein can be elevated but lack diagnostic specificity. Triglyceride, high-density lipoprotein, and glucose levels are need as baseline evaluation prior to treatment.
Plain radiographs may show erosions with overhanging edges that are generally considered characteristic for gout though also found in other diseases. Ultrasound findings show a “double-contour” sign, consisting of an irregular line of MSU crystals on the surface of articular cartilage. “Wet clumps of sugar,” representing tophic material, may be seen with bony erosions adjacent to tophaceous deposits. Computed tomography (CT) and magnetic resonance imaging (MRI) is recommended with tendon sheath involvement and when osteomyelitis is in the differential diagnosis. It is important to differentiate tophaceous gout from rheumatoid nodules. In the upper extremities, for example, RA nodules are typically found on the extensor surface of the forearm, and tophi are usually located in the bursa of the elbow. Furthermore, tophi are hard, painless, and irregular, and can erode and drain a chalky substance.
Treatment
Gout is managed in the following three stages: Treating the acute attack, providing prophylaxis to prevent acute flares, and lowering excess stores of urate to prevent flares of gouty arthritis and the prevention of tissue deposits of urate crystals. Because it is impossible to predict which patients with asymptomatic hyperuricemia will develop gout, asymptomatic hyperuricemia is not usually treated with medication.
Acute treatment of gout is directed at relief of the pain and inflammation. Agents used include nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, and should be started at the onset of symptoms. Studies on the use of ice vs heat have shown that cooling of the joint may give some relief initially but deceased temperatures increase crystal formation. Corticosteroids should be used in the treatment of patients in which NSAIDs are contraindicated.
Corticosteroids (prednisone) can be taken by mouth or injected into the intra-articular space to relieve the pain and swelling. They can also be injected intravenously if the attack does not respond to other medications or if multiple joints are affected. Similarly, injection of adrenocorticotropic hormone (ACTH) will stimulate the body to produce corticosteroids naturally. Corticosteroids and ACTH usually start working within 24 hours of administration. These drugs may also be used in combination with medication that directly lowers the serum uric acid levels.
Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack is controlled. Exceptions are in patients with renal compromise due to an extremely high uric acid load. After the acute event, management of gout is focused on lowering uric acid levels. Colchicine, though once commonly used, can reduce uric acid levels but has several drug interactions and serious side effects that make it less widely used. Because these agents change serum and tissue uric acid levels, they may precipitate acute attacks of gout. This undesired effect may be reduced by prophylaxis with NSAIDs and/or low dose steroids.
The drugs listed below all remove uric acid through renal excretion or decreased uric acid production:
Allopurinol is a xanthine oxidase inhibitor (XOI) that reduces the production of uric acid. It is often prescribed at a low daily dose and is titrated until desired effect. In rare cases, allopurinol can cause a severe allergic reaction.
Febuxostat may be used in patients who cannot tolerate allopurinol or those with renal disease. Dosage is also titrated to serum uric acid levels.
Probenecid acts on the kidneys to eliminate uric acid by inhibiting reabsorption of uric acid. The medication is taken daily and may be combined with antibiotics to boost effectiveness.
Pegloticase is used when standard medications are refractory. Pegloticase reduces uric acid quickly and to lower levels than other medications. The drug is administered every two weeks by intravenous (IV) infusion. Side effects can include infusion reactions, gout flares, nausea, bruising, sore throat, constipation, chest pain and vomiting.
Lesinurad is used with a xanthine oxidase inhibitor (XOI), such as allopurinol or febuxostat, to enhance the effects for people whose gout is not controlled by other drug regimens. Lesinurad may also increase the risk of cardiovascular events.
Anakinra has proven effective in critically ill patients who either have not responded or are not candidates for other treatment therapies. Renal failure patients appear to tolerate this medication well. The off label use of this drug has been very effective in relief management but has a very short half-life and needs to be given subcutaneously. Significant flare ups have been seen post treatment. Leukopenia is the major side effect.
Tophi can be drained or allowed to rupture on their own and treated with clean bandaging. Drainage is usually indicated only to increase range of motion. Radial excision is rarely indicated. Tophi of the eye should be treated by an ophthalmologist and monitored for reoccurrence.
Nonpharmacological measures include the reduction or avoidance of purines that result from the breakdown of certain foods. Some of these foods including organ meats, game meats, any meat in large amounts, anchovies, mackerel, sardines, herring, scallops, dried beans and peas. The use of alcoholic beverages, particularly beer and beverages with high fructose corn syrup should be avoided. To avoid the risk of renal calculi, all patients should have a high level of hydration with a minimum of 2 liters/day. Weight reduction is recommended for all patients who are obese, with the goal of a healthy body weight.
Researchers have concluded that ingestion of purine-rich foods can not only increase uric acid levels but may actually trigger a gout attack within days. Risk for gout flare is twice as high even if the patient is taking allopurinol. Gout patients should choose more low-fat dairy foods and increase their consumption of vitamin C. Protein intake should be calculated on ideal body weight with plant based foods and low purine producing fish.
Complications
Renal calculi
Bursitis, especially in the knee and elbow
Migratory polyarthritis (rare)
Posterior interosseous nerve syndrome (rare)
Eye involvement – tophaceous deposits in different locations of the eye including the eyelids, conjunctiva, cornea, iris, sclera, and orbit.
Renal calculi are the most common uric acid-related complication, affecting an estimated 1 in 5 people with gout. Due to the deposit of MSU crystals in the kidney or urinary tract, the patient will experience sudden severe back pain. Untreated these “stones” can lead to kidney infections, kidney damage and ultimately kidney failure.
Diabetes is seen at a much higher rate in people with gout, especially women. Though the cause is not known it is thought that the low level of chronic inflammation may play a role. Diabetes is not only a complication, but is also thought to be a precipitating factor.
Sleep apnea, a disorder characterized by frequent pauses in breathing, if untreated can increase the risk of obesity, diabetes, high blood pressure, heart attack and stroke. Apnea can cause periods of oxygen deprivation, which trigger uric acid to be overproduced in the blood. High levels of uric acid have been linked to a higher risk of heart failure and systolic dysfunction. Women with gout have higher incidence of non-fatal myocardial infarction than those without the disease.
Gout is not a benign disease. The first attack should be a red flag, prompting a complete health and health risk evaluation, lifestyle reassessment, and complete renal assessment.Highly effective drugs have been available for treatment of gout for several decades and new ones continue to be developed. Practitioners must recognize the potential for certain patients to develop gout so that treatment can begin immediately and continue throughout the patient’s lifespan to avoid further joint destruction. Referral to a rheumatologist should be considered for patients who require a more definitive diagnosis and treatment options.
References:
Gout. (2016). Retrieved from https://www.niams.nih.gov/Health_Info/Gout/default.asp.
Gout. (2018). Retrieved from https://www.cdc.gov/arthritis/basics/gout.html.
Gout Treatment. Retrieved from https://www.arthritis.org/about-arthritis/types/gout/treatments/types.ph…
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