What is gout?
Gout was formerly called the disease of kings. It is the most common inflammatory arthritis in men and in older women. Today, the term gout means a heterogeneous group of diseases found exclusively in humans that include the following characteristics:
These manifestations can occur in various combinations.
How much people are affected?
The incidence of gout varies among populations. Global incidence is about less than 1 percent to 15.3 percent. Gout has become more common over recent years in parallel with increased longevity and the higher prevalence of metabolic syndrome. Hyperuricaemia is an integral component of these. Prevalence is about 2.6 percent and 47.2 percent in various populations.
Uric acid and gout
How and why uric acid cause gout? Let’s see relation between uric acid and gout.
Hyperuricaemia is defined as rise of serum uric acid level greater than 2 standard deviations above the mean for the population. The risk of developing gout increases with age and with serum uric acid levels. Levels are higher in men, increase with age and are associated with body weight. Levels are higher in some ethnic groups (such as Maoris and Pacific islanders e.g. Filipinos and Samoans). When the serum urate concentration exceeds the limit of solubility of monosodium urate in the serum, which is 6.8 mg/dL at 37°C it is called hyperuricemia. In most epidemiologic studies, the upper limit has been rounded off at 7 mg/dL in men and 6 mg/dL in women. A serum urate value in excess of 7 mg/dL begins to carry an increased risk of gouty arthritis or renal stones.
About one third of the body uric acid pool is derived from dietary sources and two thirds from endogenous purine metabolism. The concentration of uric acid in body fluids depends on the balance between endogenous synthesis, and elimination by the kidneys (two thirds) and gut (one third). Purine nucleotide synthesis and degradation are regulated by a network of enzyme pathways. Xanthine oxidase catalyse the end conversion of hypoxanthine to xanthine and then xanthine to uric acid. When balance between formation and excretion of uric acid is hampered uric acid level rises in blood.
The ionized forms of uric acid readily form salts, which are monosodium and disodium or potassium urates. In extracellular fluids, in which sodium is the principal cation, approximately 98% of uric acid is in the form of monosodium salt at a pH of 7.4. As the urine is acidified along the renal tubule, a portion of urinary urate is converted to uric acid. The solubility of uric acid in aqueous solutions is substantially less than that of urate. At pH 5, urine is saturated with uric acid at 15 mg/dL; at pH 7, urine accommodates 158 to 200 mg/dL in solution. The limited solubility of uric acid in urine of pH 5 is of particular significance in patients with gout, many of whom display a tendency toward the excretion of unusually acidic urine. Then uric acid deposited due to precipitation in joints, kidney and other cavities where pH is greater. This uric acid causes inflammatory reaction and that is gout.
During the initial phase of an acute gout attack, there is an influx of polymorphonuclear leukocytes into the synovial fluid. Inflammatory cytokines stimulate the synovial lining layer to become hyperplastic and infiltrated with neutrophils, monocyte-macrophages, and lymphocytes. These inflammatory responses are triggered by monosodium urate crystals that are either formed de novo or released from preformed deposits in or around the joint. Debris or other factors within the synovial cavity may also provide an initial nucleus for early crystal development. Mast cells may play a critical role in the initial event. They contain preformed pro inflammatory substances, including histamine, cytokines, and enzymes, all of which may contribute to the promotion of downstream inflammatory cascades. Depletion of endogenous mast cells has been found to significantly inhibit neutrophil influx in a murine monosodium urate crystal induced peritonitis model.
What are the causes of gout?
Polymorphisms in several genes that are associated with gout can cause gout. The most important of which is SLC2A9, which regulates urate excretion by the kidney. Impaired renal excretion of urate also accounts for the occurrence of hyperuricaemia in chronic renal failure, and for the association between hyperuricaemia and treatment with thiazide diuretics.
Other risk factors for gout include metabolic syndrome, high alcohol intake (predominantly beer,which contains guanosine), generalised osteoarthritis, a diet relatively high in red meat or fructose or relatively low in vitamin C or coffee, and lead poisoning (saturnine gout). The association between OA and gout is thought to be due to reduction in levels of proteo glycan and other inhibitors of crystal formation in osteoarthritic cartilage, predisposing to crystal formation.
Some patients develop gout because they over produce uric acid. The mechanisms are poorly under stood, except in the case of a few rare disorders, in which gout is inherited in a Mendelian manner as the result of mutations in genes responsible for purine synthesis. Lesch–Nyhan syndrome for example, is an Xlinked recessive form of gout that is also associated with mental retardation, selfmutilation and choreo athetosis. Such conditions should be suspected if other clinical features are present or there is an early age at onset with a positive family history. Severe hyperuricaemia can also occur in patients with leukaemia undergoing chemotherapy due to increased purine turnover.
Primary hyper uricemia: These cases appear to be innate, neither secondary to an acquired disorder nor the result of a subordinate manifestation of an inborn error that leads initially to a major disease unlike gout. Some cases of primary gout have a genetic basis where others do not.
Secondary hyper uricemia: These cases develop in the course of another disease or as a consequence of drug use.
Idiopathic: In these cases, a more precise classification cannot be assigned.
What are the symptoms of gout?
Acute gouty arthritis is sudden in onset and frequently nocturnal. It may develop without apparent precipitating cause or may follow rapid increases or decreases in serum urate levels. Common precipitants are alcohol excess (particularly beer), changes in medications that affect urate metabolism, and, in the hospitalized patient, fasting before medical procedures. The MTP joint of the great toe is the most susceptible joint (“podagra”), although others, especially those of the feet, ankles, and knees, are commonly affected. Gouty attacks may develop in periarticular soft tissues such as the arch of the foot. Hips and shoulders are rarely affected. More than one joint may occasionally be affected during the same attack; in such cases, the distribution of the arthritis is usually asymmetric.
The characteristics of gout pain includes
- rapid onset, reaching maximum severity in 2–6 hours, and often waking the patient in the early morning
- severe pain, often described as the ‘worst pain ever’
- extreme tenderness, such that the patient is unable to wear a sock or to let bedding rest on the joint
- marked swelling with overlying red, shiny skin
- self limiting over 5–14 days, with complete resolution.
The involved joints are swollen and exquisitely tender and the overlying skin tense, warm, and dusky red. Fever is common and may reach 39 °C. Local desquamation and pruritus during recovery from the acute arthritis are characteristic of gout but are not always present.
Irregular firm, white nodules of deposited uric acid crystal called tophi. They may be found in the extensor surfaces of fingers, hands, feet, and olecranon, achilles tendons, prepatellar bursae and sometimes the helix of the ear. They usually develop years after the initial attack of gout. The tense, shiny, thin skin overlying the tophus may ulcerate and extrude white, chalky, or pasty material composed of urate crystals. Asymptomatic periods of months or years commonly follow the initial acute attack. After years of recurrent severe monarthritis attacks of the lower extremities and untreated hyperuricemia, gout can evolve into a chronic, deforming polyarthritis of upper and lower extremities that mimics rheumatoid arthritis. Long standing hyperuricemia may cause renal stones and renal failure.
More about symptoms of gout
The serum uric acid is elevated (> 7.5 mg/dL) in 95% of patients who have serial measurements during the course of an attack. Identification of sodium urate crystals in joint fluid or material aspirated from a tophus establishes the diagnosis. A biochemical screen, including renal function, uric acid, glucose and lipid profile, should be performed because of the association with metabolic syndrome. Elevated ESR and CRP and a neutrophilia are typical of acute gout, and they return to normal as the attack subsides.
Early in the disease, radiographs show no changes. Later, punched-out erosions with an overhanging rim of cortical bone (“rat bite”) develop. When these are adjacent to a soft tissue tophus, they are diagnostic of gout.
Treatment for gout
The presence of hyperuricemia is rarely an indication for specific antihyperuricemic drug therapy. Rather, the finding of hyperuricemia should cause the following questions to be addressed:
|What are the causes of the hyperuricemia?|
|Are associated findings present?|
|Has damage to tissues or organs occurred as a result?|
|What, if anything, should be done?|
It is, however, strongly recommended that the cause of hyperuricemia be determined and any associated factors related to the process, such as obesity, hyperlipidemia, alcoholism, and, especially, hypertension, be addressed. Fenofibrate and losartan might be appropriate agents for the treatment of hypertriglyceridemia and hypertension, respectively, in hyperuricemic individuals, because each has modest uricosuric effects.
Arthritis is treated first and hyperuricemia weeks or months later, if at all. Sudden reduction of serum uric acid often precipitates further episodes of gouty arthritis.
These drugs are the treatment of choice for acute gout. Traditionally, indomethacin has been the most frequently used agent, but all of the other newer NSAIDs are probably equally effective. Indomethacin is initiated at a dosage of 25–50 mg orally every 8 hours and continued until the symptoms have resolved (usually 5–10 days). Active peptic ulcer disease, impaired kidney function, and a history of allergic reaction to NSAIDs are contraindications. For patients at high risk for upper gastrointestinal bleeding, a cyclooxygenase type 2 (COX-2) inhibitor may be an appropriate first choice for management of an acute gout attack. Long-term use of COX-2 inhibitors is not advised because of the association with increased risk of cardiovascular events, which has led to the removal of some drugs from the US market (eg, rofecoxib and valdecoxib).
Neither oral nor intravenous colchicine should be used for the treatment of acute gout flares. The use of oral colchicine during the intercritical period to prevent gout attacks is discussed below.
Corticosteroids often give dramatic symptomatic relief in acute episodes of gout and will control most attacks. They are most useful in patients with contraindications to the use of NSAIDs. If the patient’s gout is monarticular, intra-articular administration (eg, triamcinolone, 10–40 mg depending on the size of the joint) is most effective. For polyarticular gout, corticosteroids may be given intravenously (eg, methylprednisolone, 40 mg/d tapered over 7 days) or orally (eg, prednisone, 40–60 mg/d tapered over 7 days).
Management between attacks:
Treatment during symptom-free periods is intended to minimize urate deposition in tissues. Thereby prevent tophi and to reduce the frequency and severity of recurrences.
Diet for gout
Potentially reversible causes of hyperuricemia are a high-purine diet, obesity, alcohol consumption, and use of certain medications. Beer consumption appears to confer a higher risk of gout than does whiskey or wine. Higher levels of meat and seafood consumption are associated with increased risks of gout, whereas a higher level of dairy products consumption is associated with a decreased risk. Although dietary purines usually contribute only 1 mg/dL to the serum uric acid level, moderation in eating foods with high purine content is advisable. A high liquid intake and, more importantly, a daily urinary output of 2 L or more will aid urate excretion and minimize urate precipitation in the urinary tract.
Avoidance of hyperuricemic medications:
Thiazide and loop diuretics inhibit renal excretion of uric acid and should be avoided in patients with gout. Similarly, low doses of aspirin aggravate hyperuricemia, as niacin does.
Treatment of chronic gout
Older individuals with mild chronic kidney disease, who require diuretic use and have a history of multiple attacks of gout are more likely to benefit from pharmacologic treatment. In general, the higher the uric acid level and the more frequent the attacks, the more likely that chronic medical therapy will be beneficial.
There are two indications for daily colchicine administration. First, colchicine can be used to prevent future attacks. Second, colchicine can also be used when uricosuric drugs or allopurinol are started, to suppress attacks precipitated by abrupt changes in the serum uric acid level.
Reduction of serum uric acid:
Indications for a urate lowering intervention include frequent acute arthritis not controlled by colchicine prophylaxis, tophaceous deposits, or kidney damage. Hyperuricemia with infrequent attacks of arthritis may not require treatment. The goal of medical treatment is to maintain the serum uric acid at or below 5 mg/dL.
Two classes of agents may be used to lower the serum uric acid—the uricosuric drugs and allopurinol. Here we must consider uricosuric agents, if kidney function is preserved or consider allopurinol, if kidney function is limited.
These block the tubular reabsorption of filtered urate thereby reducing the metabolic urate pool, prevent the formation of new tophi and reduce the size of those already present. When administered concomitantly with colchicine, they may lessen the frequency of recurrences of acute gout. These agents are ineffective in patients with chronic kidney disease, with a serum creatinine of > 2 mg/dL.
The following uricosuric drugs may be used: (1) Probenecid, 0.5 g orally daily initially, with gradual increase to 1–2 g daily; or (2) sulfinpyrazone, 50–100 mg orally twice daily initially, with gradual increase to 200–400 mg twice daily. Keeping daily urinary output of 2000 mL and giving alkalinizing agents (eg, potassium citrate, 30–80 mEq/d orally) can be tried to maintain a urine pH of > 6.0.
Xanthine oxidase inhibitors
They promptly lower plasma urate and urinary uric acid concentrations and facilitates tophus mobilization.
Two FDA-approved xanthine oxidase inhibitors are available for treating chronic gout, allopurinol and febuxostat. One or the other should be chosen; allopurinol and febuxostat are not to be used together. Allopurinol can be used in chronic kidney disease, but the dose must be reduced to decrease the chance of side effects.
Chronic tophaceous arthritis
With rigorous medical compliance, allopurinol or febuxostat shrinks tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid below 5 mg/dL. Surgical excision of large tophi offers mechanical improvement in selected deformities.
Newer treatment for gout
Single injections of intramuscular ACTH gel (25 to 80 IU) can terminate an acute gout attack. This treatment is effective postoperatively and may be more effective than glucocorticoids, possibly related to the mechanism of action. In addition to stimulating the adrenal cortex to produce corticosteroids, ACTH interferes with the acute inflammatory response through activation of melanocortin receptor-3.
Pegloticase is a biological treatment in which the enzyme uricase has been conjugated to monomethoxy polyethylene glycol.
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