- aka “The disease of kings” or “Rich man’s disease”
- M/C crystal arthropathy and the leading cause of inflammatory arthritis.
- M/C site: Big toe
Purine & pyrimidine catabolism and the salvage pathway:
Serum urate (sUA) levels are determined by the balance of metabolic production and excretion through the gastrointestinal tract and, most prominently, the kidneys. Among individuals who have primary hyperuricemia (that is, no acquired causes of urate overproduction or chronic kidney disease), upwards of 90% have urate elevation as a consequence of inadequate excretion.
Renal excretion:Two thirds of urate excretion occurs in the kidneys while the rest is excreted through the gastrointestinal tract (GIT). Reduced secretory function of the transporter ABCG2 leads to decreased excretion of uric acid through the GIT resulting in rise of serum levels of uric acid and enhanced renal excretion.
Hyperuricemia:Hyperuricemia is the leading cause of gout. Gout is a result of hyperuricemia above 390 µmol/L (6.5 mg/dL), is often associated with other metabolic disorders such as obesity, diabetes mellitus, and hypertonia, and carries an increased risk of cardiovascular problems.
TriggersEvery condition that causes alterations in extracellular urate concentration has the potential to trigger a flare-up.
- Stress: Surgical procedure, recent trauma or starvation)
- Dietary factors: Fatty food, beer, wine, and spirits
- Drugs: Aspirin, diuretics, or even allopurinol
Comorbidities:The prevalence of gout is also higher among individuals with chronic diseases
- Metabolic syndrome
- Psoriasis (have increased urate production and are prone to gout)
- Renal insufficiency (have decreased urate excretion, which also results in gouty attacks)
Pathogenesis of hyperuricemia:Urate is the ionized form of uric acid present in the body. Uric acid is a weak acid with pH of 5.8. Urate crystals deposition in tissues starts to occur when serum uric acid level rises above the normal threshold. Pathological threshold of hyperuricemia is defined as 6.8 mg/dL
- Overproduction of uric acid (10% cases)
- Lowered renal uric acid excretion (90% cases)
- Genetic purine metabolism disorders (rare):
- Lesch–Nyhan syndrome (HGPRT deficiency)
Inflammatory responseInflammation starts when macrophages phagocytize monosodium urate crystals and trigger the formation and activation of cytosolic protein complexes (NLRP2 inflammasome). These complexes subsequently recruit caspase-1 which activates pro-IL-1β to IL-1β. IL-1β plays an important role in the inflammatory response to gout. It promotes vasodilatation, recruitment of monocytes and initiates, as well as, amplifies the inflammatory cascade. Further IL-1beta secretion can result in bone and cartilage break down. Other cytokines, such as TNF-1, IL-6, CXCL8, and COX-2, are also involved in the inflammatory response.
Gout undergoes 4 stages during its course starting with asymptomatic hyperuriceamia.
I. Asymptomatic hyperuricemiaPatients have no symptoms or signs and are usually accidentally discovered when measuring SUA (serum level greater than 7 mg/dL). However, some patients with hyperuricemia may develop an acute gouty attack.
II. Acute gouty attack:Monoarthritic attack that peaks within hours to severely inflamed joint with cardinal signs of inflammation including redness, hotness, tenderness, swelling and loss of function. In large joints such as knees and ankles, skin signs are infrequent, but swelling and pain can be intense.
- Podagra (first metatarsal joint of great toe) (M/C site)
- Other joints: Tarsal and metatarsal joints, ankles, knees, wrists, MCPs, interphalangeal joints of hands. Rarely, hip and shoulder joints can be involved. Vertebral column involvement is extremely rare.
- Soft tissue inflammation may also occur including olecranon bursitis and Achilles tendonitis.
- Constitutional symptoms: Fever, headache, and malaise
III. Intercritical periodWhen the acute attack settles down within hours to days following the introduction of colchicine or NSAIDs, patients enter into a remission phase. This period is characterized by the absence of symptoms. It may be interrupted suddenly by newer attacks if proper treatment for hyperuriceamia has not been introduced. This quiescent stage can be prolonged after the first attack. Without proper treatment, however, attacks become more frequent and more severe.
IV. Chronic tophaceous goutUntreated disease progresses into destruction of joints with formation of palpable tophi.
- Tophi (late manifestation of chronicity and uncontrolled disease): Hard, uric acid deposits present around the joints in the ears, the subcutaneous tissue or the skin
- May lead to joint destruction and deformity
- Bony erosions may also occur as growing tophi extend to the bone.
- Septic arthritis
- Kidney stones
- Urate nephropathy
A suspected diagnosis of gout may safely be made on the basis of an episode of excessive eating and/or drinking (of alcohol) in the recent history—e.g., a barbecue—when the large toe shows the typical signs of a gout attack and the serum concentration of urate is raised.
American College of Rheumatology (ACR) preliminary diagnostic criteria:Six or more of these criteria are needed to make a diagnosis:
- > 1 attack of acute arthritis
- Maximum inflammation developed within one day
- Attack of monoarthritis
- Redness over joints
- Painful or swollen first MTP joint
- Unilateral attack on first MTP joint
- Unilateral attack on tarsal joint
- Tophus (proved or suspected)
- Asymmetric swelling within a joint on radiograph
- Subcortical cysts without erosions on radiograph
- Joint fluid culture negative for organisms during attack
Arthrocentesis (synovial fluid analysis):Monosodium urate crystal identification remains the gold standard for gout diagnosis.
- Appearance: Translucent-cloudy
- Viscocity: Low
- PMNs: > 90%
- Crystals: Needle-shaped crystals, negatively birefringent
- Gram stain: Negative
- Non-specific findings during gout flare-up: ↑ WBC count, ↑ESR, ↑ CRP
- ↑ Serum uric acid (90% cases, but not diagnostic)
- 24-hour uric acid collection (if multiple attacks/chronic gout):
- < 800 mg/dl (Underexcretion) (90% cases)
- > 800 mg/dl (Overproduction)
- Double contour sign: Monosodium urate deposition apparent as a hyperechoic enhancement over the cartilage
Dual-energy CT (DECT)Can identify urate due to the beam attenuation after exposure to two different X-ray spectra
Differential diagnosisDifferentiation of tophi from other nodules such as rheumatoid nodules, osteoarthritic Heberden’s and Bouchard’s nodules, lipomas or is essential for further management. This can be easily done by taking a simple needle biopsy that will show MSU crystals characteristic of gout
The first therapeutic goal is acute treatment of the gout attack with rapid alleviation of pain and inhibition of the inflammation. A longer-term goal is to prevent further attacks, eliminate tophi, and prevent joint destruction, by consistently reducing the level of urate.
Lifestyle management:Patients with gout are encouraged to modify their lifestyles to prevent future attacks.
- Reducing alcohol consumption
- Limiting purine-rich foods (meat, seafood, high fructose corn syrup, and sweetened soft drinks)
- Substituting low/non-fat dairy products for their higher fat content counterparts.
- Weight loss
- Adequate hydration
Acute flares:Management of acute flares aims at decreasing the inflammation and the resulting pain. The physician should start the treatment within the first 24 hours of onset to reduce the severity and duration of the flare-up.
- Non-pharmacological management: Rest with topical application of ice packs (reduce inflammation)
- Pharmacological management:
- High dose, fast-acting NSAIDs: Naproxen or diclofenac, colchicine, or systemic glucocorticoids (7-10 days)
- Colchicine (reduce pain by over 50%)
- Intra-articular glucocorticoids (for those contraindicated to NSAIDs and/or colchicine; also drugs of choice for renal insufficiency)
Urate-lowering therapy (ULT):It is postulated that gout is “curable” if existing deposits of urate crystals can be successfully removed and the formation of new precipitates prevented. To achieve this, according to international recommendations, serum urate levels in patients with recurring attacks of gout should if possible be kept below 360 µmol/L (6.0 mg/dL) (EL III)
- Colchicine prophylaxis (recommended for 3 months as during the initiation of ULT, there is an increased risk of gout flare-ups)
- Xanthine oxidase inhibitors (XOI): Inhibit synthesis of uric acid
- Allopurinol (first-line pharmacologic ULT in gout)
- Uricosuric agents: Increase renal urate clearance
- Uricase agents (for refractory gout patients): Pegloticase & Rasburicase
- Interleukin-1 (IL-1) inhibitors: