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Internal Medicine

Gout 

Chronic disease of monosodium urate (MSU) crystal deposition typically presenting as an acute, self-limiting inflammatory monoarthritis that affects the joints of the lower limb.

Introduction

Chronic disease of monosodium urate (MSU) crystal deposition typically presenting as an acute, self-limiting inflammatory monoarthritis that affects the joints of the lower limb.

  • 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
Prevalence of gout. | Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR Jr, Saag KG. Gout epidemiology: results from the UK general practice research database, 1990-1999. Ann Rheum Dis 2005;64: 267-72.

Physiology

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.
Renal excretion of uric acid: Renal excretion of uric acid is the end result of 4 phases. The first phase is the passage of UA across the Bowman’s capsule (glomerular filtration); followed by reabsorption of almost all urates passing in the proximal tubules. The third phase involves secretion of part of the reabsorbed UA ending with another reabsorption phase in the proximal tubules. The excreted UA is almost 10% of the filtered urate through Bowman’s capsule and the rest is reabsorbed in the body | Perceived and designed by Dr. EL-Shahaly | Ragab, G., Elshahaly, M., & Bardin, T. (2017). Gout: An old disease in new perspective – A review. Journal of advanced research, 8(5), 495–511. https://doi.org/10.1016/j.jare.2017.04.008

Aetiology

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.
hyperuricemia-pathogenesis-and-complications
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Triggers

Every 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
  • Hypertension
  • Diabetes
  • Hyperlipidemia
  • Metabolic syndrome
  • Psoriasis (have increased urate production and are prone to gout)
  • Renal insufficiency (have decreased urate excretion, which also results in gouty attacks)

Pathophysiology

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)
Pathogenesis of hyperuricaemia | Perceived and designed by Dr. EL-Shahaly

Inflammatory response

Inflammation 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.
Pathogenesis of acute gouty inflammation | Perceived and designed by Dr. EL-Shahaly | Ragab, G., Elshahaly, M., & Bardin, T. (2017). Gout: An old disease in new perspective – A review. Journal of advanced research, 8(5), 495–511. https://doi.org/10.1016/j.jare.2017.04.008

Clinical features

Gout undergoes 4 stages during its course starting with asymptomatic hyperuriceamia.

gout-pathogenesis-and-clinical-findings
The Calgary Guide | http://calgaryguide.ucalgary.ca/

I. Asymptomatic hyperuricemia

Patients 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
Acute gout attack with classic podagra and synovitis in the second metacarpophalangeal joint | Tausche, A. K., Jansen, T. L., Schröder, H. E., Bornstein, S. R., Aringer, M., & Müller-Ladner, U. (2009). Gout–current diagnosis and treatment. Deutsches Arzteblatt international, 106(34-35), 549–555. https://doi.org/10.3238/arztebl.2009.0549

III. Intercritical period

When 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 gout

Untreated 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.
Chronic gout: a) Tophaceous gout with destructive joint changes and subcutaneous deposits of uric acid, b) radiological changes in tophaceous gout | Tausche, A. K., Jansen, T. L., Schröder, H. E., Bornstein, S. R., Aringer, M., & Müller-Ladner, U. (2009). Gout–current diagnosis and treatment. Deutsches Arzteblatt international, 106(34-35), 549–555. https://doi.org/10.3238/arztebl.2009.0549

Complications

  • Septic arthritis
  • Kidney stones
  • Urate nephropathy

Diagnosis

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)
  • Hyperuricaemia
  • 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
CPP and Urate crystals (spiked rods of uric acid crystals) | Image courtesy S Bhimji MD

Laboratory studies:

  • 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)
445px-gichtfuss_im_roentgenbild_002
Gout in a radiograph of the [left] foot. Typical (main) localization at the metatarsophalangeal joint of the great toe. Note also the soft tissue swelling on the lateral border of the foot. | By Hellerhoff – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12077637

Ultrasonography (USG):

  • Double contour sign: Monosodium urate deposition apparent as a hyperechoic enhancement over the cartilage
Three examples of Ultrasonography in gout. (a) Intraarticular tophus, metatarsophalangeal joint; (b) Double contour sign; (c) Longitudinal image of extensor digitorum longus (EDL) tendon showing markedly distended sheath with synovial effusion, synovial hypertrophy and crystal aggregates (arrows) | Dr. Adham Aboul-Fotouh, Kasr Alainy Teaching Hospital, Cairo University

Dual-energy CT (DECT)

Can identify urate due to the beam attenuation after exposure to two different X-ray spectra
New imaging modalities for demonstrating serum urate deposition: ( A) Musculoskeletal ultrasound of a first metatarsal phalangeal joint (plantar longitudinal view) demonstrating a classic “double contour sign” (arrows), indicating the deposition of monosodium urate (MSU) crystals on the cartilage surface of the metatarsal head. ( B) Dual-energy computed tomography of a foot. Green areas indicate MSU deposition, and arrows indicate the presence of MSU deposition at the first distal interphalangeal joint, at the carpal metacarpal joint, and along the Achilles tendon. | Igel, T. F., Krasnokutsky, S., & Pillinger, M. H. (2017). Recent advances in understanding and managing gout. F1000Research, 6, 247. https://doi.org/10.12688/f1000research.9402.1

Differential diagnosis

Differentiation 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
aitc201607050tt1_table_1_conditions_that_may_be_confused_with_gout
Neogi, T. (2016) ‘GOut’, Annals of Internal Medicine, 165(1), p. ITC1-ITC16. Available at: http://dx.doi.org/10.7326/AITC201607050.

Management

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)
Treatment algorithm for gout | *1 Dose titration of allopurinol depending on serum urate level, up to a maximum of 800 mg/d with monitoring of renal function; *2 urinary alkalization using citrate compounds to prevent urate stones (EL III); *3 not available in Austria and Switzerland | COX-2, cyclooxygenase-2; PPI, proton pump inhibitor; SUA, serum urate; Crea, creatinine; GFR, glomerular filtration rate | Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group (SGAWG): British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46:1372–1374.

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)
    • Febuxostat
  • Uricosuric agents: Increase renal urate clearance
    • Probenecid
    • Lesinurad
    • Uricase agents (for refractory gout patients): Pegloticase & Rasburicase
  • Interleukin-1 (IL-1) inhibitors:
    • Anakinra
    • Canakinumab
Mechanism of action of urate-lowering drugs currently used for gout treatment | Dalbeth, N., Choi, H.K., Joosten, L.A.B. et al. Gout. Nat Rev Dis Primers 5, 69 (2019). https://doi.org/10.1038/s41572-019-0115-y

Summary

Gout is a chronic disease of monosodium urate crystal deposition, usually presenting as an acute inflammatory arthritis in response to deposited crystals. | Gout. Nat Rev Dis Primers 5, 68 (2019). https://doi.org/10.1038/s41572-019-0124-x

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