Gout Flashcards
Overview of gout
Gout is a chronic inflammatory arthritis that results from monosodium urate (MSU) crystal deposition in tissues or joints resulting from supersaturation of uric acid in extracellular fluids
- gout is a disorder of uric acid metabolism
- hyperuricemia = serum uric acid > 2SD above the mean (>7 mg/dL for men, >6 mg/dL for women)
- hyperuricemia is a precursor to gout –> not everyone who has hyperuricemia has gout
Clinical manifestations of gout
- gouty arthritis –> recurrent attacks of articular and per-articular inflammation
- tophus –> accumulation of MSU deposits in joints, bone, soft tissues and cartilage
- gouty nephrolithiasis –> uric acid calculi in urinary tract
- gouty nephropathy –> interstitial nephropathy with renal function impairment
Epidemiology
- increases with age - presents early in men than women (estrogen might be protective)
- most common cause of inflammatory arthritis in men >40 yrs old
- prevalence is on the rise in both sexes –> affects 8.3 million US adults >20 years
Risk factors and comorbidities
Comorbitiies –> HTN, CV disease, chronic kidney disease, DB mellitus, dyslipidemia, metabolic syndrome
Demographics –> advanced age, male gender, postmenopausal women
Lifestyle
- obesity
- idet
- ETOH
- high fructose corn syrup
Meds
- thiazides/furosemids
- low dose ASA
- cyclosporine
- nicotinic acid
- levodopa
Pathopys
hypoxanthin is converted to xanthine by xanthine oxidase
- xanthine converted to uric acid by xanthine oxidase
***allopurinole and febuxostat inhibit xanthine oxidase and block uric acid formation
- uric acid is normally excreted in the urine and feces –> supersaturation of monosodium urate cystals leads to precipitation of crystals and deposition in the tissues
Renal handling of urate - molecular mechanisms
Uric acid transporter (URAT1) –> receptor on luminal side of PCT epithelial cell
- major determinant of urate reabsorption
Organic acid transporters (OAT1 and 3) –> receptors located on interstitial side of PCT
- regulate transport of urate into the blood
Inflammatory response in gout
Pathophys
- phagocytosis of crystals by synoviocytes and neutrophils
- stimulation of chemotactic factors and cytokines (IL1, IL6 and TNF), prostaglandins, leukotrienes, and oxygen radicals
- activation of complement and lysosomal enzyme release
Inflammatory response
- IgG- dependent complement activation via classical and alternative pathways
- crystal associated polypeptides which activate clotting cascade –> transient fibrinogen elevation
- PMNs phagocytose MSU crystals, which cause cell lysis and release of lysosomal enzymes
- monocyte and macrophage interaction with MSU crystals cause release of pro-inflammatory cytokines, O2, LTB4, PGs and lysosomal proteases
- IL1 may account for systemic features of gout
IL1 and gout
Inflammasome - a multi-protein complex expressed in myeloid cells that is activated by infection, stress, etc., and is responsible for maturation of IL1 and activation of inflammatory processes
- IL1B produced by macrophages, monocytes + dendritic cells
- the innate immune system recognizes MSU crystals via TLRs 2 + 4 on the cell surface
- binding MSU to TLR generates reactive oxygen species which stimulate the cryopyrin NALP3 inflammasome
- this results in the processing and maturation of pro-IL-1B and secretion of mature IL-1B
Stages of gout
- Asymptomatic hyperuricemia
- Acute intermittent gout (acute flare)
- Intercritical gout
- Advanced gout
Stage 1: Asymptomatic hyperuricemia
- Hyperuricemia is a necessary precursor to gout
- Hyperuricemia is NOT gout
- –> Elevated serum urate
- –> No history of gout
- –> No clinical signs or symptoms
- No indication for pharmacologic treatment
- Few progress to gout
- Consider non-pharmacologic therapy, ie lifestyle modification
- –> weight loss
- –> reducing consumption of red meat and other high purine foods
- –> reduce alcohol consumption
- –> increase consumption of low fat dairy
- –> vit C supplements
Stage 2: Acute gout flare
Acute inflammation, rapid development of intense pain, swelling, tenderness and overlying erythema
- Often occurs at night or early morning
- Monoarticular ~90% of first attacks
- Podagra ~50% of first attacks –> instep, ankles, heels, knees, wrists, fingers and elbows too
- In advanced disease, attacks may be polyarticular, atypical, and more frequent –> non-articular sites- olecranon bursa, Achilles
Stage 3: Intercritical gout
Symptom free periods between flares
- urate crystals may still be identified –> previously inflamed joints and uninvolved/asymptomatic joints
- crystals remaining in joint may lead to:
- –> chronic, low grade inflammation
- –> risk of recurrent attacks
- –> devt of tophi
Stage 4: Advanced gout
- Persistent, destructive arthritis w/ chronic symptoms
- Results from established disease
- Usually develops after 10 or more years of acute intermittent gout
- Tophaceous deposits may become clinically apparent
- Intercritical periods no longer pain free –> persistent pain, swelling, deformities
- May be confused with rheumatoid arthritis
Diagnosis
- Identification of MSU crystals in synovial fluid or tissue (e.g., tophus)
- –> Polarized light microscopy
- Radiographic erosions typical of gout may be suggestive i.e. “rat bite”
- Synovial fluid is inflammatory i.e. 10-100,000 cells/mm3, but not specific
- Bacterial infections can co-exist with gout; always send fluid for gram stain and culture
Cyclosporine induced gout
- Occurs in 10% of transplant patients treated with cyclosporine, almost exclusively males
- Frequently complicated by calculi and tophi
- Associated with hyperuricemia, renal insufficiency, and diuretic use
- Cyclosporine-induced tubular defect in urate secretion
