BL 02-25-14 9-10AM Crystal Anthropathies-GOUT Flashcards
GOUT defn.
= a crystal anthropathy
= heterogeneous group of diseases in which tissue deposition of monosodium urate (MSU) crystals occurs due to hyperuricemia (MSU supersaturation of extracellular fluids)
—> acute or chronic arthritis
- Hyperuricemia w/out symptoms is referred to as “asymptomatic hyperuricemia,” not gout
GOUT: Results of MSU crystal deposition (manifestation)
One or more of the following manifestations:
A) Gouty arthritis
B) Tophi
C) Gouty nephropathy
D) Uric acid nephrolithiasis (kidney stones)
Gouty arthritis
recurrent attacks of severe acute or chronic articular and periarticular inflammation
Tophi
aggregated deposits of MSU occurring in joints, bones, and soft tissue
Gouty nephropathy
renal interstitial, glomerular, and/or tubular deposition of MSU crystals
Stages of Gouty Arthritis
A) Asymptomatic hyperuricemia
B) Acute Gouty Arthritis
C) Intercritical gout
D) Chronic Tophaceous Gout
Asymptomatic Hyperuricemia
- Elevated serum uric acid level w/out symptoms (NO arthritis, tophi, or nephrolithiasis)
Elevated serum urate level
= when exceeds limit of solubility of MSU in serum
= At 37C, >7.0 mg/dl
Acute Gouty Arthritis
- Abrupt onset of exquisitely painful, warm, red, swollen joint often during night or early morning
= most often involved great toe’s MTP joint (metatarsophalangeal)
= also insteps, ankles, heels, knees, wrists, fingers, & elbows - Early attacks often spontaneously resolve over 3-10 days.
- has predilection for cooler, acral sites where solubility of MSU crystals diminished due
Intercritical gout
Asymptomatic intervals between acute attacks of gout.
Chronic Tophaceous Gout
= Development of subQ, synovial, or subchondral bone deposits of MSU crystals
= commonly on digits of hands & feet, olecranon bursa, extensor surface of forearm, Achilles tendon
- less commonly in antihelix of ear
Epidemiology of Gout (age, sex, prevalence)
- Predominantly in adult men (>30 yo, peak in 50s)
- In females, postmenopause
Prevalence:
- > 2% in men over 30 & women over 50
- 9% & 6%, respectively, in men & women over 80
= most common cause of inflammatory arthritis in men over age 40
Most common medical conditions associated w/ gout
alcohol abuse
obesity
insulin resistance syndrome
HTN
Pathology of Gout
Examine fresh synovial fluid for MSU crystals
- Intracellular crystals in PMNs are needle-shaped & negatively birefringent (yellow when parallel to axis of red compensator) on polarizing microscopy
Synovial fluid is inflammatory (20,000-100,000 leukocytes/mm3 ) w/ predominance of neutrophils
Hematological eval may show
- elevated ESR
- mild neutrophil leukocytosis
- possibly reative thrombocytosis
Cause of hyperuricemia
- increased production or decreased renal excretion of urate
= MOST OFTEN UNDER-EXCRETION (90%) - In steady state, Urate Produced + Urate Absorbed (by GI) = Urate Excreted + Urate Loss (by GI)
24 hr Urinary excretion values & meaning
Normal 24 hr urinary excretion of uric = 750 mg on
- if >750 mg = overproduction of uric acid
- if <750 mg = underexcretion of uric acid
Urinary uric acid excretion – 4 Compartment Model:
1) Glomerular filtration (~100% of filtered uric acid load) followed in proximal tubule by
2) pre-secretory reabsorption
3) secretion back into tubule
4) post-secretory reabsorption
(see picture in notes)
Reabsorption of filtered uric acid
- Net tubular reabsorption of filtered uric acid is 90%
- –> only 10% excreted in urine
Urate/organic anion exchanger (URAT1) in proximal tubule
–> pre- & post-secretory uric acid reabsorption
Reabsorption favored in exchange for tubular secretion & excretion of unwanted organic acids (lactate, acetoacetate, hydroxybutyrate succinate)
Drugs/metabolites that are activators of URAT1 (result, examples)
- -> Decrease renal excretion of uric acid
- –> Cause hyperuricemia
Examples:
- nicotinate,
- pyrazinoate,
- diuretics,
- low-dose aspirin
Medications that are inhibitors of URAT1 (result, examples)
–> Increase urinary excretion of uric acid (uricosurics)
Examples:
- probenecid
- sulfinpyrazone
- a metabolite of losartan
- high-dose aspirin
Specific URAT1 inhibitors are in development.
Under-excretion mechanism of primary gout
Unknown mechanism
Not explained by function of URAT1
Renal apical surface urate transporters
URAT1 (urate/organic anion exchanger )
OAT4 and OAT10
GLUT9a
ABCG2 and MRP4
= Two major proteins on apical surface that extrude urate from epithelial cell into tubular urine
- Polymorphisms of ABCG2 are associated w/ decreased renal secretion of uric acid
- –> hyperuricemia and gout
Uric acid (origin, why we can’t break it down, normal actions)
= a product of purine metabolism
Humans lack enzyme uricase, which in other species oxidizes uric acid to highly soluble allantoin
- Human uricase gene is crippled by 2 mutations that induce premature stop codons
In humans, uric acid may serve as an antioxidant
Causes (rare) of overproduction of uric acid
- Superactivity of PRPP (phosphoribosyl-pyrophosphate) synthetase
- Deficiencies of HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
- Complete deficiency of HGPRT results in Lesch-Nyhan syndrome (mental retardation, spasticity, choreoathetosis, self-mutilation)
Mechanism of MSU (monosodium urate) crystal formation
supersaturation of serum or synovial fluid w/MSU
Factors that affect urate solubility
- Temperature
- Dehydration / volume fluxes
- Trauma
- Proteoglycan abnormalities
- pH
Temperature & Urate solubility
Urate saturation is…
- 7.0 mg/dl at 37 degrees C
- 4.5 mg/dl at 30 degrees C
Acute gouty arthritis affects primarily peripheral joints w/lower temps
Dehydration / Volume flux & Urate solubility
Overnight intra-articular dehydration may concentrate uric acid & crystallization promotors
—> onset of acute gouty arthritis in awakening morning hours
Trauma & Urate solubility
release of articular MSU crystals triggers attack
Proteoglycans & Urate solubility
- Intact proteoglycans bind & solubilize MSU
- Abnormal proteoglycans (as in osteoarthritis) may alter local urate levels & precipitate attack
pH & Urate solubility
MSU crystals are less soluble at lower pH
The Inflammatory Response—Initiation effects of MSU crystals
MSU crystals…
- Interact w/ synovial lining
- –> activate monocytes & mast cells (produce TNF-alpha, IL-6, IL-8) - Are recognized by TLR2/TLR4 (critical to inflammatory response)
- Engage caspase-1
- –> activates NLRP3 inflammasome
- –> IL-1beta production
The Inflammatory Response – Inflammatory response to MSU crystals depends on…
PMNs
PMN influx promoted by
- IL-8 & neutrophil chemoattractant protein-1
- Endothelial activation by cytokines (IL-1, TNF)
The Inflammatory Response—Other effects of MSU crystals
- activate complement
- promote leukotriene & PGs production
- induce additional cytokine release (IL-6, IL-8)
- cause superoxide radical generation
The Inflammatory Response – Phagocytosis of MSU crystals
IgG binds to crystal surface through charge interactions & H bonding
- –> facilitates phagocytosis by PMNs
- –> PMN lysis w/release of proteolytic enzymes
Later, apolipoprotein-B coating of crystals inhibits phagocytosis & a cellular response.
Self-limited nature of the acute gouty attack:
1) Modulation of cellular response by different proteins coating crystals (IgG vs. Apo-B)
2) Phagocytosis & degradation of crystals by PMNs decreases crystal concentration
3. Eventual neutrophil apoptosis.
3) Heat from inflammation increases urate solubility.
4) Enhanced ACTH secretion may suppress inflammatory response.
5) Proinflammatory cytokines (IL-1, TNF) balanced by cytokine inhibitors & regulatory cytokines (like TGF-β)
Treatment of Gout: Lifestyle & Nutritional Modification
- Weight loss
- Moderation of dietary intake of purine-rich foods (ex: meats & shellfish)
- Moderation of fructose & alcohol consumption
BUT hard to treat hyperuricemia by diet alone (diet contributes ~1.0 mg/dl to serum [uric acid])
Low-fat dairy products, coffee, vitamin C, & wine might be protective of hyperuricemia & gout
Treatment of gout: Anti-inflammatory meds
For treatment of ACUTE gouty attack Examples: - NSAIDs - colchicine - corticosteroids (systemic or intra-articular)
Colchicine action in Gout
- binds intracellular tubulin, preventing its polymerization into functional microtubules
- –> diminished PMN migration & activity
- –> may block activation of NLRP3 inflammasome in monocytes by MSU crystals
Chronic treatment of gout:
Anti-hyperuricemic medications
- reduce serum uric acid levels below supersaturation levels
Anti-hyperuricemic medications for gout - examples
Uricosuric (probenecid)
—> enhance renal excretion of uric acid in under-excreters
Xanthine oxidase inhibitor (allopurinol, febuxostat)
—> decrease uric acid production in over-producers
IV PEGylated-uricase (pegloticase)
- in pts w/ severe gout burden who are intolerant of oral urate-lowering therapy or who have refractory disease despite urate-lowering therapy
Pts at risk for severe allopurinol hypersensitivity rxns
= Koreans w/ stage 3 or worse chronic kidney disease
= Pts of Han Chinese or Thai descent
—> should undergo HLA-B*5801 screening prior to starting allopurinol
