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Gout and Hyperuricemia Cheat Sheet (DRAFT) by

Pathophysiology and Treatment

This is a draft cheat sheet. It is a work in progress and is not finished yet.

Pathop­hys­iology

Gout
Inflam­matory condition.
What makes Gout painful?
Build up of uric acid crystals in the joints, bones, or soft tissues. Usually affects one joint at a time and is most often the metatarsal phalangeal joint (MPJ)
What in the blood can lead to Gout?
Elevated uric acid levels
Hyperu­ricemia for males is what level?
>7 mg/dL
Hyperu­ricemia for
>6 mg/dL
Hyperu­ricemia does not always lead to...
does not always lead to gout.
At 37 degrees C, serum urate concen­tra­tions >7 mg/dL begin to limit...
solubility for monosodium urate.
Higher concen­tra­tions of serum urate will lead to more what?
monosodium urate crystals (MSU)
Gout is more prevalent societies with__.
Lifestyles of overin­dul­gence
Uric acid is the final step in the degrad­ation of_____
Purines
The two common abnorm­ali­tites in enzymes that lead to increased uric acid
- Increased levels of PRPP (Phsph­ori­bosyl pyroph­osphate synthe­tase) -Defic­iency of HGPRT (HYPOx­ant­hin­e-g­uanine phosph­ori­bos­ylt­ran­sfe­rase)
Tophi is created by
Uric acid binding to sodium and creating monosodium urate (msu) crystals that get deposited in tissue­s/j­oints
Tophi is
the build up of uric acid crystals in the synovial fluid
Non-Mo­dif­iable Risk factors of Gout
Age, Sex, Race, Genetic Variants
Modifiable Risk Factors of Gout
Obesity, HTN, CKD, Diabetes, Medica­tions altering urate balance
Medica­tions that alter urate balance:
Diuretics, Ethanol, Salicy­lates (<2­g/day), Nicotinic Acid, Pyrazi­namide, Cyclos­porin

Gout Prophy­laxis

First line for Gout Prophy­laxis
NSAIDs, Colchicine
Colchicine
0.6 mg PO daily or BID (QD>BID)
NSAID
Naproxen is an example (250 mg PO BID). May use a PPI if NSAID prolonged or increased GI bleeding risk.
Altern­ati­ve/­First line contra­ind­icated Prophy­laxis dosing
Low dose cortic­ost­eroids (like prednisone 10 mg/day)
Duration of Propph­ylaxis without tophi
3-6 months
Duration of Prophy­laxis with >1 tophi or radiog­raphic evidence
6-12 months

Uricosuric

2nd line Therapy for Gout Management
Probenecid
Rarely used monoth­era­py...
but can be XOI is contra­ind­icated or ineffe­ctive
Probenecid initial dosing
250 mg PO BID x1 week
Probenecid mainte­nance dosing
500 mg PO BID
Mainly for patients that...
undere­xcrete uric acid
MOA
Compet­itively inhibits the reabso­rption of uric acid at the proximal convoluted tubule, thereby promoting its excretion and reducing serum uric acid levels
Works where?
RENALLY
Contra­ind­icated
Nephro­lit­hiasis, modera­te-­severe renal impairment (CKD 3)
Effect of Salicy­lates on Probenecid
may impact the concen­tra­tions

Recomb­inant Uricase

Peglot­icase
8 mg IV infusion (over 120min) q2weeks
MOA
Pegylated recomb­inant form of urate-­oxidase enzyme, also known as uricase; which converts uric acid to allantoin (an inactive and water soluble metabolite of uric acid)
ethicacy:
4-6 months
MONOTH­ERAPY
Can only be used as monoth­erapy
Used for
Refractory gout when failed conven­tional therapies.
Produced from modified strain of
E. coli (Esche­richia coli)
Start prophy­lactic therapy
1 week PRIOR to initiation (high risk of flares)
Duration of prophy­laxis while on Pegloticas
6 months
Requir­es...
Pre-tr­eatment with antihi­sta­mines and cortic­ost­eroids to mitigate infusion reaction
Immuno­gen­icity
develops antibodies against itself
Discon­tinue therapy:
serum urate >6 mg/dL on more than one clinic visi
Contra­ind­icated:
G6PD-d­efi­ciency
G6PD-d­efi­ciency
Increase risk of Hemolysis and methem­ogl­obi­nemia
 

Diagnosis, Signs, Symptoms, Classi­fic­ation

Diagnosis of Gout
Symptoms are used for diagnosis
Signs and Symptoms of Gout
Intense pain, Erythema, warmth, Fever, Tophi, Inflam­mation of Joint
Where can inflam­mation of the joint be in Gout?
Toes, Knees, Fingers, Elbows, Ankles
Uric Acid Levels
High uric acid levels do NOT always mean Gout!
Leukoc­ytosis in Gout
MSU crystals induce inflam­mation and can INCREASE white blood cell count
Diagnostic Testing for Gout
Arthro­cen­tesis and Radiog­raphy
Arthro­centsis
Removal of synovial fluid from the affected joint, micros­copic examin­ation, can give a definitive diagnosis of gout.
Radiog­raphy
X-ray that can be used for more advanced gout, will be *unrem­arkable for first acute gout attacks, can help rule out other causes of arthritis.
Conditions that precip­itate Gout Attack
Most can't identify a trigger. Dehydr­ation, Stress, excessive alcohol intake, excessive intake of purine­-rich foods, increased physical activity, uric acid lowering agents, medica­tions that increase uric acid levels
What are the 4 Gout Classi­fic­ations
Asympt­omatic, Acute Gouty Arthritis, Interc­ritical Gout, Chronic recurrent Gout
Asympt­omatic
Hyperu­ricemia
Interc­ritical Gout
Intervals between attacks
Severity of Chronic Tophaceous Gouty Arthritis (CTGA)
Mild, Moderate, Severe
CTGA Mild
One joint, stable disease
CTGA Moderate
2-4 joints, stable disease
CTGA Severe
4+ OR Unstable, compli­cated, severe articular tophi
Large Joints:
Knee, ankle, wrist, elbow, hip, shoulder
Medium Joints:
Ankle, Wrist, Elbow
Small Joints:
Interp­hal­angeal

Xanthine Oxidase Inhibitors (XOI)

What are the Two XOI for Gout?
Allopu­rinol, Febuxostat
Allopu­rinol Initial dose
100 mg PO daily
Allopu­rinol Mainte­nance dosing
100-800 mg daily (average is 300 mg/day)
Allopu­rinol Renal adjustment
50 mg/day for CKD stage 4+
Febuxostat initial dose
40 mg PO daily
Febuxostat Mainte­nance dosing
40-80 mg daily
First line agent for
Chronic management of gout
Contra­ind­ica­tions
CVD history or recent CV event
Genotype contra­ind­ication
HLC-B*5801 haplotype
Genotype is condit­ionally recomm­ended for what race?
Southeast Asian descent, African Americans
XOI MOA
Inhibits xanthine oxidase, an enzyme respon­sible for the conversion of hypoxa­nthine to xanthine to develo­pment of uric acid. Acts on purine metabo­lism, thereby reducing uric acid production without disrupting biosyn­thesis of vital purines
Black Box Warning
Febuxostat
 

Gout Management

Non-Ph­arm­aco­logical
Dietary Modifi­cat­ions, Promote Weight Loss, Adjuvant ice therapy, Avoid heat
Pharma­cot­herapy of Acute Gout
Terminate acute attacks, Prevent Recurrent Attacks of gouty arthritis, Prevent compli­cations associated with deposition of urate crystals in tissues, Preven­t/r­everse comorb­idities associated with gout (Obesity, HTN)
Dietary Modifi­cations for Gout
Limit: Purine (meats, seafood), alcohol (beer, fortified wines/­liq­uours), high-f­ructose corn syrup, maintain adequate hydration
Acute Gout Treatment
NSAIDS, Cortic­ost­eroids, Colchicine
NSAIDS can be initiated when for a Acute attack?
24-48 hours
Celecoxib should be avoided if signif­icant history of what?
CAD
NSAIDs with Acute Gout Attack FDA indica­tion:
Indome­thacin, Naproxen, Sulindac
NSAIDs are contra­ind­icated for
Decomp­ensated heart failure.
NSAIDs MOA
Inhibit prosta­gla­ndins for anti-i­nfl­amm­atory, analgesic and antipy­retic effects via inhibition of cyclox­ygenase 1 and 2 enzymes
Cortic­ost­eroids can be initiated when for an acute gout attack?
24-48 hours
Cortic­ost­eroids for Acute Gout attack:
Predni­sone, Methyl­pre­dni­solone, Triamc­ino­lone, ACTH
ACR guidelines recommend this as an option for acute gout flare:
Cortic­ost­eroids
Cortic­otr­opin’s anti- inflam­matory properties work through:
melano­cortin type-3 receptor
Cortic­ost­eroids are contra­ind­icated when?
Active systemic infections (can worsen them), IA injections if septic arthritis, long term use decreases amoutn of physio­logical steroids so there can be rebound which is why we taper
Adverse event of cortic­ost­eroid use:
HPA axis suppre­ssion
When can Colchicine be initiated for Acute Gout attack?
12-24 hours of symptom onset. if >36 hours, consider altern­ative therapies
Colchicine for acute gout attack initial dosing:
Day 1: 1.2 mg PO once, then 0.6 mg PO 1-6 hour later
Colchicine for acute gout attack mainenance dosing: (Day 2)
12 hours after Day one, 0.6 mg PO daily or BID
Colchicine MOA
Decreases inflam­mation during gout flare by decreasing activa­tion, degran­ulation and migration of neutro­phils through inhibiting betatu­bulin polyme­riz­ation into microt­ubules
Colchicine is Contra­ind­icated when:
Blood dyscra­sias, severe renal disease (CrCl <10 ml/min)
If gout is seen on an x-ray, it's immedi­ately classified as
Severe
Initiate Monoth­erapy
Mild/M­oderate Pain intensity
Initiate Combin­ation Therapy
Severe, X-ray
Combin­ation therapy includes
Colchicine + NSAID, Colchicine + Oral Cortic­ost­eroid, NSAID + IA injection, Colchicine + IA, Oral Cortic­ost­eroid + IA
Goal Serum Urate level to maintain
<6 mg/dL
When using a ULT, what should also be used?
Anti-i­nfl­amm­atory to overlap
High level of eviden­ce/­Strong recomm­end­ation for Initiation of ULT
1 or more subcut­aneous tophi, evidence of radiog­raphic damage from gout, >2 gout flares per year
Moderate Evidence, Condit­ional recomm­end­ation
ULT is recomm­ended for patients who have previously experi­enced >1 flare but have infrequent flares (<2 per year)
ULT options for Gout
Xanthine Oxidase Inhibitors (XOI), Recomb­inant Uricase, Probenecid
Fenofi­brate
Increase clearance of hypoxa­nthine and xanthine. Consider if concom­itant Hypert­rig­lyc­eri­demia
Losartan
Inhibits tubular reabso­rption of uric acid and increases excretion. Alkali­nizes urine to reduce risk of calculi
Asympt­omatic Hyperu­ricemia treatment
No pharma­cot­herapy required , Target lifestyle modifi­cations