Uric Acid, Hyperuricemia, and Gout

____________________________________________________

Uric acid (urate) end product of purine degradation

in humans
Hyperuricemia serum urate concentration
exceeds urate solubility (~6.8 mg/dL)
- Caused by overproduction and/or underexcretion of
uric acid
- No gout without crystal deposition

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Gout deposition of monosodium urate crystals

in tissues

The Hyperuricemia Cascade

_________________________________________
Urate
Overproduction
Underexcretion
Hyperuricemia

Silent
tissue
deposition

Gout

Renal
manifestations

Associated
cardiovasclular
events and
mortality

____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________

Gout
One Chronic Disease, Best described by 4 Stages
______________________________________________
Asymptomatic
hyperuricemia

Acute flares

Elevated serum
urate with no
clinical gout

Acute
inflammation
from urate
crystallization

Intercritical
segments
Intervals
between
flares

Advanced gout
Long-term gouty
complications of
uncontrolled
hyperuricemia

Uncontrolled hyperuricemia

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

How Silent Tissue Deposition

Causes Acute Flares
____________________________________________________

1.

Hyperuricemia leads to extracellular

accumulation of urate

2.

Urate crystals form

3.

Urate crystals deposit in joint(s)

4.

Inflammatory process initiated

5.

Acute flare

___________________________
___________________________
___________________________
___________________________
___________________________
___________________________
___________________________
___________________________

Clinical manifestations
Of an Acute Gout Flare
___________________________________________
. Abrupt onset severe joint inflammation,
often at night
- Warmth, swelling, erythema, and pain
- Fever may occur

. Untreated initial attacks subside over 3-10 days

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. 90% of first initial attacks are monoarticular

- 50% podagra

Sites of Acute Flares

___________________________________________

1. 90% of gout patients eventually experience

podagra
- Acute flare in the first metatarsophalangeal
(MTP) joint
2. Gout can also occur in other joints, bursae, and
tendors

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Intercritical Segments
______________________________________________
Asymptomatic intervals between flares
- Gout clinically inactive
Disease, if untreated, may continue to advance
- Intercritical segments may shorten over time
- Crystals may still be found in asymptomatic joints
- Uncontrolled hyperuricemia continues to increase body

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

urate stores

Advanced Gout
________________________________
.

Uncontrolled hyperuricemia increases tissue

urate stores

Deposition may progress to

- Chronic arthritis
- Radiographic changes
- Development of tophi

____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________
____________________________

. Acute flares continue

Advanced Gout
Chronic Arthritis and Acute Flares
_______________________________________________

. Chronic arthritis
- Joints are persistently uncomfortable, stiff, and swollen

Intensity of pain is often less than acute flares

. Acute flares may still occur

- Polyarticular involvement may develop
- Attacks become additive and ascending

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Advanced Gout
Tophaceous Deposits
_______________________________________________

. Solid urate deposits in tissue

- Irregular, destructive nodularities produced

. Risk factors include

- Long duration of hyperuricemia
- High serum urate levels

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

- Long periods of active, untreated gout

Diagnosing Gout
_______________________________________________

. History and physical

. Synovial fluid analysis
. Serum urate not a reliable measure
- May be normal at the time of flare
Urinary uric acid excretion increased
during acute flares
- May be elevated with joint symptoms
from other causes

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Risk Factors for the

Development of Gout
______________________________________________

. Male gender
. Female gender postmenopause
. Advanced age
. Drugs
- Diuretics, low-dose aspirin (ASA), cyclosporine

. Hypertension

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Risk Factors for the

Development of Gout (contd)
____________________________________________

. Transplant
. High alcohol intake
- Highest with beer, followed by liquor
- No increased risk with wine

. High body mass index

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. Diet high in meat and seafood

Synovial Fluid Analysis
Compensated Polarized Light Microscopy
__________________________________________

. Gold standard to confirm gout

. Urate crystals identified by
- Needle and rod shapes

- Strong negative birefringence

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. Crystals intracellular during attacks

The Importance of a
Differential Diagnosis
_____________________________________________
Think about gout before diagnosing other
diseases with different and/or less specific therapies
- Pseudogout-Calcium
- Rheumatoid arthritis (RA)
pyrophosphate
. Nodules potentially
deposition
confused with
disease (CPPD)
tophi
. Chrondrocalcinosis
- Osteoarthritis
. Rhomboid-shaped
- Septic arthritis
crystal
- Cellulitis
- Psoriatic Arthritis

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Differential Diagnosis Example

CPPD
_____________________________________________

. Clinically similar to gout

- Acute attacks of inflammation in joints

. Crystals different under compensated polarized

light
- Weakly positively birefringent

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

- Rhomboid, rods, squares or irregular

The Treatment Goals for Gout

_______________________________________________
1. Rapidly terminate the acute flare
2. Protect against further flares
- Reduce the chance of crystal-induced
inflammation
3. Treat the hyperuricemia and prevent disease

progression

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

- Long-term correction of the metabolic cause

- Sufficient lowering of serum urate depletes
total body urate pool

1.Termination of the Acute Flare

_____________________________________________

. Control crystal-induced inflammation and pain

and resolve the flare
- Not cure for gout
. Resolves the symptom
. Urate crystals remain in the joint
. Serum urate should NOT be lowered
during flare
- Choice of medication not as critical as
. Rapid initiation of therapy
. Appropriate duration of therapy

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Termination of the Acute Flare:

Considerations for Agent Selection
_______________________________________________
Agent
NSAIDs

Considerations
. Contraindicated in peptic ucler disease, GI bleeds,
history of aspirin or NSAID-Induced asthma, renal
dysfunction

. Interaction with warfarin (consider COX-2)

Colchicine

. Not effective late in the flare

. Contraindicated in dailysis patience
. Use with caution with renal or hepatobillary dysfunction,
active infection, > 70 years of age
. Drug interactions with cyclosporine, statins, macrolides
. Use of IV formulation controversial and should be used with
extreme caution; IV use can cause local tissue necrosis

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Corticosteroids
And ACTH
. Worsening of glycemic control in diabetics
. May need to add other anti-inflammatories or use
moderate-to-high doses

2.Protection Against Further Flares

_______________________________________________

. Colchicine 0.5-1 mg/day or low-dose NSAIDs:

- Decrease frequency and severity of flares
- Prevent disease flares associated with initiation
of urate-lowering therapy
. Homeostatic mechanisms mobilize deposited crystals

. Will not stop destructive aspects of gout

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

3.Treating Hyperuricemia and

Preventing Disease Progression
_____________________________________________

. Lowering urate to <6 mg/dL allows depletion of

- Total body urate pool
- Deposited crystals

. Therapy should be lifelong and continuous

- Otherwise, symptoms (eg, acute flares, tophi) recur

. Available urate-lowering agents for gout

- Uricosuric agents (probenecid, losartan [mild],
fenofibrate [mild]
- Xanthine oxidase inhibitor (allopurinol)

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Advantages to Existing Arsenal

Of Urate-lowering Agents
_____________________________________________
Agent
Uricosurics

Advantage
. Reverses most common physiologic
abnormality in gout
- ~90% of patients are underexcretors of uric acid

Allopurinol

. Effective in both overproducers and

underexcretors
. Single daily dose

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. Can be efficacious in patients with renal

insufficiency

Limitations to Existing Arsenal

of Urate-lowering Agents
______________________________________________
Allopurinol

Uricosurics

Renal function an issue

Drug interaction

Target serum urate not always achieved

Potentially fatal hypersensitivity syndrome

Nonselective enzyme inhibition

Risk of nephrolithiasis

Multiple daily dosing

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Therapeutic Challenges Warrant

New Agents to Treat Gout
_____________________________________________

. Serum urate not always lowered to <6 mg/dL

. Treatment gaps exist in patients with
- Renal insufficiency
- Allergies
- Allopurinol intolerance
- Drug interactions

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Why the Increased

Epidemiology of Gout?
_____________________________________________

. Increased prevalence of risk factors and

comorbidities
- Longevity
- Diuretic and aspirin use
- Hypertension

. Dietary trends
. Improved survival from comorbidities
. Limitations in treatment

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Why Worry About Gout?

Gout May be a Signal for
Unrecognized Comorbidities
____________________________________
Comorbidities associated with hyperuricemia
. Renal manifestations
. Obesity
. Metabolic syndrome
. Diabetes mellitus

. Heart failure
. Hyperlipidemia
. Hypertension
. Cardiovascular disease

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Summary
_____________________________________________

. Gout needs to be
- Accurately diagnosed
- Recognized as a chronic disease with 4 stages
- Treated separately for
. Terminating acute flares
. Controlling chronic hyperuricemia and tissue
deposition

. Potentially exciting new therapies are under

development

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Teaching Points
_____________________________________________

Hyperuricemia is linked to comorbidities:

. Obesity

. Hyperlipidemia

. Metabolic syndrome

. Hypertension

. Diabetes mellitus

. Renal disease

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. Heart failure

Teaching Points
____________________________________
Risk factors for hyperuricemia and gout
. Heredity

. Transplanation

. Male gender
. Postmenopause
. Advanced age

. Medications

- Cyclosporine
. High alcohol intake
- Liquor, Beer

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. High body mass index

. Diet

Teaching Points
_____________________________________________

. Gout

can manifest in any joint

- 1st MTP only 50% of the time

. During the flare

- Urate may be normal 50% of the time
- Promptly initiate agents for termination

. After the flare

- Consider urate-lowering agents with prophylaxis
. Risk / Benefit assessment

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Treatment Goals
1.Termination of the Acute Flare
________________________________
. Anti-inflammatory medication to suppress
crystal-induced inflammation
- Not a cure for gout
. Resolves the symptoms
. Urate crystals remain in the joint

. For efficiency, choice of medication not as

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

critical as:
. Appropriate dose of therapy
. Appropriate duration of therapy

Treatment Goals
2. Anti-inflammatory Therapy to
Prevent Further Flares
___________________________________________________________

. Colchicine 0.6 mg qd/bid or low-dose NSAIDs:

- Decrease frequency and severity of flares
- Can decrease disease flares associated with
initiation of urate-lowering therapy
- May not stop destructive aspects of gout

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

. Safety of chronic NSAIDs vs colchicine:

- Colchicine lower GI, neuromuscular
- NSAID upper GI, renal, HTN, Na retention

Hyperuricemia and Gout

_____________________________________________

. Laboratory defined hyperuricemia is NOT the same

as biologically defined hyperuricemia

. Virtually all patients with gouty arthritis have

biologicall defined hyperuricemia
- Urate deposites in tissues when >6.8 mg/dL

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Imaging
____________________________________

. Radiographic changes of gout are seen in up to 50%

of patients

. Most common involved joint is the first MTP joint,

other toes, ankles, hands

. Bone mineralization is initially normal

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Imaging (continuing)
___________________________________________________________

. Finding include soft-tissue tophi (containing

birefringent monosodium urate crystals)

. Punched-out erosious with siderotic borders and

overhanging edges

. Preservation of the joint space

. Good bone denstity (unlike RA)

X-Ray
______________________________________________

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

Treatment Goals
3.Urate-lowering Therapy to Prevent
Flares and Disease Progression
____________________________________

. Lowering urate to <6 mg/dL

- Tophus reabsortion and uric acid excretion

. Therapy should be lifelong and continuous

- Symptoms ( eg, acute flares, tophi) recur if stopped

. Available urate-lowering agents for gout

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

- Uricosuric agents ( probenecid, losartan [mild],

fenofibrate [mild]
- Xanthine oxidase inhibitor (allopurinol)

Conclusion
___________________________________________________________

. Gout is a chronic disease caused by the deposition of

urate crystals resulting from hyperuricemia

. Uncontrolled hyperuricemia can cause significant

joint manifestations

. Hyperuricemia is associated with other prevalent

comorbidities: hypertension, obesity, hyperlipidemia,
and insulin resistance

. Anti-inflammatory agents control the symptoms of

gout, but treating the disease may require lowering
the serum urate
- Assess the risks and benefits

. When administering urate-lowering therapy, the

defined serum urate is 6 < mg/dL

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________