The Hyperuricemia Cascade

1

• 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 Elevated serum urate
with no clinical gout
Acute flares Acute inflammation from urate
crystallization

Intercritical segments Intervals between flares
Advanced gout Long-term gouty complications of
uncontrolled hyperuricemia
Uncontrolled hyperuricemia
2

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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
3

• 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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
4

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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
5

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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
6

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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
7

Termination of the Acute Flare Considerations
for Agent Selection ______________________________
_________________ Agent
Considerations NSAIDs .
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, gt 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 lt6 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)

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
8

Advantages to Existing Arsenal Of Urate-lowering
Agents ___________________________________________
__ Agent
Advantage Uricosurics . 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 v
v Drug interaction
v v Target serum
urate not always achieved v
v Potentially fatal hypersensitivity
syndrome v Nonselective enzyme inhibition
v Risk of nephrolithiasis
v Multiple daily
dosing
v
__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________

• Therapeutic Challenges Warrant
• New Agents to Treat Gout
• _____________________________________________
• . Serum urate not always lowered to lt6 mg/dL
• . Treatment gaps exist in patients with
• - Renal insufficiency
• - Allergies
• - Allopurinol intolerance
• - Drug interactions

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
9

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
. Heart failure . Obesity
. Hyperlipidemia . Metabolic
syndrome . Hypertension . Diabetes
mellitus . 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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
10

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
- Cyclosporine .
Postmenopause . High alcohol intake
. Advanced age - Liquor, Beer
. Medications . 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

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
11

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 gt6.8 mg/dL

__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________
12

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 ____________________________________________
__
13

Treatment Goals 3.Urate-lowering Therapy to
Prevent Flares and Disease Progression ___________
_________________________ . Lowering urate to lt6
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 lt mg/dL
__________________________________________________
__________________________________________________
__________________________________________________
__________________________________________________
________________________________