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GOUT
Case
A 45y/o obese male with h/o painfull ankle
associated with hottness and redness
since 2 days ago
 PMH: HTN, DM
 P/E: Signs of severe ankle arthritis

Gout
(monosodium urate crystal deposition
disease)
 is characterized biochemically by
extracellular urate supersaturation

Gout
Recurrent attacks of acute inflammatory
arthritis
 Accumulation of urate crystals in the form
of tophaceous deposits
 Uric acid nephrolithiasis
 Nephropathy

Epidemiology
incidence = 0.2-0.35/1000
 Prevalence = 1.6-13.6/1000
 Prevalance increased with age and uric
acid level
 The incidence rate of gout is 4.9% for
urate greater than 9mg/dl and 0.5% for
7-8.9 and 0.1% for less than 7mg/dl
 Familial incidence range from 11-80%

hyperuricemia
 Hyperurecemia:
Overproduction or
underexcretion of uric acid,the
byproduct of purine metabolism in
humans can result in hyperurecemia
 The upper limit = at 7 mg/dl in men
and 6 mg/dl in women

Decreased efficiency of renal uric acid
excretion is responsible for about 85 to 90
percent of primary or secondary
hyperuricemia .
 Supersaturated
concentration of urate
(> or= 6/8mg/dl)
 cause crystalization and deposition in
joints and other connective tissues
Purines
Uric acid
DNA
RNA
Pyrimidines
Energy
PRPP.Syn
APRT
GTP &
ATP &
XMP
5’N
IMP.D
HGPRT
5’N
AS.S
AMP. D
AMP.S
5’N
PNP
PNP
Guanase
Xantine oxidase
Xantine oxidase
Aden.PRT
Uric acid production
Ribose-5
phosphate
+ ATP
Uric Acid
PRPP Synthetases
PRPP
+ AMP
IMP
Salvage

Sometime free purine base are salvaged
and reused instead of degrading them all
the way to uric acid.
Salvage of purine Bases
Adenine
Phosphoribosylation
 Guanine
 Hypoxanthine

Primary
nuclotides
Hyperuricemia cascade
Dietary
purines
Tissue
nucleic
acids
Endogenous purine
synthesis
Urate
Overproduction
Underexcretion
Hyperuricemia
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid overproduction
• Primary hyperurecimia
·Idiopathic
·HGPRT deficiency
·PRPP synthetase superactivity
•Secondary hyperuricemia
·Excessive dietary purine intake
·Increased nucleotide turnover
myelo & lymphoproliferative dis. ,multiple myeloma
secondary polycytemia,pernicious anemia,hemoglobinopathy
hemolysis,infectious mononucleosis
·Accelerated ATP degradation
Glycogen storage dis( type3,5,7) ,G6PD
Fruoctose intolerance(F1P.aldolase)
Hypoxemia & tissue underperfusion
Sever muscle exertion ,acutly ill patient,MI, epilepsy
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
•Enhanced tubular urate reabsorption
•Mechanism incompletely defined
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
•Enhanced tubular urate reabsorption
•Mechanism incompletely defined
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
•Enhanced tubular urate reabsorption
•Mechanism incompletely defined
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
Competitive anions ( keto & lactic acidosis )
Polycyctic kidney, Lead nephropathy?
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
•Enhanced tubular urate reabsorption
Dehydration : diuretics,adrenal insufficency,
nephrogenic DI
Insulin resistance Syndrome
Uric acid Underexcretion
 Primary hyperurecimia
•Idiopathic
Secondary hyperuricemia
•Diminished renal function ( GFR)
• Inhibition of tubular urate secretion
•Enhanced tubular urate reabsorption
•Mechanism incompletely defined
Hypertension,Hyperparathyroidism,hypoparathyroidism
.hypothyroidism, Drugs (cyclosporine, pyrazinamide ,
ethambutol , salicylate, nicotinic acid) ,
Chronic lead nephropathy
Classification of hyperuricemia
3- Combined Overproduction & Underexcretion
• Alcohol consumption
• Inborn errors of metabolism
Glucose - 6 - phosphatase deficiency
Fructose -1- phosphate aldolase deficienccy
Conditions influencing the deposition
of urate crystals

Decreased solubility of urate
Low temperature
Low PH

Disturbance to the joint or soft tissue
Trauma or tissue injury or altered connective tissue matrix

Reabsorbtion of water resulting in
supersaturation
Lack of joint activity during sleep

Others
Gammaglobulin, insoluble collagen, proteoglycans

Urate crystal phagocytosis leads to an
inflammatory cascade and acute gouty
arthritis
Pathogenesis of acute gouty inflammation
Hyperurecimia
Urate crystals
Complement
activation
Synovial lining
Cell activation
Activation of mast cells
Activation of endothelium
Chemotactic factor
Synovitis
Neutrophil influx
Amplification of synovitis
by neutrophil activation
Extracellular urate
Urate-cell contact
Entrance of uric acid
Phagocytosis of urate
Late phagocytosis
Intracellular urate
CLINICAL SYNDROMES
1234-
Asymptomatic hyperurecemia
Acute flare
Intercritical segments
Advanced gout
Silent hyperurecemia
Silent deposition of urate crystals
 Elevated serum urate with no clinical
manifestation of gout

Acute flare
Acute inflammation in the joint caused by
urate crystallization ,often at night
 erythema. Swelling ,warmth in a joint
 Fever , chills and malaise may occure
 Untreated initial attach subside over 3-10
days
 90% first attack monoarticular( 50%
podagra)

Acute arthritis
initial or early attacks
 Lower
extremity and distal joint
involvement usually predominates
 however, the shoulders, hips,
sternoclavicular joints, and even the spine
and sacroiliac joints may become inflamed
and cause diagnostic confusion.
Polyarticular gouty arthritis
(less than 20 percent of instances), uncommon
as an initial manifestation),
 may be more frequent in patients with
secondary to a myeloproliferative or
lymphoproliferative disorder, or in organ
transplant recipients who are receiving
cyclosporine A. “
 . Polyarticular symptoms are particularly
common late in the course of untreated gout,
when multiple recurrences, short or absent
symptom free intervals, and tophaceous
deposits are common.

Acute arthritis
Acute arthritis
Precipitating factors in acute flare
Local trauma
 Binges of alcohol
 Overeating or fasting
 Concurrent acute medical or surgical
illness
 Marked rise or fall in serum uric acid
 Seasonal factors

Gouty hand
Gouty burcitis
Diagnosing Gout
Serum urate( may be normal)
 History and physical exam
 Synovial fluid analysis
 Diff is very important

Fluid analysis
microscope with crossed polarizing
filters
Birefringence phenomenon

when light enters a non-equivalent axis, it
is refracted into two rays, each polarized
with the vibration directions oriented at
perpendicular to one another and traveling
at different velocities.
Birefringent Crystals
Birefringent Crystals
Crystals bend light and become visible in joint
fluid when viewed through a microscope with
crossed polarizing filters
 When a compensator plate is used on the
microscope’,monosodium urate crystals parallel
to the axis of the compensator appear yellow
(negatively birefringent) and calcium
pyrophosphate dihydrate crystals parallel to the
axis of the compensator appear blue (positively
birefringent

Birefringent Crystals
negative birefringent Crystals
Positive birefringent Crystals
Criteria for clinical diagnosis
A classic history of one or more episodes of
monoarticular arthritis followed by intercritical periods
completely free of symptoms
 Maximum inflammation within 24 hours
 Rapid resolution of synovitis after colchicine therapy
 Unilateral first metatarsophalangeal joint attack
 Hyperuricemia
 Subcortical bone cysts apparent on plain radiograph
 Sterile joint fluid obtained from an affected joint during
an attack
 identify urate crystals, or in the presence of a negative
polarized light microscopic study

DIFFERENTIAL DIAGNOSIS
Pseudogout
 Septic arthritis
 Hydroxyapatite calcific tendinitis
 Sarcoid arthritis
 Erythema nodusum
 Rheumatoid arthritis
 Familial mediterranian fever

Etiology of
spontaneous resolution
TNF induced PMN apoptosis
 Membranolysis due to crystal ingestion
 Increased crystal coated by apolipoprotein
 Production of IL1 antagonist
 Increased tempreture and solubility
 ACTH secretion
 Increased circulation and moved crystal

ASSOSIATED CONDITION









Obesity
Diabetes mellitus
Hypertriglyceridemia
Hypertention
Athrosclerosis
Hypothyroidism
Ethanol consumption
Pregnancy
Syndrome X
NEGATIVE
ASSOCIATION CONDITION
Rheumatoid arthritis
 Systemic lupus erythmatosis
 Ankylosing spondylitis
 Long-term use of NSAID

Intercritical Segments
Clinically silent gout without crystal
deposition and potential hidden damage
 The intervals between acute flares
 The patient hasn’t any symptom but Joint
fluid revealed crystal in 12.5-58% with
mild leukocytosis
 In 78% , second attack occur within
6month to 2years

Synovial analysis during intercritical
period

extracellular urate crystals are identifiable
in synovial fluid from previously affected
joints in virtually all untreated gouty
patients
CHRONIC TOPHACEOUS GOUT
collections of solid urate in connective
tissues (which may be calcified).
 a chronic granulomatous inflammatory
response is identifiable on histological
examination of the lesions, and, on
occasion, acute inflammation mimicking
that of gouty arthritis occurs in one or
several tophi

CHRONIC ARTHRITIS

The average interval between the first
attack and chronic arthritis is 11.6 y
 2% gouty patients has crippling disease
 May polyarticular
History of intermittent attacks, additive& ascending
Gouty hand
Chronic taphus
Chronic gout
Gouty hand
Advanced gout
Advanced gout

Erosion in both
destructive and
hypertrophic leads to
overhanging edge
 Joint space is often
preserved untile very
late in the disease
process
Taphous
Over hanging
Taphous
Crystal precipitate in joint and soft
tissues
RENAL COMPLICATIONS OF
CHRONIC HYPERURICEMIA
nephrolithiasis;(only5 to 10 percent of all
urinary tract stones in the United States
and Europe)
 chronic urate nephropathy

three major risk factors for uric acid
nephrolithiasis
Increased uric acid excretion
 Reduced urine volume
 Low urine pH, a setting in which most of
the uric acid exists as the intact insoluble
acid.

Uric acid stone
Chronic urate nephropathy
urate may deposit in the renal medullary
interstitium.
 Deposition in this area induces a modest
chronic inflammatory (tophaceous)
reaction, and varying degrees of fibrosis

Treatment of Gout
•
The therapeutic aim in gout :
1- To terminate the acute attack
2- To prevent recurrence of acute gouty
arthritis
3- To prevent or reverse complications of
the diseases
4 - To prevent or reverse associated feature
( Obesity , hypertriglyceridemia and
hypertension )
Treatment
Anti-inflammatory therapy — prompt and
safe termination of the acute arthritic
attack
 Prophylaxis — prevention of recurrences
of acute gouty arthritis
 Antihyperuricemic therapy

Treatment of Gout
• Acute
Gouty arthritis
· Colchicine
· NSAID
· Corticosteroid
•· Prophylaxis
·Colchicine
· NSAID
• Control
of hyperuricemia
· Allopurinol
· Uricosuric agents ( Probenecid, sulfinpyrazone )
The recommended duration of prophylactic
colchicine or NSAIDs during the initiation of
uric acid lowering therapy
In patients without evident tophi,
prophylaxis can be safely discontinued 6
months after normal serum urate values
have been obtained.
 The optimal duration of prophylactic
therapy for patients with tophi is
uncertain.

COMORBID RISK REDUCTION

Nutritional strategies (eg, achievement of
ideal body weight, reduction of dietary
protein intake, and limitation of ethanol
consumption) can treat both the
associated conditions and hyperuricemia
general goal of antihyperuricemic
therapy

is a serum urate concentration of 5 to 6
mg/dL [297 to 357 µmol/L], a level
substantially below that at which
monosodium urate is saturating in
extracellular fluids.
Indication of antihyperurecemic
therapy






Frequent and disabling attacks of gouty arthritis
(three or more per year)
Clinical or radiographic signs of chronic gouty
joint disease
Tophaceous deposits in soft tissues or
subchondral bone
Gout with renal insufficiency
Recurrent nephrolithiasis
Urinary uric acid excretion exceeding 1100
mg/day (when determined in men < 30 years of
age and premenopausal women)
Xanthine oxidase inhibitors

xanthine oxidase inhibitors are likely to be
effective in virtually all circumstances
warranting therapy for gout ( Allopurionl)
Uricase (urate oxidase)
Uricase, an enzyme that converts urate to
a more soluble molecule ( allantoin).
 uricase can reduce the size of tophi in
patients with tophaceous disease,
 Conversion of urate to allantoin by uricase
action thus has the potential to be helpful
in patients who are allergic or refractory to
treatment with allopurinol.

Other drugs that enhance uric
acid excretion
Losartan
 Fenofibrate
