Gout it is a group of diseases characterized by hyperuricaemia and uric acid crystal formation These clinical syndromes include gouty arthritis tophaceous gout uric acid nephrolithiasis ID: 914803
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Slide1
Crystal arthropathies
Gout
Slide2it is a group of diseases characterized by hyperuricaemia and uric acid crystal formation. These clinical syndromes include gouty arthritis, tophaceous
gout, uric acid
nephrolithiasis
, and gouty nephropathy. In its more narrow and perhaps more commonly used definition, gout refers to arthritis caused by uric acid crystals
.
Risk
factors for primary gout
Male gender
Age >40 years
Obesity
Family history
Alcohol use
Renal insufficiency
Hypertension
Slide3Purine metabolism
Slide4Mechanisms of hyperuricaemia
in primary gout
Primary gout is simply defined by the absence of any identifiable underlying disease causing
hyperuricaemia
. This criterion defines the largest group of patients with gout.
Most
of these patients are older men and 80–85 per cent are
hyperuricaemic
on the basis of
underexcretion
of uric acid.
There
is no difference in rates of intestinal
uricolysis
in patients with primary gout compared with controls. Thus, the site of the abnormality in patients with primary gout who
underexcrete
is most likely to be at the kidney.
most patients with primary gout have low fractional uric acid excretion rates. The mechanism of underexcretion remains to be elucidated but is most likely a defect in secretion or
reabsorption
rather than in filtration.
A minority of patients with primary gout have high urinary uric acid levels and excessive de novo
purine
synthesis.
The best evidence to date supports a role for increased PRPP availability or decreased
purine
nucleotide concentrations (thus diminishing feedback inhibition of the synthetic enzymes) in patients with primary gout who overproduce uric acid
Slide6H G PT deficiency produces hyperuricaemia
by increasing de novo synthesis of
purine
nucleotides through increased availability of the substrate PRPP, which stimulates synthesis
.
In
its most complete form
,
H
GP
T
deficiency results in the
Lesch–Nyhan
syndrome. This syndrome presents in early childhood with severe mental retardation, self-mutilation,
choreoathetosis
, spasticity,
hyperuricaemia
, and premature gout. Although it is linked to the X chromosome, there are two reported cases in girls
.
Partial defects of HGP T result in
hyperuricaemia
alone without the severe neurological consequences of complete
H
G
P T
deficiency.
The diagnosis of
H
G
P T
deficiency can be made by documenting low
H
G
P T
activity in erythrocytes. Numerous different genetic mutations have been described
in
H
G
P T
deficiency
Slide8Mechanism through wich MSU crystal cause
inflamation
Slide9Clinical features
Articular
gout is often divided into four clinical stages. The first stage is defined by asymptomatic
hyperuricaemia
. This is followed by acute gouty arthritis and then by another asymptomatic phase termed
intercritical
gout. When allowed to proceed untreated, some patients will go on to develop chronic
tophaceous
gout.
Acute gout
The first clinical symptom of gout is usually an acute, self-limited,
monoarticular
inflammatory arthritis affecting the joints of the lower extremities. Gout has a predilection for the first
metatarsophalangeal
joint(
Podagra
). As many as 50–70 per cent of first gout attacks occur in the big toe. Other frequently involved joints include those of the foot, ankle, knee, wrist, elbow, and the small joints of the hands. The large axial joints and those of the spine are uncommon sites for early acute gout attacks.
Slide10Slide11The onset of an attack occurs suddenly and often late at night or early in the morning. Patients will describe very severe pain, associated with swelling, extreme tenderness, and redness overlying the joint. Without intervention, the attack will usually subside within 5–7 days. Low-grade fever, malaise, and anorexia may occur. The attack may be preceded by brief twinges of pain (petit attacks) in the affected joint.
Common precipitants of acute attacks include excess alcohol intake,
intercurrent
illness, surgery, starvation, trauma, and the initiation of drugs that alter
urate
metabolism. All of these precipitants alter serum
urate
levels.
Slide12Physical examination shows signs of inflammation with erythema, warmth, and swelling over the joint, often extending to the overlying skin. There is exquisite tenderness over the affected joint.
Not infrequently, an overlying
cellulitis
or accompanying
tenosynovitis
occurs. The skin may desquamate in the later days of an attack.
Acute gout can also occur in bursas, and gout is a common cause of acute inflammatory
olecranon
bursitis.
After the attack resolves, the patient will be completely asymptomatic. This phase is referred to as
intercritical
gout. Most patients will go on to have an additional attack within 2 years of the first attack.
Slide13In one study, 78 per cent had recurrent attacks within 2 years, and after 10 years, 93 per cent had had more than one attack .Untreated, the intercritical
phases become shorter. Interestingly, they still present an opportunity for diagnosis, as many joints will still have
urate
crystals in the synovial fluid during the
intercritical
phase if they were involved in a previous attack, and
urate
-lowering therapy has not been initiated
Slide14Chronic tophaceous gout
In the later stages of untreated disease, clinical manifestations characteristically change. Acute attacks are more often
polyarticular
. The
intercritical
stage shortens, and repeated joint damage results in permanent deformities, loss of motion, chronic pain, and
tophi
.
Polyarticular
gout occurs in late-stage disease, although some patients present earlier with
polyarticular
attacks.
Intercritical
stages are short or non-existent and involvement of atypical sites including the upper extremities, the spine, and axial joints may ensue. After repeated attacks in a single joint, deformity and loss of motion may occur.
Slide15Tophi are deposits of urate embedded in a matrix composed of amorphous
urates
, lipids, proteins, and
calcific
debris .
Tophi
are usually subcutaneous, but they rarely occur in bone and other organs including the heart valves and the eye.
Classic sites include the
pinna
of the ear, bursas around elbows and knees, the dorsal surfaces of the
metacarpophalangeal
joints, and the Achilles tendon.
Tophi
are not distinguishable on physical examination from rheumatoid nodules or other subcutaneous nodules. There is no accompanying inflammation and they are usually painless. The overlying skin may be taut and shiny. A thick white or whitish-yellow
exudate
is seen if the skin integrity is compromised.
Slide16Slide17Tophi or chronic polyarthritis may occur as early as 3 years or as late as 42 years after the first acute attack. In the pre-treatment era, 50 per cent of patients with gout had
tophi
after 10 years of disease . Currently, about 5 per cent of patients with gout will have
tophi
.
Their occurrence is directly correlated with serum
urate
levels, and they identify a group of patients with severe and prolonged
hyperuricaemia
.
Another group at risk of developing
tophi
and
polyarticular
gout are elderly women with primary nodal osteoarthritis on diuretic therapy
Slide18Urate nephropathy The pathological changes that define
urate
nephropathy are common. MSU crystals in the renal medulla are associated with a giant-cell inflammatory reaction. The clinical significance of these pathological findings, however, remains unclear.
Renal insufficiency is unequivocally common in patients with gout, but controversy exists as to the
aetiology
of this renal dysfunction. Current dogma states that
urate
crystals themselves produce only a minor amount of renal damage.
Slide19Most of the renal disease associated with gout is secondary to inadequately controlled hypertension, non-steroidal anti-inflammatory drug (NSAID) use, and other comorbidities Uric acid
nephrolithiasis
the risk factor is high serum
urate
&low
urin
PH.
Slide20Laboratory investigation
Synovial fluid analysis remains the single most important diagnostic study in the patient with suspected gout. Synovial fluid is usually easily obtained from a large joint, while often only a drop of fluid or blood from the joint or adjacent tissues is necessary to provide a sample for definitive diagnosis of gout in a small joint. Synovial fluid is typically inflammatory with a mean white cell count of 20 000 cells/mm
3
.
Most cells are
polymorphonuclear
leucocytes. Viscosity is often poor. A definite diagnosis can be made if typical, negatively
birefringent
, needle-shaped crystals are seen in the fluid with a polarizing light microscope .
They may be extra- or intracellular. Rarely one may see spherules of uric acid in acute gout.
Slide21Few other laboratory studies are of significant clinical utility in diagnosing acute gout. Serum uric acid levels during the acute attack may not reflect pre-attack levels and cannot be used to make a diagnosis of gout in the absence of urate
crystals in the synovial fluid.
One may see a peripheral
leucocytosis
, an elevated erythrocyte sedimentation rate, and increased levels of other acute-phase reactants during an acute attack. Synovial fluid cultures and Gram stains may help rule out concurrent infection.
Radiographs are often normal during early episodes of gout. They may be useful to differentiate other problems such as fracture or infection from acute gout. Often, soft tissue swelling is the sole radiographic finding in early gout.
Slide22Diagnosis
definitive diagnosis of gout can only be made by the identification of
urate
crystals in the synovial fluid of an affected joint. Identification of
urate
crystals in
tophi
also allows a definitive diagnosis to be made.
In the absence of these findings, other clinical criteria may be used to make a putative diagnosis of gout
As crystals may be present in the
intercritical
phase, one may aspirate an asymptomatic but previously affected joint to establish a definite diagnosis. Many clinical conditions can mimic acute gout
These include infectious arthritis, other crystal-associated
arthropathies
such as
pseudogout
or BCP-associated
periarthritis
, or trauma.
Patients with palindromic rheumatism may give a similar history of self-limited monoarticular
attacks associated with exquisite pain, tenderness, and
erythema
near the affected joint.
Rarely, other causes of
polyarticular
inflammatory arthritis, particularly psoriatic arthritis or Reiter's syndrome, may present with
monoarticular
self-limited attacks of the lower extremities that may be confused with gout.
Once
tophi
and deformities occur, gout can be misdiagnosed as rheumatoid arthritis. As many as 30 per cent of patients with gout will have positive serum rheumatoid factors .
Slide24Clinical conditions that mimic gouty arthritis CPPD disease (
pseudogout
) *Psoriatic arthritis
BCP arthritis *Rheumatoid arthritis
Cellulitis
Erythema
nodosum
arthritis
Trauma
Palindromic
rheumatism
Reiter's syndrome
Slide25Slide26Slide27Management of gouty arthritis
divided into three phases: treatment of acute gout, treatment of chronic or
tophaceous
gout, and preventive measures
Management of acute gout
Traditional therapies for acute gout include NSAIDs,
colchicine
, and steroids. Rest and splinting of the affected joint may be helpful adjuncts to any pharmacological therapy.
Colchicine
Colchicine
tends to be much more effective in the early hours of an attack and loses efficacy with time. The mechanism of action of
colchicine
is unknown. It inhibits
polymorphonuclear
leucocyte
function through its action on microtubules, but may also have very specific effects on crystal-induced inflammation .
Colchicine
can be given in intravenous and oral forms.
Slide28A dose of 1–3 mg diluted in 20 ml of normal saline can be slowly instilled into a large vein. Another 1-mg dose can be given 6 h later if the clinical response is incomplete. The maximum dose is 4 mg in 24 h. No additional doses should be given for 7 days after the initial dose. Intravenous
colchicine
is particularly useful for patients unable to take oral medications. Now that
parenteral
forms of NSAIDs are available, its use may decline further.
Absolute contraindications to the use of intravenous
colchicine
include significant renal or hepatic compromise, bone marrow suppression, or sepsis. It should be used with great caution in patients with mild renal or hepatic disease, or those on daily oral
colchicine
prophylaxis.
Slide29Side-effects range from venous sclerosis or tissue damage from extravasation of
colchicine
, to fatal bone marrow failure. Other side-effects include renal or hepatic failure, disseminated intravascular coagulation, and neuromuscular toxicity. Deaths from misuse of intravenous
colchicine
have been reported
Corticosteroids
Regimens for acute gout include intramuscular ACTH, intramuscular
triamcinolone
, and oral steroids .
These regimens are safe and well tolerated. Their efficacy remains to be proven. They may be particularly useful for patients in whom NSAIDs and
colchicine
are contraindicated. The use of intra-
articular
steroids is less controversial. Although no studies of the efficacy of intra-
articular
steroids have been published, they remain a mainstay of therapy in patients unable to tolerate more traditional therapies.
Slide30Allopurinol Allopurinol
is the drug most commonly used for the prevention of acute gout and the treatment of chronic
tophaceous
gout .It is a
xanthine
oxidase
inhibitor and thus decreases uric acid production. It may also have other actions .
It is very effective in lowering serum uric acid levels and is the drug of choice for patients with renal insufficiency, a history of
nephrolithiasis
, or
tophi
.
It is also indicated in patients who clearly overproduce uric acid such as those with
tumour
lysis
syndrome or primary metabolic defects.
Allopurinol
is usually given as a once daily dose of 300 mg.
Slide31The most common side-effects include a hypersensitivity syndrome of rash and fever. Life-threatening reactions, including fulminant hepatitis, interstitial nephritis, and toxic epidermal
necrolysis
, are even more unusual. Patients with renal disease may have a greater incidence of drug allergy.
Allopurinol
can be given cautiously to an allergic patient using available desensitization regimens .
Slide32Uricosurics Probenecid
and
sulfinpyrazone
are the most commonly used
uricosuric
drugs. They interfere with the renal handling of
urate
by altering organic anion transport, thus increasing
urate
excretion.
Uricosurics
are contraindicated in patients with
nephrolithiasis
and ineffective in patients with significant renal compromise, or those using acetylsalicylates. Side-effects include rare hypersensitivity reactions, rashes, gastrointestinal complaints, and
nephrotic
syndrome.
Benzbromarone
is a
uricosuric
drug available in Europe. Unlike other commonly used
uricosuric
drugs, it is effective in patients with renal insufficiency
Slide33Less potent uricosuric agents include the angiotensin 1 receptor antagonist
losartan
, and the lipid-lowering agents
atorvastatin
and
fenofibrate
.
New
urate
lowering agent as
Febuxostat
, which inhibits
xanthine
oxidase
through a different mechanism than
allopurinol
and
oxypurinol
, blocks substrate access to
xanthine
oxidase
by occupying a channel in the enzyme leading to the active site.
Slide34Gout & food