Post on 05-Dec-2014
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GOUTDr. Mohanad
Purines
Purines are natural substances found in all of the body's cells, and in virtually all foods.
The reason for their widespread occurrence is simple: purines provide part of the chemical structure of our genes and the genes of plants and animals
When cells die and get recycled, the purines in their genetic material also get broken down.
Uric acid is the chemical formed when purines have been broken down completely.
Hyperuricemia The condition when there are high
concentrations of uric acid in the blood.
Serum levels of uric acid are >7mg/dL (Normally, 2.4-6mg/dL in females; 3.4-7mg/dL in males)
At such a high level, uric acid tends to aggregate and form crystals
Primary Hyperuricemia: an innate defect in purine metabolism and/or uric acid excretion
Secondary Hyperuricemia: high uric acid levels due to medications/medical conditions such as diabetic ketoacidosis, psoriasis, chronic lead poisoning
Most uric acid dissolves in blood and travels to the kidneys, where it passes out in urine.
If your body produces too much uric acid or doesn't remove enough if it, you can get sick.
High levels of uric acid in the body is called Hyperuricemia.
Purine nucleotides
hypoxanthine
xanthine
Uric acid
Xanthine oxidase
Alimentary excretion
Urinary excretion
Tissue deposition in excess
Urate crystal microtophi
Phagocytosis with acute inflammation and arthritis
uricosurics
colchicine NSAID
Allopurinol
Oxypurinol
Uric Acid
Uric acid is the end product in purine metabolism
Excretion of uric acid removes nitrogenous wastes from body
2/3 of uric acid made is excreted via kidneys; 1/3 via GI tract
Urate: protonated form of uric acid
Uric acid can accumulate due to: Overproduction of purine nucleotides Enhanced cell turnover (purine degradation) Decreased in purine salvage pathway Underexcretion of uric acid
Predisposition to many diseases
People may live with elevated uric acid levels without experiencing any symptoms
GOUT
Gout and gouty arthritis
Transient attacks of acute arthritis initiated by crystallization of urates and neutrophils, followed by chronic gouty arthritis with tophi in joints and urate nephropathy
Sites: 50% have initial attack in first metatarsophalangeal joint; also ankles, heels, knees, wrists, fingers, elbows
Gout
Affects less than 0.5% of the population.
It is a common condition, presenting in 1-4% of adult men.
Due to familial disposition, incidence may be as high as 80% in families affected by disorder.
Alcohol and Gout
alcohol metabolism contributes to urate retentionsome red wines contain purines or oxypurines,
which lead to an increased purine loadalcohol may contribute to obesity which is
associated with under excretion of uric acid
Patients with a history of gout are advised to drink plenty of fluid, approximately 2 litres per day (nonalcoholic).
GOUT
Primary gout (90%): idiopathic with overproduction of uric acid
Hyperuricemia in the absence of other diseaseAsymptomatic hyperuricemia can precede gout
Impaired secretion by kidneys
Secondary gout (10%): increased nucleic acid turnover due to
chronic renal disease, HGPRT deficiency( hypoxanthine-guanine
phosphoribosyl transferase deficiency)Tumors
LeukemiasLymphomasAfter chemotherapy
AlcoholismAccelerated ATP catabolism
"se co n da ry go u t"
H G P R T
E n zym a tic d e fic ie n cy
"se co n da ry go u t"
L e u ke m ia
In c rea se d n uc le ic a c id tu rno ver
"p rim a ry g o u t"
U n kn o w n d e fe ctca u sin g d e cre a se d exc re tion
H yp e ru rice m ia
GOUT
Arthritis: synovial fluid is poorer solvent for sodium urate than plasma, so with hyperuricemia.
Urates in joint fluid crystallize, particularly in ankle due to lower temperature; crystals develop in synovial lining cells, stimulate formation of antibodies, which accelerates formation of new crystals.
Release of crystals attracts neutrophils and complement, (generates c3a, c5a, attracts more neutrophils),
Releases free radicals, releases lysosomal enzymes
GOUT
This will eventually causes acute arthritis that last days to weeks without treatment; repeated attacks of acute arthritis cause
Renal failure, urate stones
Risk factors for gout with Hyperuricemia are:
Age > 30 years, Male, familial history of gout, Alcohol use, Obesity, Thiazide administration(reduce the clearance of uric
acid)
Pathogenesis
Enzymatic deficiencies and increased nucleic acid turnover account for only 10% of gout patients.
Remaining 90% are “primary gout” due to an unknown defect limiting the ability to excrete uric acid.
Pathogenesis
Uric acid normally dissolves in plasmaPoorly soluble in synovial fluid and
precipitates out as MSU crystals (monosodium urate crystals )
Pathogenesis
Hyperuricaemia
May be asymptomatic
Deposition of monosodium urate crystals in synovial tissue(contain various Ig’s, complement, fibrinogen, fibronectin)
Complement activated
Neutrophils phagocytose & lyse crystals
Release chemical mediators (e.g. TNF-α; IL-1)
ACUTE GOUTY ARTHRITIS
May resolve & become asymptomatic
(INTERCRITICAL GOUT)
May have recurrent episodes
Large deposits of chalky white urate tophi
Chronic granulomatous inflammatory condition
Fibrosis of synovium
Erosion of articular cartilage
CHRONIC TOPHACEOUS ARTHRITIS
ankylosis
Tophi may be deposited in soft tissue
Can ulcerate if sub-cutaneous
Pathogenesis of Renal Involvement
Hyperuricaemia
Freely filtered by glomerulus, but reabsorbed in proximal convulated tubules
Precipitation in renal tubules
Tubule obstruction
Crystal formation in interstitium
Renal stones
Recurrent pyelonephritis
Crystal Studies
Sodium urate crystals viewed under polarized light with a red plate makes those in the plane of the long axis of the red plate yellow, which indicates that they are negatively birefringent.
Clinical features
Acute gouty arthritisPainfulInvolves one joint initially, then polyarticularPodagra (painful, red metatarsophalangeal
joint)Tophaceous gout
Development of tophiChalky, cheesy, yellow-white, pasty deposits of
monosodium urate crystalsHelix and antihelix of earAchilles tendon
Stages of Gout
Asymptomatic HyperuricemiaAcute AttackIntercritical PeriodChronic Gout
Acute gout
Sudden onset Lasts 1-2wMay be triggered by – trauma, operation, alcohol,
exercise
Sites 1st MTP (75%)Ankle Finger Olecranon
Chronic gout
Polyarticular gout Tophi may form around joints and often also in the
pinna of the ear and with time may ulcerate and discharge
May cause joint stiffness and deformity as a result of joint erosion
May cause renal damage due to deposition of urate crystals in the renal parenchyma
Urate urolithiasis occurs in 10%; rarely chronic urate nephropathy with renal failure may develop
Acute on chronic gout
Diagnosis
More than one attackMaximum inflammation
in one dayMonoarthritisRednessFirst MTP involvedUnilateral first MTPUnilateral tarsal attack
TophusHyperuricemiaAsymmetric swellingMSU crystals in joint
fluidJoint fluid culture
negative
Diagnosis
Based on history and physical examinationConfirmed by arthrocentesis
Urate crystals: needle-shaped negatively birefringent either free floating or within neutrophils & macrophages.
Uric acid level non specific.30% may show normal level
Urine collection:
GOUT
Gross: chalky white appearance of gouty depositsMicro: early - edematous synovium with acute and
chronic inflammatory infiltrate Late - tophi (large aggregates of urate crystals,
granulomatous inflammation, hyperplastic fibrotic synovium);
Gout crystals are long, slender, needle shaped, but difficult to visualize with routine staining because they are dissolved during formalin processing (crystals are water soluble); easier to identify on scrape or with alcohol fixation
GOUT
With chronic disease, urate deposits may be present in soft tissue, ligaments, skin
Gouty deposits may be surrounded by fibrous tissue and be rimmed by histiocytes and giant cells
Gout from sodium urate crystals Gout from sodium urate crystals deposited in joints. deposited in joints.
This is gout. Gouty arthritis results from deposition of sodium urate crystals in joints.
The joint most often affected is the first MP joint (big toe) as seen here.
Acute attacks are characterized by severe pain, swelling, and erythema of the joint.
Gout or pseudogout?
Gout >40 small joints esp 1st
MTP Severe joint pain
swelling
Uric acid crystals neg bifringent
Rest, nsiad prohylaxishyperuricaemia
Pseudogout Elderly Large joints esp knee
Mod pain and swelling
Calcium pyrophosphate positively bifringent
Rest, nsaid, joint aspiration
TreatmentLife style (food)
ColchicineProphylactic
Probenecid & sulfinpyrazoneInterfere with urate resorption
AllopurinolInhibitor of enzyme that converts the xanthine and
hypoxanthine to uric acid