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GOUT
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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
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Gout (monosodium urate crystal deposition disease)
is characterized biochemically by extracellular urate supersaturation
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Gout Recurrent attacks of acute inflammatory arthritis
Accumulation of urate crystals in the form of tophaceous deposits Uric acid nephrolithiasis Nephropathy
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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 and 0.1% for less than 7mg/dl Familial incidence range from 11-80%
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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
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Decreased efficiency of renal uric acid excretion is responsible for about 85 to 90 percent of primary or secondary hyperuricemia .
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Supersaturated concentration of urate (> or= 6/8mg/dl)
cause crystalization and deposition in joints and other connective tissues
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DNA RNA Purines Pyrimidines Uric acid Energy
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PRPP.Syn APRT GTP & ATP & AMP.S XMP IMP.D AS.S 5’N 5’N 5’N AMP. D Aden.PRT HGPRT PNP PNP Xantine oxidase Guanase Xantine oxidase
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Uric acid production Ribose-5 PRPP phosphate + AMP + ATP Uric Acid IMP
PRPP Synthetases PRPP + AMP Uric Acid IMP
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Salvage Sometime free purine base are salvaged and reused instead of degrading them all the way to uric acid.
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Salvage of purine Bases
Adenine Guanine Hypoxanthine Phosphoribosylation Primary nuclotides
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Hyperuricemia cascade
Tissue nucleic acids Dietary purines Endogenous purine synthesis Urate Overproduction Underexcretion Hyperuricemia
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid overproduction
Primary hyperurecimia Secondary hyperuricemia Idiopathic HGPRT deficiency PRPP synthetase superactivity 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
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic Diminished renal function ( GFR) Inhibition of tubular urate secretion Enhanced tubular urate reabsorption Mechanism incompletely defined
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic Diminished renal function ( GFR) Inhibition of tubular urate secretion Enhanced tubular urate reabsorption Mechanism incompletely defined
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic Diminished renal function ( GFR) Inhibition of tubular urate secretion Enhanced tubular urate reabsorption Mechanism incompletely defined
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic Diminished renal function ( GFR) Inhibition of tubular urate secretion Competitive anions ( keto & lactic acidosis ) Polycyctic kidney, Lead nephropathy?
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic Diminished renal function ( GFR) Inhibition of tubular urate secretion Enhanced tubular urate reabsorption Dehydration : diuretics,adrenal insufficency, nephrogenic DI Insulin resistance Syndrome
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Uric acid Underexcretion
Primary hyperurecimia Secondary hyperuricemia Idiopathic 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
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Classification of hyperuricemia
3- Combined Overproduction & Underexcretion Alcohol consumption Inborn errors of metabolism Glucose phosphatase deficiency Fructose -1- phosphate aldolase deficienccy
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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
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Urate crystal phagocytosis leads to an inflammatory cascade and acute gouty arthritis
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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
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Extracellular urate
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Urate-cell contact
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Entrance of uric acid
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Phagocytosis of urate
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Late phagocytosis
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Intracellular urate
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CLINICAL SYNDROMES 1- Asymptomatic hyperurecemia 2- Acute flare
3- Intercritical segments 4- Advanced gout
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Silent hyperurecemia Silent deposition of urate crystals
Elevated serum urate with no clinical manifestation of gout
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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)
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Acute arthritis
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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.
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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.
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Acute arthritis
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Acute arthritis
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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
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Gouty hand
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Gouty burcitis
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Diagnosing Gout Serum urate( may be normal) History and physical exam
Synovial fluid analysis Diff is very important
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Fluid analysis
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microscope with crossed polarizing filters
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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.
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Birefringent Crystals
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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
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Birefringent Crystals
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negative birefringent Crystals
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Positive birefringent Crystals
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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
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DIFFERENTIAL DIAGNOSIS
Pseudogout Septic arthritis Hydroxyapatite calcific tendinitis Sarcoid arthritis Erythema nodusum Rheumatoid arthritis Familial mediterranian fever
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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
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ASSOSIATED CONDITION Obesity Diabetes mellitus Hypertriglyceridemia
Hypertention Athrosclerosis Hypothyroidism Ethanol consumption Pregnancy Syndrome X
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NEGATIVE ASSOCIATION CONDITION
Rheumatoid arthritis Systemic lupus erythmatosis Ankylosing spondylitis Long-term use of NSAID
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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 % with mild leukocytosis In 78% , second attack occur within 6month to 2years
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Synovial analysis during intercritical period
extracellular urate crystals are identifiable in synovial fluid from previously affected joints in virtually all untreated gouty patients
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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
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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
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Gouty hand
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Chronic taphus
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Chronic gout
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Gouty hand
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Advanced gout
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Advanced gout Erosion in both destructive and hypertrophic leads to overhanging edge Joint space is often preserved untile very late in the disease process
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Taphous
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Over hanging
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Taphous
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Crystal precipitate in joint and soft tissues
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RENAL COMPLICATIONS OF CHRONIC HYPERURICEMIA
nephrolithiasis;(only5 to 10 percent of all urinary tract stones in the United States and Europe) chronic urate nephropathy
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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.
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Uric acid stone
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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
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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 )
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Treatment Anti-inflammatory therapy — prompt and safe termination of the acute arthritic attack Prophylaxis — prevention of recurrences of acute gouty arthritis Antihyperuricemic therapy
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Treatment of Gout Acute Gouty arthritis Prophylaxis
Control of hyperuricemia Colchicine NSAID Corticosteroid Allopurinol Uricosuric agents ( Probenecid, sulfinpyrazone )
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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.
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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
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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.
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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)
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Xanthine oxidase inhibitors
xanthine oxidase inhibitors are likely to be effective in virtually all circumstances warranting therapy for gout ( Allopurionl)
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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.
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Other drugs that enhance uric acid excretion
Losartan Fenofibrate
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