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By Dr: Abd El Hameed Fureeh MD, Lecturer of Internal Medicine, Mansoura faculty of Medicine Diabetes, endocrinology and Metabolism unit Www.MansFans.coM
What is gout?
is a syndrome caused by the inflammatory response to tissue deposition of monosodium urate crystals (MSU). v Nicknamed the “Disease of Kings” because it can be caused by rich foods, alcohol, and royalty often had it.
prevalence of asymptomatic hyperuricemia is 5 to 8%. v The prevalence of gout is 13 cases per 1000 men and 6.4 cases per 1000 women. v The higher the uric acid, the higher the risk to develop gout. v 90% of patients with primary gout are men.
rarely develop gout before the menopause, because estrogens are thought to be uricosuric. v Peak incidence in men is in the fifth decade. v Primary gout is associated with: obesity, hyperlipidemia, diabetes mellitus, hypertension and atherosclerosis.
is the common denominator in gout. v Two-thirds of uric acid are excreted by the kidney and the rest in the GI tract. v 90% of cases of gout are secondary to under-excretion. v Overproduction is secondary to defects in the HGPRT or PRPP.
inflammatory response is secondary to the response of the leukocytes to the MSU crystals. v Acute gout is most likely secondary to the formation of new crystals. v Factors that precipitate gout includes: surgery, trauma, alcohol, starvation and medications.
GOUT RISK FACTORS
Male v Postmenopausal female v Older v Hypertension v Pharmaceuticals: Diuretics, ASA, cyclosporine
GOUT RISK FACTORS
v Transplant v Alcohol
intake Highest with beer Not increased with wine v High BMI (obesity) v Diet high in meat & seafood
most frequent sites of deposition of MSU crystals are: cartilage, epiphyseal bone, periarticular structures and the kidney. v A tophus is a foreign body reaction that includes the MSU crystals surrounded by fibrous tissue. v In the kidney the deposition of MSU crystals causes interstitial fibrosis and arteriosclerosis.
4 clinical phases if untreated: v asymptomatic hyperuricemia, v acute/recurrent gout, v intercritical gout, v chronic tophaceous gout
elevated urate levels without symptoms of gout, nephrolithiasis, or kidney stones. Hyperuricemia is defined: >7 mg/dL (0.42mmol/L) in men and postmenopausal women >6 mg/dL (0..36mmol/L) in premenopausal women. urate <7 mg/dL 0.1% annual incidence of gout urate >=9 mg/dL 4.9% annual incidence. the clustering of glucose intolerance, central obesity, dyslipidemia, hypertension, and increased prothrombotic and antifihrinolytic factors in an individual.
Cause of hyperuricemia -- decreased renal excretion
Primary Secondary Hypertension Idiopathic Hyperparathyroidism Myxoedema Familial juvenile Down’s syndrome gouty nephropathy Increased level of organic level
Lead nephropathy Sarcoidosis Bartter’s syndrome Beryllium poisoning Drug: diuretics, B-blocker, ACEI, salicylates (low dose), PEA, EMB, cyclosporin, nicotinic acid Chronic renal failure Volume depletion NDI
Cause of hyperuricemia -- increased uric acid production
Primary Idiopathic HPRT def. PPRT overactivity Ribose-5phosphate overproduction AMP-deaminase def. Secondary
Glycogen storage disease type II (G6PD), type III, V, VII Hereditary fructose intolerance Lymphoproliferative and myeloproliferative diseases ( leukemia, Hodgkin’s d’z, lymphosarcoma, myeloma, PV, Waldenstrom’s macroglobulinemia ) Cytotoxic drugs Carcinomatosis Gaucher’s disease Chronic hemolytic anemia Severe exfoliative psoriasis
symptoms: sudden onset of severe pain,
inflammation, limited range of motion, and warmth at the affected joint(s). The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable, slight fever, leukocytosis, elevation of ESR, and elevation of CRP
90% of first attacks are monoarticular with first metatarsophalangeal joint, known as podagra. v Left untreated, the symptoms are selflimiting but may take up to 21 week to subside.
90% of gout patients eventually have podagra : 1st MTP joint
Table. Characteristics of Classic Gout vs Atypical Gout
Classic Gout Can present at any age, including patients older than 60 years Predominantly men Monarthritis Asymmetric Usually in lower extremity Tophi rare at presentation Acute Can be misdiagnosed as cellulitis or infection Atypical Gout Observed in elderly patients Diagnosed in as many women as men Polyarthritis Symmetric or asymmetric Any joint, upper or lower extremity Tophi common at presentation Chronic but can have acute flareups Chronic form can be misdiagnosed as rheumatoid arthritis or osteoarthritis: acute flare-ups can be misdiagnosed as cellulitis or infection
v Chronic v X-ray v Tophi v Acute
Changes Develop Flares continue
Chronic Arthritis v Polyarticular acute flares with upper extremities more involved
It is the asymptomatic period between crises, but MSU crystals can still be recovered if necessary.
duration of this period varies, but untreated patients may have a second episode within two years. v Some patients evolve to chronic polyarticular gout without pain free intercritical episodes.
Chronic Tophaceous Gout
Tophi are usually present after 10 to 20 years of inadequately treated chronic gout. v Visible tophi occur in 12% of patients after 5 years of gout and in 55% of patients after 20 years. v most common sites of tophaceous gout: olecranon bursae (elbow) and the joints of the hand and feet. Other sites: the helix of the ear, the Achilles tendons, and the knees.
Chronic Tophaceous Gout
patients treated with cyclosporine and/or diuretics have an increased risk for tophaceus gout. v The most common sites for tophi are: the olecranon, prepatellar bursa, ulnar surface and Achilles tendon.
Chronic Tophaceous Gout
in the hands can cause joint destruction. v Tophi can ulcerate the skin and excrete a chalky material composed of MSU crystals. v Tophi progress insidiously with increased stiffness and pain.
Solid urate deposits in tissues
Irregular & destructive
TOPHI RISK FACTORS
duration of hyperuricemia serum urate
v Higher v Long
periods of active, untreated gout
v Urolithiasis, v Urate
nephropathy (deposition of MSU crystals in the interstitium), and v Uric nephropathy ( deposition of MSU crystals in the collecting tubes). v The prevalence of urolithiasis is 22% in primary gout and 42% in secondary gout.
prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels. v Serum urate levels 13 mg/dl v Urinary uric acid excretion > 1100 mg/d
of monosodium urate crystals surrounded by a giant cell inflammatory reaction in the medullary intrerstitium and pyramids. v Clinically: silent or cause proteinuria, hypertension and renal insufficiency.
Uric acid nephropaty
Precipitation in renal tubules and collecting ducts cause obstruction to urine flow. Following sudden urate overproduction and marked hyperuricaciduria:
x x x
Dehydration and acidosis Lymphoma Cytolytic therapy
Complication of gout
destruction v Soft tissue v nerve entrapment syndrome: CTS, tarsal tunnel syndromes v kidney: uric acid calculi(10-15%), chronic urate nephropathy, and acute uric acid nephropathy v Heart: ischemic heart disease
GOUTY ARTHRITIS & TOPHI
Diagnosis of gout
diagnosis: Triad of 1- hyperurecemia 2- Acute monoarticular arthritis 3- Response to colchicine v Laboratory diagnosis v Differential diagnosis
Criteria for clinical diagnosis
American Rheumatism Association sub-committe on classification criteria for gout 1977 v v v
presence of characteristic urate crystals in the joint fluid Tophus proved to contain urate crystals by negative polarized light microscopic study If none of above, diagnosis is 6/12 clinical, radiographic, and laboratory criteria include: 1. more than one attack of acute arthritis 2. Maximum inflammation within 24 hours 3. Attack of monoaricular arthritis 4. Joint redness observed 5. first MTP joint painful or swollen 6. Unilateral attack involving first MTP 7. Unilateral attack involving tarsal joint 8. Suspected tophus 9. Hyperuricemia 10. Asymmetric swelling within a joint ( roentgenogram ) 11. Subcortical bone cysts without erosions ( roentgenogram ) 12. Negative synovial culture during attack of joint inflammation
Even the clinical appearance strongly suggests gout. The diagnosis should be confirmed by needle aspiration of acute or chronically inflamed joints or tophaceous deposits. v Acute septic arthritis several of the other crystalline – associated arthropathies, and psoriatic arthritis may present with similar clinical features.
SYNOVIAL FLUID ANALYSIS (Polarized Light Microscopy)
v v v v
The Gold standard Crystals intracellular during attacks Needle & rod shapes Strong negative birefringence meaning that the crystals are yellow when aligned parallel to the slow ray of the compensator and that they are blue when they are perpendicular.
of MSU crystals do not exclude the possibility of septic arthritis, for this reason it is also recommended to request a Gram smear.
- Cloudy due to leukocytes and a large amounts crystals ocassionally produce a thick pasty or chalky joint fluid. -Increased leukocytes: >15,000/cc WBCs, primarily PMNs
SERUM URATIC ACID LEVELS
This is the most misused test in the diagnosis
of gout. v Not reliable
May be normal with flares May be high with joint Sx from other causes
Serum uric acid
male 3-8 mg/dl female 1.5-6 mg/dl children 3-4 mg/dl ("normal" values may vary between laboratories) -False elevation by:
levodopa if colorimetric method used
Uric acid in 24-hour urine sample
urine collection for uric acid determination is useful in assessing the risk of renal stones and planning for therapy. v Urinary levels above 750 mg/dl in 24h in gout or > 1100 mg/dl in asymptomatic hyperuricemia indicates urate overproduction.
changes, well-defined erosions described as punched-out lytic lesion. v Soft tissue calcified masses (chronic tophaceous gout) v Is helpful to exclude other kinds of arthritis.
v v v v
Renal function before deciding on therapy Plasma glucose: Patients with gout are at an increased risk of developing diabetes mellitus. Abnormal liver function tests need to be considered when therapy is selected. CBC count: The WBC count may be elevated in patients during the acute gouty attack, particularly if it is polyarticular. Lipids: Hypertriglyceridemia and low high-density lipoproteins are associated with gout. Urinalysis: Patients with gout are at an increased risk of renal stones
Infective arthritis Bursitis, cellulitis, tenosynovitis Other crystal arthropathy ( pseudogout, apatite or brushite arthritis or periarthritis ) Traumatic arthritis Hemoarthrosis RA with palindromic onset Reactive arthritis Spondarthritis with peripheral involvement Psoriatic arthritis Sarcoid arthritis Rheumatic fever
Chronic Nodular rheumatoid arthritis Psoriatic arthritis Osteoarthritis with Heberden’s and Bouchard’s nodes Sarcoid arthritis xanthomatosis
Gout vs. CPPD
Similar Acute attacks v Different crystals under Micro;
Rhomboid, irregular in CPPD Pseudogout crystals are positively birefringent. Pragmatically, this means that their colors are opposite those of gout. Thus, pseudogout crystals are blue when aligned parallel to the slow ray of the compensator and yellow when they are perpendicular.
Crystal-Induced Arthritis Characteristic
1.5 to 2.6 cases per 1000 individuals; increases with age in men and postmenopausal women; 15/1000 at age 58; men:28/1000, women:11/1000
<1 case per 1000 individuals; increases with age
Crystals Chemistry Appearance Articular involvement Most frequently affected joints Monosodium urate Negatively birefringent; needle-shaped Monoarticular > oligoarticular; polyarticular < 30% First MTP joint － initially 50% － eventuall 90% Ankles, knees, other Hyperuricemia*, obesity, hypertension, hyperlipidemia, alcohol ingestion, lead ingeation, hereditary enzyme defect (rare) Calcium pyrophosphate dihydrate Weakly positively birefringent; linear or rhomboidal Monoarticular > oligoarticular Knee, wrist other
Predisposing conditions/risk factors
Hypothyroidism, hemochromatosis, OA, chronic renal insufficiency, diabetes, hyperparathyroidism, hereditary (rare)
Acute attacks: Acute attacks: － NSAIDs, corticosteroids, － NSAIDs, corticosteroids, colchicine colchicine Chronic management Chronic management － Urate-lowering agents, colchicine － NSAIDs ± colchicine *Drugs associated with hyperuricemia include diuretios, low-dose salicylates, nicotinic acid, oyclosporine, ethanol and ethambutol. Adapted from Am J Med 1997; 103 : 68S. 53
RA vs Gout
have polyarticular, symmetric arthritis can be mistaken for RA nodules
Treatment of gout
and safe pain relieve (end acute flares) v Protect against future flares v Prevent disease progression v Correct metabolic cause
ENDING ACUTE FLARES
inflammation & pain & resolve the flare v Not a cure v Crystals remain in joints v Don’t try to lower serum urate during a flare v Choice of med not as critical as alacrity & duration
Acute Flare Med Choices
NSAIDS Colchicine Corticosteroids
1. Mechanism of action -decreases inflammatory response through binding of microtubular proteins which interferes with granulocyte mobility 2. Efficacy: somewhat diagnostic for gout because -90% respond to colchicine if treatment is initiated within a few hours after onset, response rates decline if acute attack is >24hrs old -colchicine is relatively specific therapy for acute gout
Dosing: -colchicine has a narrow therapeutic index -doses should be decreased in renal and hepatic dysfunction, but there are no standard guidelines -PO: 1.2mg stat, then 0.6mg every hour until: response is achieved, or gastrointestinal toxicity (diarrhea, abd. pain), or maximum dose of 12 tablets is taken
-IV: 2mg in 20cc NS infused slowly, may repeat with 1mg after 6hrs but no more than 4mg in 24hours -Decrease total dose to 2mg/24hrs in elderly patients or patients who have been on colchicine maintenance -Give only to patients who cannot tolerate the oral tablets -Avoid extravasation because it causes soft tissue necrosis
Adverse reactions -Gastrointestinal: diarrhea, nausea, vomiting, hemorrhagic colitis, occurs in 70-80% of patients on oral therapy, less frequent with IV therapy but may see with high doses -Bone marrow depression: cumulative toxicity -Renal dysfunction: toxic side effect seen after large doses, hematuria, oliguria -Necrosis of soft tissue after extravasation: do not give IM/SC
Mechanism of action:
-anti-inflammatory effects through inhibition of prostaglandin synthesis and inhibition of motility of PMNs -not specific for gout—adequate doses will relieve inflammation from any cause
Agents and Dosing -Indomethacin: 75mg stat, 25-50mg q6hr, taper as symptoms resolve -avoid in elderly -Any non-salicylate NSAID should be effective if given in anti-inflammatory doses -avoid salicylates because of effect on uric acid elimination
NSAIDS : Interaction with warfarin Contraindicated in: Renal disease PUD GI bleeders ASA-induced RAD
-Effective anti-inflammatory agents
-Reserve for patients who cannot tolerate oral colchicine or NSAID therapy and who are not candidates for IV colchicine -Limited to 4 injections per joint per year Can use: -Methylprednisolone (Depomedrol) -Triamcinolone hexocetanide
-IM injection of depot corticosteroid product (e.g. DepoMedrol ) or ACTH -Tapering effect of depot product prevents rebound gout attacks -Efficacy comparable to NSAID in studies -Limited toxicity due to short term use
- Worse glycemic control May need to use mod-high doses
PROTECTION VS. FUTURE FLARES
Colchicine : 0.5-1.0 mg/day Low-dose NSAIDS Both decrease freq & severity of flares Prevent flares with start of urate-lowering RX Best with 6 mos of concommitant RX
Won’t stop destructive aspects of gout
PREVENT DISEASE PROGRESSION
urate to < 6 mg/dl : Depletes Total body urate pool Deposited crystals v RX is lifelong & continuous v MED choices : Uricosuric agents Xanthine oxidase inhibitor
in patients with normal renal function, under-excretion and no evidence of tophi. v Patients taking uricosuric agents are at risk for urolithiasis. This can be decreased by ensuring high urinary output and by adding sodium bicarbonate 1 gram TID.
available agents include: probenecid (1-2 g/day) and sulfinpyrazone (50-400 mg BID). v Dose should be increased to decrease uric acid < 6.0 mg/ml
Uricosuric: has Increased potency vs probenecid Has antiplatelet effect at doses of 600-800mg/day Dosing: 50mg bid-400mg/day, may go up to 800mg/day Adverse reactions: -Hypersensitivity reactions (uncommon): rash, may cause bronchoconstriction in patients with ASA intolerance, contraindicated in patients allergic to phenylbutazone/pyrazoles -Gastrointestinal irritation: take with food or milk
XANTHINE OXIDASE INHIBITOR
conversion of hypoxanthine to uric acid v Decreases uric acid in overproducers and underexcreters; it is also indicated in patients with a history of urolithiasis, tophaceus gout, renal insufficiency and in prophylaxis of tumor lysis syndrome.
dose is 300 mg/day. Maximal recommended dose is 800 mg/day. v In renal insufficiency dose should be decreased to 200 mg/day for creatinine clearance < 60ml/min and to 100 mg/day if clearance < 30 ml/min).
with small doses of allopurinol to reduce the risk of precipitating an acute gout attack. v Most common side effects are rash (2% of patients) but rarely patients can develop exfoliative dermatitis that can be lethal. v Chronic use of colchicine (0.6-1.2 mg/day) is used as prophylaxis for acute attacks.
-Start at 100mg per day, increase weekly as needed -70% of patients will be controlled on 300mg/day -May give up to 1200mg/day if necessary -May be given once daily because of long half life of active metabolite, but divided doses recommended if total daily dose >300mg -Renal disease requires dose adjustment
Allopurinol Adverse Reactions
Hypersensitivity rash: maculopapular/purpuric: usually occurs within 1st5weeks , resolves with drug DC . rechallenge cautiously, may cause fatal reactions severe hypersensitivity more common in pts with impaired renal function & ampicillin treatment Gastrointestinal: nausea, vomiting,abdominal pain, hepatomegaly.
new xanthine oxidase inhibitor v Metabolized by the liver (used in RI) v No hypersensitivity reaction v Dose: 80-120 mg/d
choice on above considerations & whether pt is an overproducer or underexcretor : Need to get a 24-hr. urine for urate excretion: < 700 --- underexcretor (uricosuric) > 700 --- overproducer (allopurinol)
Purine nucleotides hypoxanthine xanthine Uric acid Urinary excretion uricosurics colchicine Alimentary excretion Allopurinol
Tissue deposition in excess Urate crystal Phagocytosis with acute inflammation and arthritis microtophi
gaps : v Can’t always get urate < 6 v Allergies v Drug interactions v Allopurinol intolerance v Worse Renal disease
Catabolize urate to allantoin: More soluble, excretable form Currently approved for hypoeruricemia in tumor lysis syndrome Some concerns: fatal immunogenicity & unknown long-term effects
Treating the Asymptomatic Hyperuricemic Patient:
Controversial, no set guidelines, but consider in the following patient groups: A. Develops symptoms B. Excretes >900mg of uric acid/24hr: risk for kidney stones C. Serum uric acid >12mg/dl, D. Patient with malignancy using chemotherapy
impractical, ineffective and rarely adhered to in clinical practice. v Indications for pharmacological therapy includes: inability to reverse secondary causes, tophaceus gout, recurrent acute gout and nephrolithiasis.
Prophylaxis A. When to treat
1. Recurrent attacks: choice of treatment will depend on the frequency of the attacks. Attacks once yearly may be better treated with colchicine/NSAID acutely rather than exposing the patient to yearlong therapy. Frequency of attacks >1-2/year are a good indication for prophylactic or uric acid lowering therapy.
Prophylaxis A. When to treat
2. Tophi: indicator of long-standing disease, will regress/disappear with uric acid lowering therapy, patients with tophi should be treated e even if gout attacks are not frequent 3. Uric acid nephrolithiasis: treatment will prevent further stones (and development of renal dysfunction due to gouty nephropathy?)
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