GOUT

What is Gout?
y connective tissue disorder y peripheral arthritis, due to deposition of MSU

crystals y in articular, periarticular, subcutaneous tissues y recurring attacks of acute arthritis with intervals of freedom y crippling deforming arthritis, nephritis, urinary calculi and cardiovascular lesions

History
y First by Egyptians (2640 B.C) y unwalkable disease -- Hippocrates (5th Century

B.C) y Tophi -- Claudius Galen y Gout -- coined by dominican monk Randolphus of bocking y Gutta or Drop Latin

y Crystals -- Anton von leevenhoek 16th century y chemical identity of uric acid Scheeles y thread test -- Sir Alfred Baring Garrod y metabolism of purines yielded uric acid -- Emil

Fischer

EPIDEMIOLOGY
y adult men-- with peak in 5th decade. y Rare -- before puberty and in premenopausal

women. y Less than 25% of hyperuricemic develop GOUT y Duration and serum uric acid directly correlate with Gout development y 20% -- family history

Gout Types Primary gout

y under excretion of uric acid rather than

to overproduction y men above 40 y Have family history of gout y In born error of metabolism

Secondary gout
y Due to renal impairment or drug therapy y Found in women over age 65 y Does not have family history

causes
y Intrinsic renal disease y Diuretic therapy y Drugs y Starvation, lactic acidosis, dehydration,

preeclampsia, diabetic ketoacidosis hyperuricemia y Overproduction in myeloproliferative disorders, hemolytic anemia, polycythemia and cyanotic congenital heart disease

Uric acid metabolism

y 1/3 --dietary sources y 2/3 -- endogenous purine metabolism y Serum concentration depends upon the balance

between the synthesis and excretion by kidneys(2/3) and gut (1/3) y Ph 7.4 -- >98% of uric acid exists as MSU crystals y Ph influences the serum uric acid levels y Serum uric acid levels -- influence

Hyperuricemia
y serum uric acid concentration above 7 mg per dL.

Hyperuricemia is generally divided into 3 path physiologic categories, 1. uric acid under excretion, 2. uric acid overproduction, and 3. combined causes.

Under excretion
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Idiopathic Familial juvenile gouty nephropathy: Renal insufficiency Syndrome X: Drugs:. Hypertension Acidosis . Preeclampsia and eclampsia:. Hypothyroidism Hyperparathyroidism Sarcoidosis Lead intoxication (chronic). Trisomy

Over production
1. Idiopathic 2. HGPRT deficiency (Lesch-Nyhan syndrome): 3. Partial deficiency of HGPRT (Kelley4. 5. 6. 7. 8.

Seegmiller syndrome) Increased activity of PRPP synthetase Purine-rich diet Increased nucleic acid turnover. Tumor lysis syndrome:. Glycogenoses III, V, and VII

Common causes
1. Alcohol 2. Exercise. 3. Deficiency of aldolase B (fructose-1-phosphate

aldolase). 4. Glucose-6-phosphatase deficiency

DRUGS - HYPERURICEMIA
Decreased renal excretion y Cyclosporine y Alcohol y Nicotinic acid y Thiazide y Lasix(furosemide) y Ethambutol y Aspirin (low dose) y Pyrazinamdie Unknown mechanism y Levodopa y Theophylline y Didanosine

urate
overproduction

urate
hyperuraec emia
underexcretion

Leads to

Silent tissue deposition

gout

Renal manifestation

Associated cardio vascular events and mortality

A CASE STUDY : GOUT

y A 45 year old man awoke from sleep with a

painful and swollen right great toe. On the previous night he had eaten a mean of fried liver and onions, after which he met with his poker group and drank a number of beers y He saw his doctor that morning, gouty arthritis was diagnosed and some tests were ordered. His serum uric acid level was elevated at 8mg/dl y The man recalled his father and his grand father, both of whom were alcoholics often complained of joint pain and swelling in their feet

A CASE STUDY : GOUT

y The doctor recommended that the man use

NSAIDS for pain and swelling, increase his fluid intake (but not with alcohol) and rest and elevate his foot. He also prescribed allopurinol. y A few days later the condition had resolved and allopurinol had been stopped. A repeat uric acid level was obtained (7.1mg/dl). The doctor gave the man some advice regarding life style changes

Gout pathophysiology
y Urate components are found in cartilage,

synovium, tendon sheaths, subcutaneous layers of skin and interstitial areas of kidneys. y These are not found in muscular tissue, brain, liver, spleen and lung y PPL components of cartilage containing protein polysaccharides, compounds of protein and chondrotin sulphate

Mechanism of gout inflammation

1. Crystals in synovial fluid 2. Mechanical damage 3. Shedding of crystals into articular surface 4. Inflammation of cells 5. Crystal initiated chemical reactions

y Crystals in the joint cavity y Phagocytosed by neutrophils y Release of crystal induced chemotactic factor

and leucotrienes y Cause of active inflammation y Neutrophils also release of lysosomal enzymes, oxygen derived free radicals, leukotrienes and prostaglandin metabolities, collagenases and protease

Sequence in gout
y Asymptomatic hyperuricaemia y Acute gouty arthritis y Interval and interstitial gout y Chronic tophaceous gout

Monoarthric attack
y 75% affect lower

Polyarthritic attack
y Ascending

extremity first metacarpal joint podagra (acute attack of gout in great toe (50%) of all attacks

assymetric pattern insteps/heels/ankles /knee/fingers/wrists /elbow

Podegra (gout of 1st MTP) Gout of ankle joint

y Acute onset y Gout affect 1st MTP 75% y Severe pain y Erythema y Very tender y May be febrile y Resolve 3-10 days

Gout stages
y Acute gouty arthritis y Interval or intersititial gout y Chronic tophaceous gout y Renal manifestations

Acute gouty arthritis

y Alcoholic consumption/

y y y y y

obesity/hypertension/lead exposure/eating large amount of protein and purine rich foods abrupt change in serum uric acid concentration agonizing pain with signs of inflammation (swelling/erythema /warmth/ tenderness) low grades of fever ( attacks during night) peak 1-2days 10 days Great toe and lower extremity parts ( lower body temperature and decreased MSU soluability)

y Weight bearing joints at day results in effusion

due to activity while at the night water is reabsorbed MSU concentration increases y Pain and inflammation ( due to humoral and cellular inflamatory process) y Differencitial diagnosis are septic arthritis and celluitis

SITES OF ACUTE FLARES

y 90% of gout patients

eventually have podagra : 1st MTP joint

Flare: A Vets Description

Ive been shot, beat up, stabbed and thrown out of a helicopter, but none of that compared to the gout. Birmingham, Alabama VA Hospital March, 2001

Interval gout
y Time period after acute attack has ceased or

resolvbed and patient became asymptomatic Prophylactic therapy is started when there is 1. repeated attacks 2. Hyperuricemia 3. Chronic gout 4. Tophi 5. Goutyarthritis 6. Nephrolithiasis

FLARE INTERVALS
y Silent tissue

deposition & Hidden Damage

Chronic tophaceous gout

y Massive deposits in y Deposits are also

the 1.Articular cartilage 2.Subchondral bone 3.Synovial membrane 4.Capsular and periarticular tissues 5.Tendon sheath

found in 1. Helix of eyelid 2. Nasal cartilage 3. Cornea 4. Tongue 5. Epiglottis 6. Vocal cords 7. penis

y Bursae lining membrane is similar to synovium y Deposits will be appearing 12 years after the attack y Tophi yellow colored and discharge chalky

material y Cartilage initial deposits in superficial layers fragmentation and erosion of cartilage spread to subchondral areas (penetration) osseous areas by cystic fibrosis y Vilous proliferation of synovial membrane villi containing urates along with gaint cells and macrophages

y Inflammatory synovial tissue/ pannus grows

from edges of joint -- result in chronic arthritis y Complications are 1. Pain 2. Joint destruction 3. Nerve compression syndromes

Tophacous Gout

Tophi hands and olecranon bursa

Olecranon bursitis

Renal manifestations
y Three features of renal manifestations y Nephrolithiasis acidic uric with high uric acid

crystals spontaneous stone formation nidus for other calcium oxalate/phosphate stones y Acute gout nephropathy due to massive malignant cell turnover that occurs due to treatment myeloproliferative / lymphoproliferative disorders blockage of urine flow secondary to precipitation of uric acid across collecting ducts and ureters renal failure

y Chronic gout nephropathy long term

deposition crystals microtophi formation causes giant cell inflammatory reaction results in proteinuria and inability to concentrate urine

Eular recommendations for diagnosis of gout

Acute attack, rapid development of severe pain, swelling and tenderness. Maximum with in just 612 hours. Overlying erythema. Highly suggestive of crystal inflammation through not specific of gout 2. Typical presentation of gout ( recurrent podgra with hyperuricemia) clinically diagnosed is resonably accurate but not definite with out crystal confirmation 3. MSU crystals in synovial fluid and tophi aspiration can lead to definite diagnosis 4. Routine search for MSU crystal in synovial fluid samples obtained for undiagnosed inflamed joint
1.

5. 6.

7. 8.

9.

Identification of MSU crystal from asymptomatic joint allows definitive diagnosis in intercritical periods Gout and sepsis may coexists synovial fluid should be sent for gram staining and culture should be performed even MSU crystals are present Serum uric acid levels neither conform nor exclude gout Renal uric acid should be determined in selected gout patients ( family history and young onset of gout/ onset under the age of 25 years/ renal caliculi ) Radiology useful in differential diagnosis. Typical features in chronic gout cannot confirm diagnosis of early gout

y Risk factor associated co morbid conditions should be

assessed including features of metabolic syndrome obesity hyperglycemia, hyperlipidemia, hypertension

American college of rheumatologists criteria for diagnosis of gout

y Gout may be diagnosed

1. 2.
y

1. 2. 3. 4.

MSU crystals synovial fluid Tophi confirmed with crystal examination Presumptive diagnosis at least of six of following finding Asymmetric swelling with in joint on radiograph First metatarsophalangeal joint is tender or swollen (i.e, podagra ) Hyperuricaemia Maximal inflammation developed with in one day

5. 6. 7. 8. 9. 10. 11. 12.

Mono arthritic attack Greater than one acute attack of arthritis Redness discovered over joints Subcortical cysts with or with out erosions on radiograph Suspected tophi Synovial fluid culture and sensitivity negative for organisms during acute attack Unilateral first MTP joint attack Unilateral tarsal joint attack

Diagnosis
y Complete blood count y Urine analysis y 1. 2. 3. y

Renal function tests Serum creatinine Serum uric acid Blood urea Cardiovascular/ renal systems evaluation

radiology
y Acute gout 1. Generally y Chronic gout 1. Bony abnormalities 2. Bony erosions

nonspecific consists of soft tissue swelling around the joint 2. Normal mineralisation Normal joint spaces preserved

punched out erosion are seen with sclerotic borders 3. Joint spaces reduced in chronic cases

Gout
y Soft tissue swelling because

of Tophi y Large erosions involving DIPs, with hanging edges

Gout
y Soft tissue swelling around

1st MTP y Erosion around 1st MTP y This takes time to develop (Years)

MRI
y Tophaceous gout mass reveals

heterogeneously low to intermediate signal intensity

Synovial fluid
y Rule of 7 to determine which patients are at high risk of

gout and should undergo further testing with joint aspiration to test for presence of MSU crystal 1. Male sex 2. Previous patient reported with arthritis attack 3. Onset with in one day 4. joint reddness 5. MTP first joint involvement 6. Atleast one CVS disease 7. Sr. uric acid level > 5.88mg/dl y Poly morphonuclear leukocytes y Monosodium urate crystals

SYNOVIAL FLUID

Synovial Fluid Findings

y Needle shaped

crystals of monosodium urate monohydrate that have been engulfed by neutrophils

DIFFERENTIAL DIAGNOSIS
y Pseudogout: Chondrocalcinosis, CPPD y Psoriatic Arthritis y Osteoarthritis y Rheumatoid arthritis y Septic arthritis y Cellulitis

Presenting Symptoms y Systemic: fever rare but patients may have

fever, chills and malaise y Musculoskeletal: Acute onset of monoarticular joint pain. First MTP most common. Usually affected in 90% of patients with gout. Other joints knees, foot and ankles. Less common in upper extremities y Postulated that decreased solubility of MSU at lower temperatures of peripheral structures such as toe and ear

y Skin: warmth, erythema and tenseness of skin

overlying joint. May have pruritus and desquamation y Genito-Urinary: Renal colic with renal calculi formation in patients with hyperuricemia

GOUT TREATMENT

yGout prevalence doubled increased over

past 20years yFactors 1.longevity 2.diuretic use 3. low dose ASA 4.obesity 5.end stage renal disease 6.hypertension 7.metabolic syndrome-pharm.

y Non pharmacologic y pharmocologic

CORE ASPECTS OF MANAGEMENT

yPatient Education yWeight loss obesity is an independent risk factor for gout y DIET

1. Purine rich meat and fish correlated with increased serum uric acid and gout 2. no associated with total protein or purine rich vegetables 3. low fat dairy products may be protective 4. vitamic C is uricosuric yAlcohol Beer> liquor wine imposes no gout risk ( may be protective )
- beer > liquor associated with SUA and gout risk - wine imposes no gout risk and may be protective

Choi, H. K. et. al. Ann Intern Med 2005;143:499-516

MANAGEMENT OF ACUTE GOUT

y NSAID:indomethacin used more than other

NSAIDs my use any other NSAIDs at full dose like ibuprofen 800mg TID or Naprosyn 500mg bid expect to as effective as indomethacin and my be less toxic y Know NSAID toxicities y Know NSAIDs contraindications,

Acute Gout Treatment

y NSAID y Most commonly used. y No NSAID found to work better than others y Regimens:
y Indomethacin 50mg bid or tid for 2-3 days and then

taper y Ibuprofen 400mg q4-6 hr max 3.2g/day y Ketorolac 60mg IM or 30mg IV X1 dose in patients<65 y 30mg IM or 15mg IV in single dose in patients >65yo, or with patients who are renal impaired y Continue medications until pain and inflammation have resolved for 48hr

CONTINUE ACUTE GOUT MANAGMENT

y Colchicine: 0.6-1mg bid oral 6

7mg/day orally 1. 12-36 hrs of attacks 2. Inhibiting microtubule aggregation, phagocyctosis of uric acid 3. Blocking the release of chemotatic factor 4. Anti inflammatory / no analgesic activity

Limited because of toxicity 1. Main side effects GI :abdominal pain/diarrhea/nause 2. renal impairment and hepatic damage 3. May cause myelosuppression 4. May be linked to azospermia and infertility 5. IV Colchicine very toxic to bone marrow

steriods
y Steroids safe for acute management with fast

results,and when NSAID and Colchicine use not warranted y Intra-articular injection of triamcinolone is fastest way to get relief ,at the same time can get synovial fluid for analysis y Oral or parentral steroids e.g.:prednisolone oral 20-40 mg daily for 5-7 days ,equivalent doses of IV steroids may be used if unable to take oral y Always make sure no infection coexist.

Prophylaxis Till hyperuricemia controlled

y May use Colchicine y NSAID

Prevention of recurrent attacks

y Should not be started until acute attacks subsides or else

results in mobilization of uric acid stores y Goal is to maintain serum uric acid <6mg/dl

Prevention and control of hyperuricemia indications

1-recurrent attacks of Gout 2-renal stones 3-tophaceous Gout 4-chronic gout with joint damage and erosions 5-hyperuricemia uric acid > 12mg/dl 6-24 hr urine excretion of >1100 mg uric acid

Uricosuric drugs
y Decrease serum uric acid y Increases renal excreation

Probencid,sulfinprazone
y Who is the bad

candidate
1. Serum urine out

y Who is good

candidate
1. age <60 2. 24 h-Creatinine

put is < 1ml/min 2. Serum creatinine < 50ml/min 3. Renal failure

clearance >50ml/min 3. Sr urine of uric acid < 700mg(under excretion) 4. 4-No history of renal stone

Cause slow decrease renal function as with aging

y Probencid 1. 1-2 gm/day 2. 60-85% patient

y Sulfinpyrazone
1. Releated

control 3. Blocks tubular secretion of other organic acids 4. Increases the plasma concentration of pencillions, cephalosporines, sulfonamides, indomethacin

phenylbutazone y Complications 1. Antiplatelet activity and bleeding problems 2. GI problems

URICOSURIC AGENTS
y Probenecid, (Losartan & fenofibrate for mild disease) y Increased secretion of urate into urine y Reverses most common physiologic abnormality in gout (

90% pt.s are underexcretors)

Xanthine oxidase inhibitor Allopurinol

Hyperuricemia with : y Urinary uric acid >1000mg y Uric acid nephropathy y Nephrolithiasis y Before chemotherapy y Renal insufficiency GFR<50 y Allergy to Uricosuric agents

ALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR

A SUBSTRATE ANALOG IS CONVERTED TO AN INHIBITOR, IN THIS CASE A SUICIDE-INHIBITOR

Allopurinol
y Average dose 300mg y Renal impairment use lower dose y May precipitate acute gout when first used y Side effects can be very serious range from

dyspepsia,headache,diarrhea,rash,to more severe including fever,esosinophilia,interstitial nephritis,hepatitis,vasculitis,acute renal failure,toxic epidermal necrolysis,and hypersensitivity syndrome.

URATE LOWERING DRUGS

Allopurinol drug interactions
y Coumadin y Vidarabine y Cyclosporin y Azothiaprine

allopurinol may prolong life of these drugs and increase toxicity

URATE LOWERING DRUGS

The Future:
1. fuboxistat NEJM 2005; 353:2450 - more selective non-purine xanthine oxidase inhibitor - mainly metabolized in liver - more info needed about short and long term safety 2. natural uricase - issues with toxicity- Ab formation, anaphylaxis, fever 3. uricase with HMW polyethylene glycol PEG 4. ? new treatment targeting URAT1 anion exchange

Newer Therapies
y Uricase y Enzyme that oxidizes uric acid to a more soluble form y Natural Uricase from Aspergillus flavus and Candida

utilis under investigation y Febuxostat

y New class of Xanthine Oxidase inhibitor y More selective than allopurinol y Little dependence on renal excretion

y Losartan
y ARB given as 50mg/dL can be urisuric. When given with HCTZ, it can blunt the

effect of the diuretic and potentiate its antihypertensive action

y Fenofibrate
y Studies note when used in combo with Allopurinol produced additional lowering of

the urate

URICASE ENZYMES (Stay Tuned)

y Catabolize urate to allantoin:

More soluble, excretable form

y Currently approved for hypoeruricemia in tumor lysis

syndrome
y Some concerns: fatal immunogenicity & unknown long-

term effects

Gout in transplnat
y Patient usually on Steroids,azathioprine,cyclosporine y Colchicine and NSAID use potentially toxic y Allopurinol increase level of azathioprine and toxicity y Steroids intra-articular ,oral or parentral can be used y May need adjust or change transplant medications

Lesch-Nyhan Syndrome
y A defect in production or activity of

HGPRT y Causes increased level of Hypoxanthine and Guanine ( o in degradation to uric acid) y Also, PRPP accumulates y stimulates production of purine nucleotides (and thereby increases their degradation) y Causes gout-like symptoms, but also neurological symptoms spasticity, aggressiveness, self-mutilation y First neuropsychiatric abnormality that was attributed to a single enzyme
y

Purine Autism
y 25% of autistic patients may overproduce purines y To diagnose, must test urine over 24 hours
y Biochemical findings from this test disappear in adolescence y Must obtain urine specimen in infancy y Pink urine due to uric acid crystals may be seen in diapers

Crystals found in synovial fluid

y Monosodium urate monohydrate acute gout, tophaceous y y y y y

gout, asymptomatic Calcium pyrophosphate bihydrate acute pseudogout, destructive arthropathy, asymptomatic Basic calcium phosphate acute calciofic periarthritis, acute arthritis, destructive arthopathy Calcium oxalate acute and subactue arthritis asymptomatic Lipid acute arthritis Cholesterol asympotmatic

Refernces
y Harrison text of medicine 16th edition y Appleys text book of orthopaedics y Cme.mediscape.com y E medicine.com y Text book of orthopaedics by kulkarni y Text book of pathology by Robins