GoutGout

Dr. Wael H.Mansy, MDDr. Wael H.Mansy, MDAssistant ProfessorAssistant Professor

College of Pharmacy College of Pharmacy King Saud UniversityKing Saud University

GoutGout Gout is defined as a peripheral Gout is defined as a peripheral

arthritis resulting from the arthritis resulting from the deposition of sodium urate crystals deposition of sodium urate crystals in one or more joints.in one or more joints.

Uric AcidUric Acid URIC ACID: Is the final breakdown URIC ACID: Is the final breakdown

product of purine degradation in humansproduct of purine degradation in humans URATE: The ionized forms of uric acid, URATE: The ionized forms of uric acid,

predominante in plasma, extracellular predominante in plasma, extracellular fluid and synovial fluid.fluid and synovial fluid.

Approximately 98% existing as Approximately 98% existing as monosodium urate at pH 7.4monosodium urate at pH 7.4

Uric AcidUric Acid Plasma is saturated with monosodium urate at Plasma is saturated with monosodium urate at

a concentration of 6.8 mg/dl.a concentration of 6.8 mg/dl. At higer concentrations, plasma is therfore At higer concentrations, plasma is therfore

supersaturated, creating the potential for supersaturated, creating the potential for urate crystal precipitation.urate crystal precipitation.

Urate production varies with the purine Urate production varies with the purine content of the diet and the rates of purine content of the diet and the rates of purine biosyntesis, degradation and salvage.biosyntesis, degradation and salvage.

2/3 to 2/3 to ¾¾ of urate is excreted by kidneys, and of urate is excreted by kidneys, and most of the remainer is eliminated through the most of the remainer is eliminated through the intestines. intestines.

Uric AcidUric Acid Uric acid is more soluble in urine than in Uric acid is more soluble in urine than in

water.water. The pH of urine greatly influences its The pH of urine greatly influences its

solubility.solubility. pH 5 urine is saturated with uric acid at pH 5 urine is saturated with uric acid at

concentrations ranging from 6 to 15 concentrations ranging from 6 to 15 mg/dl. mg/dl.

At pH 7 saturation is reached at At pH 7 saturation is reached at concentration between 158 and concentration between 158 and 200mg/dl.200mg/dl.

Uric AcidUric Acid Serum urate levels vary with age Serum urate levels vary with age

and sex.and sex. Children: 3 to 4 mg/dlChildren: 3 to 4 mg/dl Adult men: 6 to 6.8 mg/dlAdult men: 6 to 6.8 mg/dl

EpidemiologyEpidemiology Prevalence of hyperuricemiaPrevalence of hyperuricemia 2.3 – 41.4% in various populations. 2.3 – 41.4% in various populations. Corresponds with serum creatinine /BUN Corresponds with serum creatinine /BUN

levels, body weight, height, age, blood pressure, levels, body weight, height, age, blood pressure, and alcohol intake. (Taiwan)and alcohol intake. (Taiwan)

Body bulk (as estimated by body weight, Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be surface area, or body mass index) has proved to be one of the most important predictors of one of the most important predictors of hyperuricemia in people of widely differing races hyperuricemia in people of widely differing races and cultures.and cultures.

Incidence of GoutIncidence of Gout Varies depending on population studied – 1.8 Varies depending on population studied – 1.8

/1000 – 3.2/1000/1000 – 3.2/1000 RR for blacks slightly higher (1.3) RR for blacks slightly higher (1.3)

HyperuricemiaHyperuricemia

Defined as a plasma urate Defined as a plasma urate concentration > 7.0 mg/dlconcentration > 7.0 mg/dl

HyperuricemiaHyperuricemia Can result from:Can result from:

Increased production of uric acidIncreased production of uric acid Decreased excretion of uric acidDecreased excretion of uric acid Combination of the two processes.Combination of the two processes.

Increased Urate Increased Urate ProductionProduction

Diet provides an exogenous source Diet provides an exogenous source of purines and, accordingly, of purines and, accordingly, contributes to the serum urate in contributes to the serum urate in proportion to its purine content.proportion to its purine content.

Foods high in nucleic acid: liver, red Foods high in nucleic acid: liver, red meat and anchovy.meat and anchovy.

Restriction intake: reduces: 1 mg/dlRestriction intake: reduces: 1 mg/dl

Endogenous sources:Endogenous sources: De novo purine biosynthesis.Increased De novo purine biosynthesis.Increased

phosphoribosyl pyrophosphatase phosphoribosyl pyrophosphatase (PRPP) synthetase activity and (PRPP) synthetase activity and Hypoxanthine Hypoxanthine phosphoribosyltransferase (HPRT) phosphoribosyltransferase (HPRT) deficiency are associated with deficiency are associated with overproduction of purine, overproduction of purine, hyperuricemia and hyperuricaciduria.hyperuricemia and hyperuricaciduria.

Decreased Uric Acid Decreased Uric Acid ExcretionExcretion

Alterated uric acid excretion could Alterated uric acid excretion could result from: result from:

1.1. Decreased glomerular filtration.Decreased glomerular filtration.2.2. Decreased tubular secretion.Decreased tubular secretion.3.3. Enhanced tubular reabsorption.Enhanced tubular reabsorption.

Decreased tubular secretion of urate Decreased tubular secretion of urate causes the secondary hyperuricemia of causes the secondary hyperuricemia of acidosis.acidosis.

Diabetic ketoacidosis, starvation, ethanol Diabetic ketoacidosis, starvation, ethanol intoxication, lactic acidosis, and salicylate intoxication, lactic acidosis, and salicylate intoxication are accompanied by intoxication are accompanied by accumulations of organic acids (B-accumulations of organic acids (B-hydroxybutyrate, acetoacetate, lactate or hydroxybutyrate, acetoacetate, lactate or salicylates) that compete with urate for salicylates) that compete with urate for tubular secretion.tubular secretion.

Combined MechanismsCombined Mechanisms Alcohol intake promotes hyperuricemia: Alcohol intake promotes hyperuricemia:

Fast hepatic breakdown of ATP and Fast hepatic breakdown of ATP and increases urate production. increases urate production.

Can induce hyperlacticacidemia, and Can induce hyperlacticacidemia, and inhibition of uric acid secretion. inhibition of uric acid secretion.

The higher purine content in some alcoholic The higher purine content in some alcoholic beverages such as beer may also be a factor.beverages such as beer may also be a factor.

Evaluation of Evaluation of HyperuricemiaHyperuricemia

Hyperuricemia does not represent a Hyperuricemia does not represent a disease. disease.

Is not an specific indication for Is not an specific indication for therapy.therapy.

The finding of hyperuricemia is an The finding of hyperuricemia is an indication to determine its cause.indication to determine its cause.

The hyperuricemia of individuals The hyperuricemia of individuals who excrete high uric acid amounts who excrete high uric acid amounts while on a purine-free diet is due to while on a purine-free diet is due to purine overproductionpurine overproduction

Whereas it is due to decreased Whereas it is due to decreased excretion in those who excrete lower excretion in those who excrete lower amounts on the purine-free diet. amounts on the purine-free diet.

Complications of Complications of HyperuricemiaHyperuricemia

The most recognized complication The most recognized complication of hyperuricemia is gouty arthritisof hyperuricemia is gouty arthritis

NephrolithiasisNephrolithiasis Urate Nephropathy Urate Nephropathy Uric Acid NephropathyUric Acid Nephropathy

Gout = Crystal-induced Gout = Crystal-induced arthritisarthritis

MSU (monosodium urate)MSU (monosodium urate) CPPD (calcium pyrophosphate CPPD (calcium pyrophosphate

dihydrate)dihydrate) HA (calcium hydroxyapatite)HA (calcium hydroxyapatite) Calcium oxalate (CaOx)Calcium oxalate (CaOx)

MonosodiumuratMonosodiumurate Goute Gout

Monosodiumurate GoutMonosodiumurate Gout Affecting middle-aged to elderly Affecting middle-aged to elderly

men.men.

Women represent only 5 to 17% of Women represent only 5 to 17% of all patients. all patients.

Monosodiumurate GoutMonosodiumurate Gout

Associated with an increased uric Associated with an increased uric acid, hyperuricemia, episodic acute acid, hyperuricemia, episodic acute and chronic arthritis, and deposition and chronic arthritis, and deposition of MSU crystals in connective tissue of MSU crystals in connective tissue tophi and kidneys.tophi and kidneys.

Acute and chronic Acute and chronic arthritisarthritis

Acute arthritis is the most frequent Acute arthritis is the most frequent early clinical manifestation of MSU early clinical manifestation of MSU gout.gout.

Usually only one joint is affected Usually only one joint is affected initiallyinitially

Polyarticular acute gout is also seen in Polyarticular acute gout is also seen in male hypertensive patients with male hypertensive patients with ethanol abuse as well as in ethanol abuse as well as in postmenopausal women. postmenopausal women.

The metatarso phalangeal joint of The metatarso phalangeal joint of the first toe is often involved.the first toe is often involved.

Ankles, and knees are also Ankles, and knees are also commonly affected.commonly affected.

In elderly patients, finger joints may In elderly patients, finger joints may be inflamed. be inflamed.

Acute and chronic Acute and chronic arthritisarthritis

Acute and chronic Acute and chronic arthritisarthritis

The first episode of acute gouty The first episode of acute gouty arthritis frequently begins at night.arthritis frequently begins at night.

With dramatic joint pain and swelling.With dramatic joint pain and swelling. Early attacks tend to subside Early attacks tend to subside

spontaneously within 3 to 10 days. spontaneously within 3 to 10 days. Most of the patients do not have Most of the patients do not have

residual symptoms until next episode.residual symptoms until next episode.

Acute and chronic Acute and chronic arthritisarthritis

Signs and SymptomsSigns and Symptoms Chronic:Chronic:

Destructive tophacous gout.Destructive tophacous gout. Much greater chance if untreatedMuch greater chance if untreated Rarely presents as a chronic Rarely presents as a chronic

NephrolithiasisNephrolithiasis The prevalence of nephrolithiasis The prevalence of nephrolithiasis

correlates with the serum and correlates with the serum and urinary uric acid levels.urinary uric acid levels.

Serum urate levels 13 mg/dlSerum urate levels 13 mg/dl Urinary uric acid excretion > 1100 Urinary uric acid excretion > 1100

mg/dmg/d

DiagnosisDiagnosis Based on history and physicalBased on history and physical Confirmed by arthrocentesisConfirmed by arthrocentesis

Urate crystals: needle-shaped negatively Urate crystals: needle-shaped negatively birefringent either free floating or within birefringent either free floating or within neutrophils & macrophages.neutrophils & macrophages.

Uric acid level non specific.Uric acid level non specific. 30% may show normal level30% may show normal level

Urine collection:Urine collection: <800 mg dl/d underexcertor (<600 purine-<800 mg dl/d underexcertor (<600 purine-

free diet)free diet)

X-rayX-ray AcuteAcute

Soft tissue Soft tissue swellingswelling

ChronicChronic chronic tophaceous chronic tophaceous

gouty arthritis, gouty arthritis, extensive bony extensive bony erosions are noted erosions are noted throughout the throughout the carpal bones carpal bones

PrognosisPrognosis Generally goodGenerally good More severe course when Sx present More severe course when Sx present

< 30 y/o< 30 y/o Up to 50% progress to chronic Up to 50% progress to chronic

disease if untreated.disease if untreated. Surgical intervention may be Surgical intervention may be

required for tophi.required for tophi.

TreatmentTreatment Acute:Acute:

NSAID’s anti-inflammatory dosesNSAID’s anti-inflammatory doses Colchicine 0.5 mg po q2 hours, may require 6 Colchicine 0.5 mg po q2 hours, may require 6

mg.mg. Stop with response or side effect (diarrhea)Stop with response or side effect (diarrhea) Can be used for chronic disease, increased risk for Can be used for chronic disease, increased risk for

BM suppressionBM suppression Aspirate followed by administration of Aspirate followed by administration of

corticosteroidscorticosteroids PrednisonePrednisone ACTH 40-80 IM/IV ACTH 40-80 IM/IV

TreatmentTreatment Chronic:Chronic:

Diet will decrease uric acid 1 mg/dL at Diet will decrease uric acid 1 mg/dL at bestbest

Weight lossWeight loss Modification of medicationsModification of medications

Avoid low dose ASA, diuretics, etc.Avoid low dose ASA, diuretics, etc.

TreatmentTreatment

ChronicChronic Uricosuric: for under-excretorsUricosuric: for under-excretors

Probenicid: Probenicid: Sulfinpyrazone: toxic side effectsSulfinpyrazone: toxic side effects Avoid with renal diseaseAvoid with renal disease Consider NSAIDs to avoid exacerbation of Consider NSAIDs to avoid exacerbation of

gout.gout.

TreatmentTreatment ChronicChronic

Indications for AllopurinolIndications for Allopurinol Tophaceous depositesTophaceous deposites Uric acid consistently >9 mg/dl.Uric acid consistently >9 mg/dl. Persistent Sx with moderate UA levelsPersistent Sx with moderate UA levels Impaired renal functionImpaired renal function Prophylaxis for tumor-lysis syndromeProphylaxis for tumor-lysis syndrome

Consider NSAID’s to avoid exacerbationConsider NSAID’s to avoid exacerbation