GOUT METABOLIC DISORDER Of purine catabolism. Elevated levels of uric acid. It is a disorder of enzyme PRPP synthetase. Gouty arthritis. Gouty nephropathy. Incidence 3 per 1000 population. 5-10% Renal stone are of Uric Acid.
GOUT Normal adult male excrete 0.5-0.7 gof uric acid /day. It comes from diet,breakdown ofendogenous purines. Diet 300mg,synthesis 400mg. Body uric acid pool is1200mg/20,000-30,000 in gout. Uric acid is ANTIOXIDANT. Normal levels in M 3-7,F 2-5mg%
Gout encompasses a group ofdisorders that occur alone or incombination and include (1)hyperuricemia, (2) attacks ofacute, typically monarticular,inflammatory arthritis, (3)tophaceous deposition of uratecrystals in and around joints, (4)interstitial deposition of uratecrystals in renal parenchyma,and (5) urolithiasis
GoutGout Gout is defined as aGout is defined as aperipheral arthritisperipheral arthritisresulting from theresulting from thedeposition of sodiumdeposition of sodiumurate crystals in one orurate crystals in one ormore joints.more joints. It is nine times asIt is nine times ascommon in men as incommon in men as inwomenwomenHyperuricemiaHyperuricemia : serum uric acid >7mg% (males): serum uric acid >7mg% (males)and >6mg% (females)and >6mg% (females)
DefinitionDefinitionHeterogeneous group of diseases involvingHeterogeneous group of diseases involving :: An elevated serum uric acid concentrationAn elevated serum uric acid concentration(hyperuricemia)(hyperuricemia) Recurrent attacks of acute arthritis inRecurrent attacks of acute arthritis inwhich monosodium urate monohydratewhich monosodium urate monohydratecrystals are demonstrable in synovial fluidcrystals are demonstrable in synovial fluidleukocytesleukocytes Aggregates of sodium urate monohydrateAggregates of sodium urate monohydratecrystals (tophi) deposited chiefly in andcrystals (tophi) deposited chiefly in andaround joints, which sometimes lead toaround joints, which sometimes lead todeformity and cripplingdeformity and crippling Renal disease involving glomerular,Renal disease involving glomerular,tubular, and interstitial tissues and bloodtubular, and interstitial tissues and bloodvesselsvessels Uric acid nephrolithiasis
The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)Synthesis of purine nucleotidesCYTOPLASM
The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)Regulation ofsynthesisof purinenucleotides
Principal differences between metabolismof purines and pyrimidinespurines pyrimidinesformation ofN-glycosidicbondin 1ststep of theirbiosynthesis(PRDP is the 1stsubstrate)a heterocyclic ring isformed first, then itreacts with PRDPlocation ofbiosynthesiscytoplasm cytoplasm + 1 enzymeis in a mitochondrionproducts ofdegradationuric acid(poor solubility in H2O),NH3CO2, NH3, β-Aminoisobutyric acid(soluble in H2O)
Degradation of purines
The figure was adopted from Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2
Classification of Hyperuricemia andClassification of Hyperuricemia andGoutGoutAA.. Primary Hyperuricemia and GoutPrimary Hyperuricemia and Goutwith No Associated Conditionwith No Associated Condition Uric acid undersecretion(80%–Uric acid undersecretion(80%–90%)90%) Idiopathic /PregnancyIdiopathic /Pregnancy Urate overproduction (10%–Urate overproduction (10%–20%)20%)IdiopathicIdiopathicG-6PD, HGPRT deficiencyG-6PD, HGPRT deficiency
B. Secondary Hyperuricemia and GoutB. Secondary Hyperuricemia and Goutwith Identifiable Associated Conditionwith Identifiable Associated Condition1.1. Uric acid undersecretionUric acid undersecretion( a.) Renal insufficiency( a.) Renal insufficiency (b) Polycystic kidney disease(b) Polycystic kidney diseaseLead nephropathy Lead nephropathy (c) Drugs ( Diuretics, Salicylates, Pyrazinamide, Ethambutol,(c) Drugs ( Diuretics, Salicylates, Pyrazinamide, Ethambutol,Niacin, Cyclosporine, Didanosine )Niacin, Cyclosporine, Didanosine )2.2. Urate overproductionUrate overproduction Myeloproliferative/ Lymphoproliferative diseases HemolyticMyeloproliferative/ Lymphoproliferative diseases Hemolyticanemias, Polycythemia vera, Other malignancies, Psoriasis,anemias, Polycythemia vera, Other malignancies, Psoriasis,Glycogen storage diseaseGlycogen storage disease 3.3. Dual mechanismDual mechanism Obesity, ETOH,Hypoxemia and hypoperfusionObesity, ETOH,Hypoxemia and hypoperfusion
EpidemiologyEpidemiology Prevalence of hyperuricemiaPrevalence of hyperuricemia2.3 – 41.4% in various populations.2.3 – 41.4% in various populations.Corresponds with serum creatinine /BUN levels, bodyCorresponds with serum creatinine /BUN levels, bodyweight, height, age, blood pressure, and alcohol intake.weight, height, age, blood pressure, and alcohol intake.(Taiwan)(Taiwan)Body bulk (as estimated by body weight, surface area, orBody bulk (as estimated by body weight, surface area, orbody mass index) has proved to be one of the mostbody mass index) has proved to be one of the mostimportant predictors of hyperuricemia in people of widelyimportant predictors of hyperuricemia in people of widelydiffering races and cultures.differing races and cultures. Incidence of GoutIncidence of GoutVaries depending on population studied – 1.8 /1000 –Varies depending on population studied – 1.8 /1000 –3.2/10003.2/1000Recurance Rate for blacks slightly higher (1.3)Recurance Rate for blacks slightly higher (1.3)
DiagnosisDiagnosis Clinical :Clinical : In men , initial attack monoarticular – 1In men , initial attack monoarticular – 1ststMTPMTPjoint(50% of cases)joint(50% of cases)Other jts involved – instep/knees/wrists/Other jts involved – instep/knees/wrists/olecranon bursa. Often begins at night.olecranon bursa. Often begins at night.Usually abrupt , severely painful.Usually abrupt , severely painful. Later attacks – polyarticular , assoc withLater attacks – polyarticular , assoc withsystemic signs., most often initial presentingsystemic signs., most often initial presentingcomplaint in women. (hands/tarsal jts/knees)complaint in women. (hands/tarsal jts/knees) Precipitants – Minor trauma , Ethyl alcohol,Precipitants – Minor trauma , Ethyl alcohol,diuretic Rx, Surgery, severe medical illness,diuretic Rx, Surgery, severe medical illness,hypouricemic Rx.hypouricemic Rx. Tophi – Classically , helix/ antihelix ,but rare ;Tophi – Classically , helix/ antihelix ,but rare ;more common , hands, feet, olecranon bursa.more common , hands, feet, olecranon bursa.Complications : ulceration/infection.Complications : ulceration/infection.
DiagnosisDiagnosis RadiologicRadiologic X RAY :X RAY : Punched out erosions – only 45%Punched out erosions – only 45%of pts have them, takes 6 yrs toof pts have them, takes 6 yrs todevelopdevelop Martel’sMartel’ssignsign CT/MRI/US/Bone scanCT/MRI/US/Bone scan Sensitive , non specificSensitive , non specific
Affects less than 0.5% of the populationAffects less than 0.5% of the population Due to familial disposition, incidenceDue to familial disposition, incidencemay be as high as 80% in familiesmay be as high as 80% in familiesaffected by disorder.affected by disorder. Typical sequence involves progressionthrough:asymptomatic hyperuricemiaacute gouty arthritisinterval or intercritical goutchronic or tophaceous gout
Signs and SymptomsSigns and SymptomsAcute attackAcute attack:: Over hours frequently nocturnalOver hours frequently nocturnal Excruciating painExcruciating pain Swelling, redness and tendernessSwelling, redness and tenderness Podagra: 1Podagra: 1ststMTP classic presentationMTP classic presentation May effect knees, wrist, elbow, and rarely SI andMay effect knees, wrist, elbow, and rarely SI andhips.hips.Chronic:Chronic: Much greater chance if untreatedMuch greater chance if untreated Destructive tophacousDestructive tophacous Rarely presents as a chronicRarely presents as a chronic
Cont………………………….Cont…………………………. Inflammation of metatarsophalangyealInflammation of metatarsophalangyealjoint,heels,knees,wrist and fingers.joint,heels,knees,wrist and fingers. Mild inflammation of small joints.Mild inflammation of small joints. Pain is more at night because of low bodyPain is more at night because of low bodytemperature.temperature. Fatigue and fever.Fatigue and fever. Renal lithiasis.Renal lithiasis. Uric acid nephropathy.Uric acid nephropathy. Urate nephropathyUrate nephropathy..
DiagnosisDiagnosis Based on history and physicalBased on history and physical Confirmed by arthrocentesisConfirmed by arthrocentesis Urate crystals: needle-shaped negativelyUrate crystals: needle-shaped negativelybirefringent either free floating or withinbirefringent either free floating or withinneutrophils & 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 underexcertor(<600 purine-free<800 mg underexcertor(<600 purine-freediet)diet)
Microscopic DiagnosisMicroscopic Diagnosis
X-rayX-ray AcuteAcute Soft tissue swellingSoft tissue swelling ChronicChronic chronic tophaceous gouty arthritis,chronic tophaceous gouty arthritis,extensive bony erosions are notedextensive bony erosions are notedthroughout the carpal bonesthroughout the carpal bones Sclerosis and joint-space narrowingSclerosis and joint-space narrowingare seen in the firstare seen in the firstmetatarsophalangeal joint, as well asmetatarsophalangeal joint, as well asin the fourth interphalangeal joint .in the fourth interphalangeal joint .
Differential DiagnosisDifferential Diagnosis Septic arthritis: must be excludedSeptic arthritis: must be excluded Acute Rheumatic feverAcute Rheumatic fever Palindromic RheumatismPalindromic Rheumatism Psoriatic arthritisPsoriatic arthritis
ProphylaxisProphylaxis Only indicated if patient is started onOnly indicated if patient is started onurate lowering Rx.urate lowering Rx. Colchicine( 1-3 pills a day)/ NSAID( inColchicine( 1-3 pills a day)/ NSAID( incolchicine intolerant).colchicine intolerant). Does not alter crystal deposition andDoes not alter crystal deposition anddevelopment of tophi.development of tophi. Continue till serum urate levels stabilizeContinue till serum urate levels stabilizeand no attacks for 3 – 6 mths.and no attacks for 3 – 6 mths. If long term prophylactic colchicine given,If long term prophylactic colchicine given,
TreatmentTreatment Acute gouty arthritisAcute gouty arthritis:: Anti- inflammatory drugs ( if s.creat < 2mg/dl,Anti- inflammatory drugs ( if s.creat < 2mg/dl,no PUD)no PUD) Colchicine preferred in pts without confirmedColchicine preferred in pts without confirmeddiagnosis of gout.diagnosis of gout. Endpoints – improvement in jt symptoms/ GIEndpoints – improvement in jt symptoms/ GIsymptoms/ 10 doses taken.symptoms/ 10 doses taken. NSAIDs if diagnosis confirmed. Any NSAIDNSAIDs if diagnosis confirmed. Any NSAIDcan be used .can be used . Newer agents – Etoricoxcib 120 OD comparableNewer agents – Etoricoxcib 120 OD comparableto indomethacin 50 TID.to indomethacin 50 TID. In c/o renal failure /PUD - IM ACTH , oral /ivIn c/o renal failure /PUD - IM ACTH , oral /ivprednisone.prednisone. Avoid adjusting dosage of urate loweringAvoid adjusting dosage of urate lowering
Treatment (contd)Treatment (contd) Adjuvant RAdjuvant Rxx Control obesity ,ETHANOL intake, hyperlipidemiaControl obesity ,ETHANOL intake, hyperlipidemia,HTN,HTN Losartan / fenofibrate – weakly uricosuric.Losartan / fenofibrate – weakly uricosuric. Diet – moderation in purine intake. Makes a differenceDiet – moderation in purine intake. Makes a differenceof up to 1mg % in s. uric acid.of up to 1mg % in s. uric acid. AVOID:AVOID: Beer, other alcoholic beverages.Beer, other alcoholic beverages. Anchovies, sardines in oil, fish roes, herring.Anchovies, sardines in oil, fish roes, herring. Yeast.Yeast. Organ meat (liver, kidneys, sweetbreads)Organ meat (liver, kidneys, sweetbreads) Legumes (dried beans, peas)Legumes (dried beans, peas) Meat extracts, consommé, gravies.Meat extracts, consommé, gravies. Mushrooms, spinach, asparagus, cauliflowerMushrooms, spinach, asparagus, cauliflower
Genral Precaution to Pt.Genral Precaution to Pt. Diet will decrease uric acid 1 mg/dLDiet will decrease uric acid 1 mg/dLat bestat best Weight lossWeight loss Limit ETHANOLLimit ETHANOL Modification of medicationsModification of medicationsAvoid low dose ASA, diuretics, etc.Avoid low dose ASA, diuretics, etc.All cancer pts allopurinol isAll cancer pts allopurinol isadvised.advised.
Cont…………..Cont…………..Uricosuric: for under-excretorsUricosuric: for under-excretorsProbenicid:Probenicid:Sulfinpyrazone: toxic sideSulfinpyrazone: toxic sideeffectseffectsAvoid with renal diseaseAvoid with renal diseaseConsider NSAIDs to avoidConsider NSAIDs to avoidexacerbation of goutexacerbation of gout
PrognosisPrognosis Generally goodGenerally good More severe course whenMore severe course whenpatients present < 30 years ofpatients present < 30 years ofage.age. Up to 50% progress to chronicUp to 50% progress to chronicdisease if untreated.disease if untreated. Surgical intervention may beSurgical intervention may berequired for tophi.required for tophi.
LESCH-NYHAN SYNDROMELESCH-NYHAN SYNDROME Over production of uric acid.Over production of uric acid. Episodes of Uric acid lethiasis.Episodes of Uric acid lethiasis. HGPRT Enzyme defect (enzyme ofHGPRT Enzyme defect (enzyme ofPurines Salvage pathway).Purines Salvage pathway).Rise inRise in intracellularintracellular PRPP,resultsPRPP,resultsin purine Over Production.in purine Over Production. Mutations that decrease or abolishMutations that decrease or abolishHGPRT include deletion,frameshiftHGPRT include deletion,frameshiftmutations and mRNA splicing.mutations and mRNA splicing.
Cont……. Charcterised by spasticity,mentalretardation,self injurious behaviour andgout. HGPRT is present on X-chromosomehence affects males. Compulsive neurosis, desire to bitethere fingers ,lips and behaveaggresively towards others. Allopurinol is used ,but it has no effecton neurological disorders.
VON GIERKE DISEASEVON GIERKE DISEASE Purines overproduction andPurines overproduction andhyperuricemia.hyperuricemia. Enzyme deficient isEnzyme deficient is Glucose-Glucose-6phosphatase6phosphatase.. Enhanced productio of PRPP,precursorEnhanced productio of PRPP,precursorof ribose-5phosphate.of ribose-5phosphate. This is associated with LacticThis is associated with Lacticacidosis,decreased uric acid secretionacidosis,decreased uric acid secretionand elevating total uric acid.and elevating total uric acid. Glucose enters towards HMP shunt.Glucose enters towards HMP shunt.
HYPOURICEMIAHYPOURICEMIA Increased excretion of hypoxantheneIncreased excretion of hypoxantheneand xanthene.and xanthene. This is due to Xanthene oxidaseThis is due to Xanthene oxidasedeficiency.deficiency. Xanthene oxidase defi. Is due toXanthene oxidase defi. Is due togenetic defect or to severe livergenetic defect or to severe liverdamage.damage. Patients with severe enzyme deficiencyPatients with severe enzyme deficiencymay exhibit XANTHINURIA andmay exhibit XANTHINURIA andXANTHINE LITHIASIS.XANTHINE LITHIASIS.
ADENOSINE DEAMINASEDEFICIENCY Associated with immunodeficiency diseasein which both thymus-derived lymphocytes(T cell) and bone marrow-derivedlymphocytes (B-cell) are sparse anddysfunctional. Purine nucleotide phosphorylasedeficiency is associated with a severedeficiency of T cells but apparently normalB cell function. Immune dysfunctions appears to result fromaccumulation of dGTP and ATP,whichinhibit ribonucleotide reductase and thereby deplete cells of DNA precursors.
OROTIC ACIDUREA Due to de novosynthesis of pyrimidinenucleotides. Severe anaemia,growth retardationHigh levels orotic acid in urine. Uridine rich diet no synthesis of OroticAcid . Hyperammonemia may be associated with oroticacidurea,excess ammonia in liver mitochondria,comesto cytosole that leads to raised levels of orotic acid.