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.

GOUTNormal adult male excrete 0.5-0.7 g of uric acid /day.

It comes from diet,breakdown of endogenous purines.

Diet 300mg,synthesis 400mg.Body uric acid pool is 1200mg/20,000-30,000 in gout.

Uric acid is ANTIOXIDANT.Normal levels in M 3-7,F 2-5mg%

GoutGout

Gout encompasses a group of disorders that occur alone or in combination and include (1) hyperuricemia, (2) attacks of acute, typically monarticular, inflammatory arthritis, (3) tophaceous deposition of urate crystals in and around joints, (4) interstitial deposition of urate crystals in renal parenchyma, and (5) urolithiasis

Copyright© 1998 McGraw-Hill. All rights reserved.

GoutGout

Gout is defined as Gout is defined as a peripheral a peripheral arthritis resulting arthritis resulting from the from the deposition of deposition of sodium urate sodium urate crystals in one or crystals in one or more joints.more joints.

It is nine times as It is nine times as common in men common in men as in womenas in womenHyperuricemiaHyperuricemia : serum uric acid >7mg : serum uric acid >7mg

% (males) and >6mg% (females)% (males) and >6mg% (females)

DefinitionDefinitionHeterogeneous group of diseases involvingHeterogeneous group of diseases involving : : An elevated serum uric acid An elevated serum uric acid

concentration (hyperuricemia) concentration (hyperuricemia) Recurrent attacks of acute arthritis in Recurrent attacks of acute arthritis in

which monosodium urate monohydrate which monosodium urate monohydrate crystals are demonstrable in synovial crystals are demonstrable in synovial fluid leukocytes fluid leukocytes

Aggregates of sodium urate monohydrate Aggregates of sodium urate monohydrate crystals (tophi) deposited chiefly in and crystals (tophi) deposited chiefly in and around joints, which sometimes lead to around joints, which sometimes lead to deformity and crippling deformity and crippling

Renal disease involving glomerular, Renal disease involving glomerular, tubular, and interstitial tissues and tubular, and interstitial tissues and blood vessels blood vessels

Uric acid nephrolithiasis Uric acid nephrolithiasis

The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)

Synthesis of purine nucleotides

CYTOPLASM

The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)

Regulation of

synthesisof purine

nucleotides

Principal differences between metabolism of purines and

pyrimidinespurines pyrimidines

formation of N-glycosidic bond

in 1st step of their biosynthesis(PRDP is the 1st substrate)

a heterocyclic ring is formed first, then it reacts with PRDP

location of biosynthesis

cytoplasm cytoplasm + 1 enzymeis in a mitochondrion

products of degradation

uric acid (poor solubility in

H2O),

NH3

CO2, NH3, -

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 Classification of Hyperuricemia and GoutHyperuricemia and Gout

AA. . Primary Hyperuricemia and Gout with Primary Hyperuricemia and Gout with No Associated ConditionNo Associated Condition

Uric acid undersecretion(80%–90%) Uric acid undersecretion(80%–90%) Idiopathic /Pregnancy Idiopathic /Pregnancy Urate overproduction (10%–20%)Urate overproduction (10%–20%) Idiopathic Idiopathic G-6PD, HGPRT deficiencyG-6PD, HGPRT deficiency PRPP synthetase overactivityPRPP synthetase overactivity

B. Secondary Hyperuricemia B. Secondary Hyperuricemia and Gout with Identifiable and Gout with Identifiable Associated ConditionAssociated Condition1. 1. Uric acid undersecretionUric acid undersecretion ( a.)  Renal insufficiency ( a.)  Renal insufficiency      (b)  Polycystic kidney disease(b)  Polycystic kidney disease Lead nephropathy  Lead nephropathy   (c)  Drugs ( Diuretics, Salicylates, (c)  Drugs ( Diuretics, Salicylates, Pyrazinamide,  Ethambutol, Pyrazinamide,  Ethambutol, Niacin, Cyclosporine, Didanosine )Niacin, Cyclosporine, Didanosine )

2. 2. Urate overproductionUrate overproduction    Myeloproliferative/ Lymphoproliferative Myeloproliferative/ Lymphoproliferative diseases  Hemolytic anemias, Polycythemia diseases  Hemolytic anemias, Polycythemia vera, Other malignancies, Psoriasis, Glycogen vera, Other malignancies, Psoriasis, Glycogen storage diseasestorage disease

       3. 3. Dual mechanismDual mechanism         Obesity, ETOH,Hypoxemia and hypoperfusionObesity, ETOH,Hypoxemia and hypoperfusion

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 surface area, or body mass index) has proved to be one of the most important predictors of be 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 Recurance Rate for blacks slightly higher (1.3) Recurance Rate for blacks slightly higher (1.3)

Diagnosis Diagnosis Clinical :Clinical :

In men , initial attack monoarticular – 1In men , initial attack monoarticular – 1stst MTP joint(50% of cases)MTP joint(50% of cases)

Other jts involved – Other jts involved – instep/knees/wrists/ olecranon bursa. instep/knees/wrists/ olecranon bursa. Often begins at night. Usually abrupt , Often begins at night. Usually abrupt , severely painful. severely painful.

Later attacks – polyarticular , assoc with Later attacks – polyarticular , assoc with systemic signs., most often initial systemic signs., most often initial presenting complaint in women. presenting complaint in women. (hands/tarsal jts/knees)(hands/tarsal jts/knees)

Precipitants – Minor trauma , Ethyl Precipitants – Minor trauma , Ethyl alcohol, diuretic Rx, Surgery, severe alcohol, diuretic Rx, Surgery, severe medical illness, hypouricemic Rx.medical illness, hypouricemic Rx.

Tophi – Classically , helix/ antihelix ,but Tophi – Classically , helix/ antihelix ,but rare ; more common , hands, feet, rare ; more common , hands, feet, olecranon bursa. Complications : olecranon bursa. Complications : ulceration/infection.ulceration/infection.

DiagnosisDiagnosis

RadiologicRadiologic X RAY :X RAY :

Punched out erosions – Punched out erosions – only 45% of pts have only 45% of pts have them, takes 6 yrs to them, takes 6 yrs to developdevelop

Martel’sMartel’s sign sign

CT/MRI/US/Bone scan CT/MRI/US/Bone scan Sensitive , non specificSensitive , non specific

Affects less than 0.5% of the Affects less than 0.5% of the populationpopulation

Due to familial disposition, Due to familial disposition, incidence may be as high as 80% incidence may be as high as 80% in families affected by disorder.in families affected by disorder.

Typical sequence involves progression through:asymptomatic hyperuricemiaacute gouty arthritisinterval or intercritical goutchronic or tophaceous gout

Cont…………………Cont………………… Primary gout:Primary gout:

Overproducers: 10%Overproducers: 10%Under-excretors: 90%Under-excretors: 90%

Secondary gout:Secondary gout: Excess nucleoprotein turnover Excess nucleoprotein turnover

(lymphoma, leukemia)(lymphoma, leukemia) Increased cell proliferation/death Increased cell proliferation/death

(psoriasis(psoriasis Rare genetic disorder Lesch-Nyan Rare genetic disorder Lesch-Nyan

SyndromeSyndrome pharmaceuticalspharmaceuticals

Signs and SymptomsSigns and Symptoms

Acute attackAcute attack:: Over hours frequently nocturnalOver hours frequently nocturnal Excruciating painExcruciating pain Swelling, redness and tendernessSwelling, redness and tenderness Podagra: 1Podagra: 1stst MTP classic presentation MTP classic presentation May effect knees, wrist, elbow, and rarely May effect knees, wrist, elbow, and rarely SI and hips.SI and hips.

Chronic:Chronic: Much greater chance if untreatedMuch greater chance if untreated Destructive tophacousDestructive tophacous Rarely presents as a chronic Rarely presents as a chronic

Cont………………………….Cont………………………….

Inflammation of metatarsophalangyeal Inflammation of metatarsophalangyeal joint,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 Pain is more at night because of low

body temperature.body 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 Urate crystals: needle-shaped negatively birefringent either free negatively birefringent either free floating or within neutrophils & floating or within neutrophils & macrophages.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 <800 mg underexcertor(<600

purine-free diet)purine-free diet)

Microscopic DiagnosisMicroscopic Diagnosis

X-rayX-ray AcuteAcute

Soft tissue swellingSoft tissue swelling

ChronicChronic chronic tophaceous gouty chronic tophaceous gouty

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

Sclerosis and joint-space Sclerosis and joint-space

narrowing are seen in the narrowing are seen in the first metatarsophalangeal first metatarsophalangeal joint, as well as in the fourth joint, as well as in the fourth interphalangeal joint .interphalangeal joint .

Differential DiagnosisDifferential Diagnosis

Septic arthritis: must be Septic arthritis: must be excludedexcluded

Acute Rheumatic feverAcute Rheumatic fever Palindromic RheumatismPalindromic Rheumatism Psoriatic arthritisPsoriatic arthritis

Prophylaxis Prophylaxis

Only indicated if patient is started Only indicated if patient is started on urate lowering Rx.on urate lowering Rx.

Colchicine( 1-3 pills a day)/ Colchicine( 1-3 pills a day)/ NSAID( in colchicine intolerant).NSAID( in colchicine intolerant).

Does not alter crystal deposition Does not alter crystal deposition and development of tophi.and development of tophi.

Continue till serum urate levels Continue till serum urate levels stabilize and no attacks for 3 – 6 stabilize and no attacks for 3 – 6 mths.mths.

If long term prophylactic colchicine If long term prophylactic colchicine given, given,

Treatment Treatment Acute gouty arthritisAcute gouty arthritis::

Anti- inflammatory drugs ( if s.creat < 2mg/dl, no Anti- inflammatory drugs ( if s.creat < 2mg/dl, no PUD) PUD)

Colchicine preferred in pts without confirmed Colchicine preferred in pts without confirmed diagnosis of gout.diagnosis of gout.

Endpoints – improvement in jt symptoms/ GI Endpoints – improvement in jt symptoms/ GI symptoms/ 10 doses taken.symptoms/ 10 doses taken.

NSAIDs if diagnosis confirmed. Any NSAID can be NSAIDs if diagnosis confirmed. Any NSAID can be used . used .

Newer agents – Etoricoxcib 120 OD comparable Newer agents – Etoricoxcib 120 OD comparable to indomethacin 50 TID.to indomethacin 50 TID.

In c/o renal failure /PUD - IM ACTH , oral /iv In c/o renal failure /PUD - IM ACTH , oral /iv prednisone.prednisone.

Avoid adjusting dosage of urate lowering agents.Avoid adjusting dosage of urate lowering agents.

Treatment (contd) Treatment (contd) Adjuvant RAdjuvant Rx x

Control obesity ,ETHANOL intake, Control obesity ,ETHANOL intake, hyperlipidemia ,HTN hyperlipidemia ,HTN

Losartan / fenofibrate – weakly uricosuric.Losartan / fenofibrate – weakly uricosuric. Diet – moderation in purine intake. Makes a Diet – moderation in purine intake. Makes a

difference of up to 1mg % in s. uric acid.difference 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, cauliflower Mushrooms, spinach, asparagus, cauliflower

Genral Precaution to Pt.Genral Precaution to Pt.Diet will decrease uric acid 1 Diet will decrease uric acid 1 mg/dL at bestmg/dL at best

Weight lossWeight lossLimit ETHANOLLimit ETHANOLModification of medicationsModification of medications

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

All cancer pts allopurinol is All cancer pts allopurinol is advised.advised.

Cont…………..Cont………….. Uricosuric: for under-Uricosuric: for under-excretorsexcretorsProbenicid: Probenicid: Sulfinpyrazone: toxic side Sulfinpyrazone: toxic side effectseffects

Avoid with renal diseaseAvoid with renal diseaseConsider NSAIDs to avoid Consider NSAIDs to avoid exacerbation of goutexacerbation of gout

PrognosisPrognosisGenerally goodGenerally goodMore severe course when More severe course when patients present < 30 patients present < 30 years of age.years of age.

Up to 50% progress to Up to 50% progress to chronic disease if chronic disease if untreated.untreated.

Surgical intervention may Surgical intervention may be required for tophi.be required for tophi.

LESCH-NYHAN LESCH-NYHAN SYNDROMESYNDROME

Over production of uric acid.Over production of uric acid. Episodes of Uric acid lethiasis.Episodes of Uric acid lethiasis. HGPRT Enzyme defect (enzyme HGPRT Enzyme defect (enzyme

of Purines Salvage pathway).of Purines Salvage pathway). Rise in Rise in intracellularintracellular

PRPP,results in purine Over PRPP,results in purine Over Production.Production.

Mutations that decrease or Mutations that decrease or abolish HGPRT include abolish HGPRT include deletion,frameshift mutations deletion,frameshift mutations and mRNA splicing.and mRNA splicing.

Cont……. Charcterised by spasticity,mental

retardation,self injurious behaviour and gout.

HGPRT is present on X-chromosome hence affects males.

Compulsive neurosis, desire to bite there fingers ,lips and behave aggresively towards others.

Allopurinol is used ,but it has no effect on neurological disorders.

VON GIERKE DISEASEVON GIERKE DISEASE Purines overproduction and Purines overproduction and

hyperuricemia.hyperuricemia. Enzyme deficient is Enzyme deficient is Glucose-Glucose-

6phosphatase6phosphatase.. Enhanced productio of Enhanced productio of

PRPP,precursor of ribose-PRPP,precursor of ribose-5phosphate.5phosphate.

This is associated with Lactic This is associated with Lactic acidosis,decreased uric acid acidosis,decreased uric acid secretion and elevating total uric secretion and elevating total uric acid.acid.

Glucose enters towards HMP shunt.Glucose enters towards HMP shunt.

HYPOURICEMIAHYPOURICEMIA Increased excretion of Increased excretion of

hypoxanthene and xanthene.hypoxanthene and xanthene. This is due to Xanthene oxidase This is due to Xanthene oxidase

deficiency.deficiency. Xanthene oxidase defi. Is due to Xanthene oxidase defi. Is due to

genetic defect or to severe liver genetic defect or to severe liver damage.damage.

Patients with severe enzyme Patients with severe enzyme deficiency may exhibit deficiency may exhibit XANTHINURIA and XANTHINE XANTHINURIA and XANTHINE LITHIASIS.LITHIASIS.

ADENOSINE DEAMINASE DEFICIENCY

Associated with immunodeficiency disease in which both thymus-derived lymphocytes (T cell) and bone marrow-derived lymphocytes (B-cell) are sparse and dysfunctional.

Purine nucleotide phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function.

Immune dysfunctions appears to result from accumulation of dGTP and ATP,which inhibit ribonucleotide reductase and there by deplete cells of DNA precursors.

SCID treated by ADA gene in 1990.

OROTIC ACIDUREA

Due to de novosynthesis of pyrimidine nucleotides.

Severe anaemia,growth retardation High levels orotic acid in urine.

Uridine rich diet no synthesis of Orotic Acid .

Hyperammonemia may be associated with orotic acidurea,excess ammonia in liver mitochondria,comes to cytosole that leads to raised levels of orotic acid.