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Gout 13
1.
2. 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.
3. GOUT
Normal 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%
5. 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
6. GoutGout
Gout is defined as aGout is defined as a
peripheral arthritisperipheral arthritis
resulting from theresulting from the
deposition of sodiumdeposition of sodium
urate crystals in one orurate crystals in one or
more joints.more joints.
It is nine times asIt is nine times as
common in men as incommon in men as in
womenwomen
HyperuricemiaHyperuricemia : serum uric acid >7mg% (males): serum uric acid >7mg% (males)
and >6mg% (females)and >6mg% (females)
7. DefinitionDefinition
Heterogeneous 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 in
which monosodium urate monohydratewhich monosodium urate monohydrate
crystals are demonstrable in synovial fluidcrystals are demonstrable in synovial fluid
leukocytesleukocytes
Aggregates of sodium urate monohydrateAggregates of sodium urate monohydrate
crystals (tophi) deposited chiefly in andcrystals (tophi) deposited chiefly in and
around joints, which sometimes lead toaround joints, which sometimes lead to
deformity and cripplingdeformity and crippling
Renal disease involving glomerular,Renal disease involving glomerular,
tubular, and interstitial tissues and bloodtubular, and interstitial tissues and blood
vesselsvessels
Uric acid nephrolithiasis
8. The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)
Synthesis of purine nucleotides
C
Y
T
O
P
L
A
S
M
9. The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)
Regulation of
synthesis
of purine
nucleotides
10.
11. Principal differences between metabolism
of purines and pyrimidines
purines 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 enzyme
is in a mitochondrion
products of
degradation
uric acid
(poor solubility in H2O),
NH3
CO2, NH3, β-
Aminoisobutyric acid
(soluble in H2O)
13. The figure was adopted from Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2
14. Classification of Hyperuricemia andClassification of Hyperuricemia and
GoutGout
AA.. Primary Hyperuricemia and GoutPrimary Hyperuricemia and Gout
with 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%)
IdiopathicIdiopathic
G-6PD, HGPRT deficiencyG-6PD, HGPRT deficiency
15. B. Secondary Hyperuricemia and GoutB. Secondary Hyperuricemia and Gout
with Identifiable Associated Conditionwith Identifiable Associated Condition
1.1. 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, 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 Hemolytic
anemias, 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
16. 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 levels, bodyCorresponds with serum creatinine /BUN levels, body
weight, 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, or
body mass index) has proved to be one of the mostbody mass index) has proved to be one of the most
important predictors of hyperuricemia in people of widelyimportant predictors of hyperuricemia in people of widely
differing races and cultures.differing races and cultures.
Incidence of GoutIncidence of Gout
Varies depending on population studied – 1.8 /1000 –Varies depending on population studied – 1.8 /1000 –
3.2/10003.2/1000
Recurance Rate for blacks slightly higher (1.3)Recurance Rate for blacks slightly higher (1.3)
17. DiagnosisDiagnosis
Clinical :Clinical :
In men , initial attack monoarticular – 1In men , initial attack monoarticular – 1stst
MTPMTP
joint(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 with
systemic signs., most often initial presentingsystemic signs., most often initial presenting
complaint 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.
18. 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 to
developdevelop
Martel’sMartel’ssignsign
CT/MRI/US/Bone scanCT/MRI/US/Bone scan
Sensitive , non specificSensitive , non specific
19.
20.
21.
22.
23. Affects less than 0.5% of the populationAffects less than 0.5% of the population
Due to familial disposition, incidenceDue to familial disposition, incidence
may be as high as 80% in familiesmay be as high as 80% in families
affected by disorder.affected by disorder.
Typical sequence involves progression
through:
asymptomatic hyperuricemia
acute gouty arthritis
interval or intercritical gout
chronic or tophaceous gout
25. 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 presentationMTP classic presentation
May effect knees, wrist, elbow, and rarely SI andMay effect knees, wrist, elbow, and rarely SI and
hips.hips.
Chronic:Chronic:
Much greater chance if untreatedMuch greater chance if untreated
Destructive tophacousDestructive tophacous
Rarely presents as a chronicRarely presents as a chronic
26. Cont………………………….Cont………………………….
Inflammation of metatarsophalangyealInflammation 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 bodyPain is more at night because of low body
temperature.temperature.
Fatigue and fever.Fatigue and fever.
Renal lithiasis.Renal lithiasis.
Uric acid nephropathy.Uric acid nephropathy.
Urate nephropathyUrate nephropathy..
27. DiagnosisDiagnosis
Based on history and physicalBased on history and physical
Confirmed by arthrocentesisConfirmed by arthrocentesis
Urate crystals: needle-shaped negativelyUrate crystals: needle-shaped negatively
birefringent either free floating or withinbirefringent 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 underexcertor(<600 purine-free<800 mg underexcertor(<600 purine-free
diet)diet)
29. 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 noted
throughout the carpal bonesthroughout the carpal bones
Sclerosis and joint-space narrowingSclerosis and joint-space narrowing
are seen in the firstare seen in the first
metatarsophalangeal joint, as well asmetatarsophalangeal joint, as well as
in the fourth interphalangeal joint .in the fourth interphalangeal joint .
30. Differential DiagnosisDifferential Diagnosis
Septic arthritis: must be excludedSeptic arthritis: must be excluded
Acute Rheumatic feverAcute Rheumatic fever
Palindromic RheumatismPalindromic Rheumatism
Psoriatic arthritisPsoriatic arthritis
31. ProphylaxisProphylaxis
Only indicated if patient is started onOnly indicated if patient is started on
urate lowering Rx.urate lowering Rx.
Colchicine( 1-3 pills a day)/ NSAID( inColchicine( 1-3 pills a day)/ NSAID( in
colchicine intolerant).colchicine intolerant).
Does not alter crystal deposition andDoes not alter crystal deposition and
development of tophi.development of tophi.
Continue till serum urate levels stabilizeContinue till serum urate levels stabilize
and 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,
32. 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 confirmed
diagnosis of gout.diagnosis of gout.
Endpoints – improvement in jt symptoms/ GIEndpoints – improvement in jt symptoms/ GI
symptoms/ 10 doses taken.symptoms/ 10 doses taken.
NSAIDs if diagnosis confirmed. Any NSAIDNSAIDs if diagnosis confirmed. Any NSAID
can be used .can be used .
Newer agents – Etoricoxcib 120 OD comparableNewer agents – Etoricoxcib 120 OD comparable
to 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 /iv
prednisone.prednisone.
Avoid adjusting dosage of urate loweringAvoid adjusting dosage of urate lowering
33. 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 difference
of 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
34. Genral Precaution to Pt.Genral Precaution to Pt.
Diet will decrease uric acid 1 mg/dLDiet will decrease uric acid 1 mg/dL
at bestat best
Weight lossWeight loss
Limit ETHANOLLimit ETHANOL
Modification of medicationsModification of medications
Avoid low dose ASA, diuretics, etc.Avoid low dose ASA, diuretics, etc.
All cancer pts allopurinol isAll cancer pts allopurinol is
advised.advised.
35. Cont…………..Cont…………..
Uricosuric: for under-excretorsUricosuric: for under-excretors
Probenicid:Probenicid:
Sulfinpyrazone: toxic sideSulfinpyrazone: toxic side
effectseffects
Avoid with renal diseaseAvoid with renal disease
Consider NSAIDs to avoidConsider NSAIDs to avoid
exacerbation of goutexacerbation of gout
36. PrognosisPrognosis
Generally goodGenerally good
More severe course whenMore severe course when
patients present < 30 years ofpatients present < 30 years of
age.age.
Up to 50% progress to chronicUp to 50% progress to chronic
disease if untreated.disease if untreated.
Surgical intervention may beSurgical intervention may be
required for tophi.required for tophi.
37. 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 of
Purines Salvage pathway).Purines Salvage pathway).
Rise inRise in intracellularintracellular PRPP,resultsPRPP,results
in purine Over Production.in purine Over Production.
Mutations that decrease or abolishMutations that decrease or abolish
HGPRT include deletion,frameshiftHGPRT include deletion,frameshift
mutations and mRNA splicing.mutations and mRNA splicing.
38. 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.
39. VON GIERKE DISEASEVON GIERKE DISEASE
Purines overproduction andPurines overproduction and
hyperuricemia.hyperuricemia.
Enzyme deficient isEnzyme deficient is Glucose-Glucose-
6phosphatase6phosphatase..
Enhanced productio of PRPP,precursorEnhanced productio of PRPP,precursor
of ribose-5phosphate.of ribose-5phosphate.
This is associated with LacticThis is associated with Lactic
acidosis,decreased uric acid secretionacidosis,decreased uric acid secretion
and elevating total uric acid.and elevating total uric acid.
Glucose enters towards HMP shunt.Glucose enters towards HMP shunt.
40. HYPOURICEMIAHYPOURICEMIA
Increased excretion of hypoxantheneIncreased excretion of hypoxanthene
and xanthene.and xanthene.
This is due to Xanthene oxidaseThis is due to Xanthene oxidase
deficiency.deficiency.
Xanthene oxidase defi. Is due toXanthene oxidase defi. Is due to
genetic defect or to severe livergenetic defect or to severe liver
damage.damage.
Patients with severe enzyme deficiencyPatients with severe enzyme deficiency
may exhibit XANTHINURIA andmay exhibit XANTHINURIA and
XANTHINE LITHIASIS.XANTHINE LITHIASIS.
41. 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.
42. 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.