4. Purines
Purines are natural substances found in
all of the body's cells, and in virtually all
foods.
The reason for their widespread
occurrence is simple: purines provide part
of the chemical structure of our genes and
the genes of plants and animals
5. When cells die and get recycled, the
purines in their genetic material also get
broken down.
Uric acid is the chemical formed when
purines have been broken down
completely.
6. Hyperuricemia
The condition when there are high
concentrations of uric acid in the blood.
Serum levels of uric acid are >7mg/dL
(Normally, 2.4-6mg/dL in females; 3.4-
7mg/dL in males)
At such a high level, uric acid tends to
aggregate and form crystals
Primary Hyperuricemia: an innate
defect in purine metabolism and/or uric
acid excretion
Secondary Hyperuricemia: high uric
acid levels due to medications/medical
conditions such as diabetic ketoacidosis,
psoriasis, chronic lead poisoning
7. Most uric acid dissolves in blood and
travels to the kidneys, where it passes out
in urine.
If your body produces too much uric acid
or doesn't remove enough if it, you can get
sick.
High levels of uric acid in the body is
called Hyperuricemia.
10. Uric Acid
Uric acid is the end product in purine metabolism
Excretion of uric acid removes nitrogenous wastes from
body
2/3 of uric acid made is excreted via kidneys; 1/3 via GI
tract
Urate: protonated form of uric acid
11. Uric acid can accumulate due to:
Overproduction of purine nucleotides
Enhanced cell turnover (purine degradation)
Decreased in purine salvage pathway
Underexcretion of uric acid
Predisposition to many diseases
People may live with elevated uric acid levels
without experiencing any symptoms
12. GOUT
Gout and gouty arthritis
Transient attacks of acute arthritis initiated by
crystallization of urates and neutrophils, followed
by chronic gouty arthritis with tophi in joints and
urate nephropathy
Sites: 50% have initial attack in first
metatarsophalangeal joint; also ankles, heels,
knees, wrists, fingers, elbows
14. Gout
Affects less than 0.5% of the population.
It is a common condition, presenting in 1-4%
of adult men.
Due to familial disposition, incidence may be
as high as 80% in families affected by
disorder.
15. Alcohol and Gout
alcohol metabolism contributes to urate retention
some red wines contain purines or oxypurines,
which lead to an increased purine load
alcohol may contribute to obesity which is
associated with under excretion of uric acid
Patients with a history of gout are advised to
drink plenty of fluid, approximately 2 litres per
day (nonalcoholic).
16. GOUT
Primary gout (90%): idiopathic with
overproduction of uric acid
Hyperuricemia in the absence of other
disease
Asymptomatic hyperuricemia can precede gout
Impaired secretion by kidneys
17. Secondary gout (10%): increased nucleic acid
turnover due to
chronic renal disease,
HGPRT deficiency( hypoxanthine-guanine
phosphoribosyl transferase deficiency)
Tumors
Leukemias
Lymphomas
After chemotherapy
Alcoholism
Accelerated ATP catabolism
18. "se co n da ry go u t"
H G P R T
E n zym a tic d e ficie n cy
"se co n d a ry g o u t"
L e u ke m ia
In crea se d n ucle ic a cid tu rn o ve r
"p rim a ry g o u t"
U n kn o w n d efe ct
ca u sin g d e cre a se d excre tion
H yp e ru rice m ia
19. GOUT
Arthritis: synovial fluid is poorer solvent for sodium
urate than plasma, so with hyperuricemia.
Urates in joint fluid crystallize, particularly in ankle due
to lower temperature; crystals develop in synovial lining
cells, stimulate formation of antibodies, which
accelerates formation of new crystals.
Release of crystals attracts neutrophils and complement,
(generates c3a, c5a, attracts more neutrophils),
Releases free radicals, releases lysosomal enzymes
20. GOUT
This will eventually causes acute arthritis that last days
to weeks without treatment; repeated attacks of acute
arthritis cause
Renal failure, urate stones
21. Risk factors for gout with Hyperuricemia are:
Age > 30 years,
Male, familial history of gout,
Alcohol use,
Obesity,
Thiazide administration(reduce the clearance of uric
acid)
22. Pathogenesis
Enzymatic deficiencies and increased
nucleic acid turnover account for only 10%
of gout patients.
Remaining 90% are “primary gout” due to
an unknown defect limiting the ability to
excrete uric acid.
23. Pathogenesis
Uric acid normally dissolves in plasma
Poorly soluble in synovial fluid and
precipitates out as MSU crystals
(monosodium urate crystals )
24. Pathogenesis
Hyperuricaemia
May be asymptomatic
Deposition of monosodium urate crystals in synovial tissue
(contain various Ig’s, complement, fibrinogen, fibronectin)
Complement activated
Neutrophils phagocytose & lyse crystals
Release chemical mediators (e.g. TNF-α; IL-1)
ACUTE GOUTY ARTHRITIS
May resolve & become asymptomatic
(INTERCRITICAL GOUT)
25. May have recurrent episodes
Large deposits of chalky white urate tophi
Chronic granulomatous inflammatory condition
Fibrosis of synovium
Erosion of articular cartilage
CHRONIC TOPHACEOUS ARTHRITIS
ankylosis
Tophi may be deposited in soft tissue
Can ulcerate if sub-cutaneous
26. Pathogenesis of Renal Involvement
Hyperuricaemia
Freely filtered by glomerulus, but reabsorbed in proximal
convulated tubules
Precipitation in renal tubules
Tubule obstruction
Crystal formation in interstitium
Renal stones
Recurrent pyelonephritis
29. Crystal Studies
Sodium urate crystals viewed under polarized
light with a red plate makes those in the plane of
the long axis of the red plate yellow, which
indicates that they are negatively birefringent.
32. Clinical features
Acute gouty arthritis
Painful
Involves one joint initially, then polyarticular
Podagra (painful, red metatarsophalangeal
joint)
Tophaceous gout
Development of tophi
Chalky, cheesy, yellow-white, pasty deposits of
monosodium urate crystals
Helix and antihelix of ear
Achilles tendon
36. Chronic gout
Polyarticular gout
Tophi may form around joints and often also in the
pinna of the ear and with time may ulcerate and
discharge
May cause joint stiffness and deformity as a result of
joint erosion
May cause renal damage due to deposition of urate
crystals in the renal parenchyma
Urate urolithiasis occurs in 10%; rarely chronic urate
nephropathy with renal failure may develop
41. Diagnosis
More than one attack
Maximum
inflammation in one
day
Monoarthritis
Redness
First MTP involved
Unilateral first MTP
Unilateral tarsal
attack
Tophus
Hyperuricemia
Asymmetric swelling
MSU crystals in joint
fluid
Joint fluid culture
negative
42. Diagnosis
Based on history and physical examination
Confirmed by arthrocentesis
Urate crystals: needle-shaped negatively birefringent
either free floating or within neutrophils & macrophages.
Uric acid level non specific.
30% may show normal level
Urine collection:
44. GOUT
Gross: chalky white appearance of gouty deposits
Micro: early - edematous synovium with acute and
chronic inflammatory infiltrate
Late - tophi (large aggregates of urate crystals,
granulomatous inflammation, hyperplastic fibrotic
synovium);
Gout crystals are long, slender, needle shaped, but
difficult to visualize with routine staining because they
are dissolved during formalin processing (crystals are
water soluble); easier to identify on scrape or with
alcohol fixation
45. GOUT
With chronic disease, urate deposits may
be present in soft tissue, ligaments, skin
Gouty deposits may be surrounded by
fibrous tissue and be rimmed by
histiocytes and giant cells
46. Gout from sodium urate crystalsGout from sodium urate crystals
deposited in joints.deposited in joints.
47. This is gout. Gouty arthritis results from
deposition of sodium urate crystals in
joints.
The joint most often affected is the first
MP joint (big toe) as seen here.
Acute attacks are characterized by severe
pain, swelling, and erythema of the joint.