URIC ACID

Uric acidis the end product of purine

metabolism in humans.
At physiological pH, uric acid is 98% ionized and
is therefore present mainly as the urate ion.
In the extracellular fluid (ECF), where sodium is
the major cation, uric acid effectively exists as a
solution of its sodium salt, monosodium urate.
This salt has low solubility, and the ECF
becomes saturated at concentrations a little
above those that normally prevail.
In patients with hyperuricaemia, there is thus a
tendency for crystals of monosodium urate to
form.

In addition to acute arthropathy, other

manifestations of gout include renal calculi (which
may lead to chronic kidney disease) and tophi
(accretions of sodium urate in soft tissues).
A sudden increase in urate production, typically
seen as a consequence of treatment of
haematological malignancy (tumour lysis
syndrome) , can lead to widespread
crystallization in the renal tubules, causing
obstruction and acute kidney injury (acuteurate
nephropathy).
This is usually avoidable by giving allopurinol ,
but if it does occur it can be treated with
rasburicase, a recombinant fungus-derived

Uric acid
metabolism
Purine nucleotides
are components of nucleic
acids; they are also intimately involved in energy
transformation and phosphorylation reactions and
act as second messengers.
There are three sources of purines in man:
(1)The diet.
(2)Degradation of endogenous nucleotides.
(3)De novosynthesis.
Urate is excreted by the kidney and the
intestine. In the intestine, urate is metabolized to
carbon dioxide and ammonia by bacterial action
("uricolysis").

Urate handling by the kidney is complex. It is

filtered by the glomeruli and then almost
completely reabsorbed in the proximal tubules; in
the distal tubules, both reabsorption and
secretion occurs.
Net urate clearance is only 10% of the filtered
load. If the filtered load is increased in normal
subjects, excretion is increased.
In patients with renal failure, however, urate
excretion decreases with decrease in glomerular
filtration rate, and the serum level rises.
Dietary purines account only for 30% of
excreted urates.
The metabolic pathways leading to endogenous
uric acid synthesysis are mediated by several
enzymes in a complex fashion.

There isde novosynthesisfrom ribose-1phosphate toinosineas well as asecondary

"salvage" pathwaywhich leads to the
production of uric acid by converting guanine and
adenine bases intoinosine, which is in themain
pathwayof xanthine production.
Xanthineis oxidized by xanthine oxidase to
uric acid.

Uric acid in
Serum concentrations of uric acid arehigher in
serum
menthan in women(gout
is much more common
in men), tend torise with age, and tend to
behigherin individuals of higher economic
classes and inobesepeople.
There isconsiderable variationin serum urate
concentrations betweendifferent ethnic groups.
Althoughthe mechanism of gout has not been
completely elucidated, thelikelihood of gout
increases with increased serum urate levels.
However, only a small proportion of individuals
with elevated uric acid levels develop gout (in the
Western Hemisphere, it is estimated that 10% of
the population has high uric acid levels, but only

The solubility of urate decreases with

decreasing temperature, explaining the increased
incidence of gout in peripheral joints (which are
cooler).
Hyperuricemia can be caused byincreased
formation of uric acid,byreduced excretion by
the kidneys,or by acombinationof both
mechanisms.
Increased formation of uric acid occurs
with:-(A)High dietary intake.
(B)Increased purine synthesis:-(1)Idiopathic.
(2)Inherited(several genetic mechanisms have
been described).
(C)Increased nucleic acid turnover:-

(3) Secondary polycythemia.

(4)Carcinomatosis.
(5)Chronic hemolytic anemias.
(6)Cytotoxic drugs.
Reduced excretion of uric acid by the
kidneys occurs with:-(A)Chronic renal disease:(1)Drugs:-(i)Thiazides.
(ii)Salicylates.
(2)Poisons.
(3)Increased organic acid concentration in blood:(i)Lactic acid.
(ii)Acetoacetic acid.
(iii)Beta-hydroxybutyrate.
(4)Hyperparathyroidism

Gout
Gout may be eitherprimary(unknown cause;
"idiopathic"), orsecondary(due to a condition
known to cause hyperuricemia).

Pathogenesis of gout
(1)Sodium urate crystals precipitate in tissues
(classically within joints) of hyperuricemic
patients.
(2)The crystals exert chemotactic action on
neutrophils (PMNs) and are phagocytized by
macrophages.

(3)PMNs are attracted by the crystals.

They temporarily phagocytize the crystals, and
subsequently release them (You have to
remember that neutrophils are the first cells to
respond in the inflammatory process and that
they have phagocytic properties).
(4)The neutrophils are lysed, releasing their
Lysosomal enzymes, which became activated
and produce acute inflammation and tissue injury
locally, e.g. within joints.
(5)Macrophages also phagocytize crystals. They
secrete Interleukin-1 (IL-1) and tumor necrosis
factor-alpha (TNF-a), which release of proteases
from the synovial and cartilaginous cells of the

The proteases in turn add their deleterious action

to the destructive action of the lysosomal
enzymes of the neutrophils, resulting
indestruction of joint tissue.
Even though this theoretical chain of events
appears plausible, certain phenomena remain
unexplained in the pathogenesis of gout:(1) What
initiates crystallization of urates in joints?
(2)Why are certain peripheral joints preferentially
involved?
(3)Why isn't there a perfect correlation between
high levels of uric acid and the occurrence of
gouty arthritis?

Anatomic Pathology
Changes
Tissue injury is due
to the deposition of crystals
in joints.
Thecharacteristicpathological changes in
gout are:
(1)Acute arthritis:PMN leukocytes
phagocytized urate crystals. The synovium is
congested and contains histiocytes, lymphocytes
and plasma cells. When the crystals resolubilize,
the attack remits.
(2)Chronic tophaceous arthritis:This is the
result of repetitive attacks.
Tophi (singular "tophus") are the gross
morphologic hallmark of gout. Atophusconsists

Tophi can be encountered in joints, in juxtaarticular soft tissues, and also within the ear
lobes ("pinnae") and kidneys.
When they become large, they can produce
severe tissue destructionand ulceration of the
overlying skin.
The deposition of crystals leads to chronic
inflammation in which the synovium becames
hyperplastic, fibrotic and thickened. The
inflammatory cells form a"pannus"(a
membrane of granulation tissue covering a
surface), and the enzymes released by the
inflammatory cells destroy the cartilage, there are
also deposits of crystals inside the bone (bone
histology andbone histology ).
This results injuxta-articular bone erosionswhich

(3)Gouty nephropathy, characterized by:(A)Deposition of crystals in the interstitium

forming tophi
(B)Intratubular deposition of crystals
(C)Production of uric acid urinary tract stones
(D)Pyelonephritisis a common complication
NOTE:-*The uric acid crystals of gout are
dissolved during routine processing, and
consequently cannot usually be identified in
routinely-stained tissue sections.
*Rather, the space previously occupied by the
crystals is seen, with its collar of cells (Special
precautions have to be taken in the processing of
specimens if preservation of crystals is desired.)

Clinical Presentation
Acute gouty arthritis
(1)Excruciating pain:sudden onset.
Lower extremity, peripheral joints.
50% ingreat toe.
(2)Joints are red, swollen and tender (mimicking
suppurative/infectious arthritis).
(3)Frequently, there is somestress prior to
attack:dietary overindulgencence, excessive
alcohol intake, physical or emotional fatigue.
(4)Pain subsides with therapy or spontaneously
after a couple of days.

(5)The disease may relapse even after years of

quiescence.

Chronic gouty arthritis

(1)Follows multiple attacks of acute gout.
(2)Occurs in only 10-15% of patients.
(3)Tophi appear in subcutaneous tissues around
joints.
(4)Limitation of motion ranges from mild to
severe.
(5)The soft tissue tophi are painless and
nontender.
(6)90% of patients develop some form of renal
function impairment:
Nephrolithiasis.

(7)Patients are also prone to develop

arteriosclerosis
anddiabetes mellitus.

Diagnosis
(1)Characteristic clinical presentation.
(2)Elevated serum urate level.
(3)Microscopy of joint fluid: long needle crystals
show strongnegative birefrigencewhen
examined under the polarizing microscope.