GOUT
Content
• Gout
• Epidemology of gout
• Etiology
and Pathophysiology
Objective
At the end of this lecture, student will be able to
- Define gout
- Explain
the epidemiology of gout
- Describe the etiology of gout
- Explain pathophysiology of gout
GOUT
• The term gout describes a heterogeneous clinical
spectrum of diseases including hyperuricemia, recurrent attacks of acute
arthritis associated with monosodium urate crystals in synovial fluid
leukocytes, deposits of monosodium urate crystals (tophi) in tissues in and
around joints, interstitial renal disease, and uric acid nephrolithiasis.
• The underlying metabolic disorder of gout is
hyperuricemia, defined physiochemically as serum that is supersaturated with
monosodium urate.
Epidemiology
• There is a direct correlation between serum uric acid
concentration and both the incidence and prevalence of gout.
• Population studies have shown that serum urate
concentration correlates with increasing age, serum creatinine, blood urea
nitrogen, male gender, blood pressure, body weight, and alcohol intake.
• The incidence of gout -higher for individuals -higher
amounts of meat or fish.
• Gout affects men about seven to nine times more often
than women.
• The incidence of gout increases with age, peaking at
30 to 50 years of age, with an annual incidence ranging from 1 in 1,000 for men
ages 40 to 44 years and 1.8 in 1,000 for those ages 55 to 64 years.
• The lowest rates of gout are observed in young women,
approximately 0.8 cases per 10,000 patient-years.
• Serum uric acid levels in women approach those of men
once menopause has occurred
• Gout in men younger than 30 years of age or in
premenopausal women may indicate an inherited enzyme defect or the presence of
renal disease
Etiology and Pathophysiology of Gout
• In humans, the production of uric acid is the terminal
step in the degradation of purines.
• Normal uric acid levels are near the limits of urate
solubility, because of the delicate balance that exists between the amount of
urate produced and excreted.
• Humans have higher uric acid levels than other mammals
because they do not express the enzyme uricase, which converts uric acid to the
more soluble allantoin.
• Gout occurs exclusively in humans in whom a miscible
pool of uric acid exists
• Under normal conditions, the amount of accumulated
uric acid is about 1,200 mg in men and about 600 mg in women
• The size of the urate pool is increased several fold
in individuals with gout.
• This excess accumulation may result from either
overproduction or underexcretion of uric acid
• Several conditions are associated with either
decreased renal clearance or an overproduction of uric acid, leading to
hyperuricemia
OVERPRODUCTION OF URIC ACID
• The purines from which uric acid is produced originate
from three sources:
– Dietary purine
– Conversion of tissue nucleic acid to purine
nucleotides
– De novo synthesis of purine bases
• The purines derived from these three sources enter a
common metabolic pathway leading to the production of either nucleic acid or
uric acid
• Under normal circumstances, uric acid may accumulate
excessively if production exceeds excretion
Purine metabolism
• The average human produces about 600 to 800 mg of uric
acid each day.
• Dietary purines play an unimportant role in the
generation of hyperuricemia in the absence of some derangement in purine
metabolism or elimination.
• Diet modifications are important for patients with
such problems who develop symptomatic hyperuricemia.
• Several enzyme systems regulate purine metabolism.
Conditions Associated with Hyperuricemia
• Abnormalities in these regulatory systems can result
in overproduction of uric acid.
• Uric acid may also be overproduced as
– A consequence of increased breakdown of tissue nucleic
acids
– Excessive rates of cell turnover
– Myeloproliferative and lymphoproliferative disorders
– Polycythemia vera
– Psoriasis
– Some types of anemias
• Cytotoxic medications used to treat these disorders
can result in overproduction of uric acid secondary to lysis and breakdown of
cellular matter.
• Two enzyme abnormalities resulting in an
overproduction of uric acid have been well described
• The first is an increase in the activity of
phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased
concentration of PRPP
• PRPP is a key determinant of purine synthesis and uric
acid production
• The second is a deficiency of hypoxanthine-guanine
phosphoribosyltransferase (HGPRT)
• HGPRT is responsible for the conversion of guanine to
guanylic acid and hypoxanthine to inosinic acid
• These two conversions require PRPP as the cosubstrate
and are important reactions involved in the synthesis of nucleic acids
• A deficiency in the HGPRT enzyme leads to increased
metabolism of guanine and hypoxanthine to uric acid and to more PRPP to
interact with glutamine in the first step of the purine pathway
• Complete absence of HGPRT results in the childhood
Lesch-Nyhan syndrome, characterized by choreoathetosis, spasticity, mental
retardation, and markedly excessive production of uric acid
• A partial deficiency of the enzyme may be responsible for
marked hyperuricemia in otherwise normal, healthy individuals
UNDEREXCRETION OF URIC ACID
• Normally, uric acid does not accumulate as long as
production is balanced with elimination
• About two thirds of the daily uric acid production is
excreted in the urine and the remainder is eliminated through the
gastrointestinal tract after enzymatic degradation by colonic bacteria
• The vast majority of patients (80% to 90%) with gout
have a relative decrease in the renal excretion of uric acid for an unknown
reason (primary idiopathic hyperuricemia)
• A decline in the urinary excretion of uric acid to a
level below the rate of production leads to hyperuricemia and an increased
miscible pool of sodium urate
• Almost all the urate in plasma is freely filtered
across the glomerulus
• The concentration of uric acid appearing in the urine
is determined by multiple renal tubular transport processes in addition to the
filtered load.
• Evidence favors a four-component model including
glomerular filtration, tubular reabsorption, tubular secretion, and
postsecretory reabsorption
• Approximately 90% of filtered uric acid is reabsorbed
in the proximal tubule, probably by both active and passive transport
mechanisms
• There is a close linkage between proximal tubular
sodium reabsorption and uric acid reabsorption
• A conditions that enhance sodium reabsorption (e.g.,
dehydration) also lead to increased uric acid reabsorption
• The exact site of tubular secretion of uric acid has
not been determined; this too appears to involve an active transport process.
• Postsecretory reabsorption occurs somewhere distal to
the secretory site.
• By enhancing renal urate reabsorption, insulin
resistance is also associated with gout.
• The pathophysiologic approach to the evaluation of
hyperuricemia requires determining whether the patient is overproducing or
underexcreting uric acid
• This can be accomplished by placing the patient on a
purine-free diet for 3 to 5 days and then measuring the amount of uric acid
excreted in the urine in 24 hours
• As it is very difficult to maintain a purine-free diet
for several days, this test is done infrequently in clinical practice
• Nevertheless, when it is performed, individuals who
excrete more than 600 mg on a purine-free diet may be considered overproducers
• Nevertheless, when it is performed, individuals who
excrete more than 600 mg on a purine-free diet may be considered overproducers
SUMMARY
• Prevalence
is greater in men (5.9%; 6.1 million) than women (2.0%; 2.2 million)
• Caused by
the deposition of monosodium urate crystals in tissues
• Uric acid is a metabolic by-product of purine catabolism
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