section 27.8
Catabolism of Purine Nucleotides
631
the extremities initiate an inflammatory foreign body reac-
tion (acute arthritis) that involves leukocytes, complement,
and other mediators (Chapter 35). This reaction causes
severe pain, swelling, redness, and heat in the affected
areas. Initial attacks are usually acute and frequently af-
fect the metatarsophalangeal joint of one big toe. Tophi
may also be present in subcutaneous tissues, cartilage,
bone, and kidneys. Formation of urinary calculi (urolithi-
asis) of urate is common. Gout is potentially chronic and
disfiguring.
Primary gout
is a disorder of purine metabolism seen
predominantly in men. The condition is multifactorial
and involves genetic and nongenetic factors. Occurrence
in women is uncommon; when it does occur, it is usu-
ally found in postmenopausal women. The blood urate
concentration of normal men is ~1 mg/dL higher than
that in women, but this difference disappears after the
menopause. Thus, in women, the postmenopausal rise in
serum urate levels may increase the risk of developing
gout. Gout is very rare in children and adolescents.
Primary gout may be due to overproduction or underex-
cretion of uric acid or to a combination of both. Frequently,
siblings and other close relatives of afflicted individuals
have high levels of uric acid in blood but do not develop
gout, indicating that hyperuricemia is not the only fac-
tor involved. Primary renal gout is due to underexcretion
caused by a renal tubular defect in uric acid transport. Pri-
mary metabolic gout is due to overproduction of purines
and uric acid. The prevalence of gout is high in some pop-
ulations (e.g., 10% of adult male Maori of New Zealand).
In Europe and the United States, the prevalence rate is
0.13-0.37%.
Secondary gout
develops as a complication of hy-
peruricemia caused by another disorder (e.g., leukemia,
chronic nephritis, polycythemia). This type of hyper-
uricemia usually is associated with abnormally rapid
turnover of nucleic acids. The rare cases of gout in ado-
lescents and children are usually of this type.
Overproduction o f PRPP
The mechanism of the hyperuricemia in most individu-
als who have gout is unknown. Following is a discussion
of biochemical lesions that lead to hyperuricemia and may
eventually lead to gout. Enhanced PRPP synthesis results
from X-chromosome-linked mutants of PRPP synthetase.
Several variants show increased Vmax, resistance to feed-
back inhibition, or a low
Km
for ribose 5-phosphate.
PRPP levels can also be increased as a result of un-
derutilization in purine salvage pathways. Thus, HPRT
deficiency (partial or complete) causes hyperuricemia as
an X-linked recessive trait. In situations in which ATP is
consumed more rapidly than it is synthesized or in which
ATP synthesis is impaired, ADP and AMP accumulate and
eventually are converted to uric acid. Hyperuricemia can
occur in hypoxic conditions (e.g., adult respiratory dis-
tress syndrome), glucose-
6
-phosphatase deficiency, and
acute illness (e.g., severe hemorrhagic shock). Further-
more, hyperuricemia may serve as a marker for cellu-
lar energy crises. Ethanol ingestion causes hyperuricemia
owing to increased degradation of ATP to AMP. The lat-
ter occurs in ethanol metabolism during the conversion
of acetate to acetyl-CoA (Chapter 18). In all these in-
stances of production of uric acid by xanthine oxidase,
the formation of cytotoxic byproducts of the reaction,
namely, hydrogen peroxide and superoxide radical, also is
increased.
Patients with glucose-
6
-phosphatase deficiency (glyco-
gen storage disease type 1; see Chapter 15) exhibit hy-
peruricemia from infancy and some develop gout later
in life. The hyperuricemia is due to decreased excretion
and increased production of uric acid. Because of their
hypoglycemia, these patients develop marked hyperlac-
tic acidemia, and lactate reduces the renal clearance of
uric acid by suppressing its tubular secretion. Renal ex-
cretion of urate is complex, comprising glomerular fil-
tration, tubular reabsorption, and tubular secretion. The
urate in the urine is thought to arise almost entirely by
tubular secretion. The increased production of uric acid
in glucose-
6
-phosphatase deficiency has been attributed
to enhanced ATP turnover and consequent adenine nu-
cleotide depletion, with release of feedback inhibition of
amidophosphoribosyltransferase, and to acceleration of
de novo
purine nucleotide synthesis. Diminished levels
of ATP and P; result from the presence of increased levels
of phosphorylated glycolytic intermediates (Chapter 15).
A similar mechanism has been proposed for the hyper-
uricemia that results when fructose is administered intra-
venously to humans.
Excessive
production
of
organic
acids
leads
to
elevated levels of uric acid. Lactate, acetoacetate, and
fi
-hy drox ybiityrate (the latter two are known as ketone
bodies) compete with uric acid for secretion by the
kidney tubules. Lactic acidemia can occur in glucose-
6
-phosphatase
deficiency
and
in
alcohol
ingestion.
Ketonemia and ketonuria occur in untreated diabetes mel-
litus, starvation, glucose-
6
-phosphatase deficiency, etc.
(Figure 27-17).
Treatment
A variety of drugs are used in the management of gout
in three clinical situations:
1. To treat acute gout arthritis,
2. To prevent acute attacks, and
3. To lower serum urate concentrations.
