PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE
Physiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD,
Associate Editor; William J. Koopman, MD, Associate Editor
Annals of Internal Medicine: Paul Epstein, MD, Series Editor
Pathogenesis of Gout
Hyon K. Choi, MD, DrPH; David B. Mount, MD; and Anthony M. Reginato, MD, PhD
Clinical Principles
The overall disease burden of gout is substantial and may be
increasing.
As more scientific data on the modifiable risk factors and
comorbidities of gout become available, integration of
these data into gout care strategies may become essential.
Hyperuricemia and gout are associated with the insulin
resistance syndrome and related comorbid conditions.
Lifestyle modifications that are recommended for gout
generally align with those for major chronic disorders (such
as the insulin resistance syndrome, hypertension, and
cardiovascular disorders); thus, these measures may be
doubly beneficial for many patients with gout and
particularly for individuals with these comorbid conditions.
Effective management of risk factors for gout and careful
selection of certain therapies for comorbid conditions (such
as hypertension or the insulin resistance syndrome) may
also aid gout care.
The urate–anion exchanger URAT1 (urate transporter-1) is a
specific target of action for both antiuricosuric and
uricosuric agents.
The long-term health effect of hyperuricemia (beyond the
increased risk for gout) needs to be clarified, including any
potential consequences associated with the chronic
hyperuricemia that anti-inflammatory treatment does not
correct.
G out is a type of inflammatory arthritis that is triggered by
the crystallization of uric acid within the joints and is
often associated with hyperuricemia (Figure 1). Acute gout is
and may be increasing. The prevalence of self-reported,
physician-diagnosed gout in the Third National Health
typically intermittent, constituting one of the most painful
conditions experienced by humans. Chronic tophaceous gout
usually develops after years of acute intermittent gout, al-
though tophi occasionally can be part of the initial presenta-
tion. In addition to the morbidity that is attributable to gout
itself, the disease is associated with such conditions as the
insulin resistance syndrome, hypertension, nephropathy, and
disorders associated with increased cell turnover (1, 2).
Ann Intern Med. 2005;143:499-516.
For author affiliations, see end of text.
For definition of terms used, see Glossary.
Review
Pathophysiologic Principles
A direct causal relationship exists between serum urate levels
and the risk for gout.
Lifestyle factors, including adiposity and dietary habits,
appear to contribute to serum uric acid levels and the risk
for gout.
Urate is extensively reabsorbed from the glomerular
ultrafiltrate in the proximal tubule via the brush-border
urate–anion exchanger URAT1.
Sodium-dependent reabsorption of anions increases their
concentration in proximal tubule cells, resulting in increased
urate exchange via URAT1, increased urate reabsorption by
the kidney, and hyperuricemia.
Genetic variation in renal urate transporters or upstream
regulatory factors may explain the hereditary susceptibility
to conditions associated with high urate levels and a
patient’s particular response to medications; these
transporters may also serve as targets for future drug
development.
Urate crystals are able to directly initiate, to amplify, and to
sustain an intense inflammatory attack because of their
ability to stimulate the synthesis and release of humoral
and cellular inflammatory mediators.
Cytokines, chemokines, proteases, and oxidants involved in
acute urate crystal–induced inflammation also contribute to
the chronic inflammation that leads to chronic gouty
synovitis, cartilage loss, and bone erosion.
The overall disease burden of gout remains substantial
See also:
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Conversion of figures and table into slides
© 2005 American College of Physicians 499
Review Pathogenesis of Gout
and Nutrition Examination Survey was found to be greater
than 2% in men older than 30 years of age and in women
older than 50 years of age (3). The prevalence increased
with increasing age and reached 9% in men and 6% in
women older than 80 years of age (4). Furthermore, the
incidence of primary gout (that is, patients without di-
uretic exposure) doubled over the past 20 years, according
to the Rochester Epidemiology Project (4). Dietary and
lifestyle trends and the increasing prevalence of obesity and
the metabolic syndrome may explain the increasing inci-
dence of gout.
Researchers have recently made great advances in de-
fining the pathogenesis of gout, including elucidating its
risk factors and tracing the molecular mechanisms of renal
urate transport and crystal-induced inflammation. This ar-
ticle reviews key aspects of the pathogenesis of gout with a
focus on the recent advances.
ABSENCE OF URICASE IN HUMANS
Humans are the only mammals in whom gout is
known to develop spontaneously, probably because hyper-
uricemia only commonly develops in humans (5). In most
fish, amphibians, and nonprimate mammals, uric acid that
has been generated from purine (see Glossary) metabolism
undergoes oxidative degradation through the uricase en-
zyme, producing the more soluble compound allantoin. In
humans, the uricase gene is crippled by 2 mutations that
introduce premature stop codons (see Glossary) (6). The
absence of uricase, combined with extensive reabsorption
of filtered urate, results in urate levels in human plasma
that are approximately 10 times those of most other mam-
mals (30 to 59 ␮mol/L) (7). The evolutionary advantage of
these findings is unclear, but urate may serve as a primary
antioxidant in human blood because it can remove singlet
oxygen and radicals as effectively as vitamin C (8). Of note,
levels of plasma uric acid (about 300 ␮M) are approxi-
mately 6 times those of vitamin C in humans (8, 9). Other
potential advantages of the relative hyperuricemia in pri-
mate species have been speculated (8, 10, 11). However,
hyperuricemia can be detrimental in humans, as demon-
strated by its proven pathogenetic roles in gout and neph-
rolithiasis and by its putative roles in hypertension and
other cardiovascular disorders (12).
THE ROLE OF URATE LEVELS
Uric acid is a weak acid (pKa, 5.8) that exists largely as
urate, the ionized form, at physiologic pH. As urate con-
centration increases in physiologic fluids, the risk for su-
persaturation and crystal formation generally increases.
Population studies indicate a direct positive association be-
tween serum urate levels and a future risk for gout (13, 14),
as shown in Figure 2. Conversely, the use of antihyperuri-
cemic medication is associated with an 80% reduced risk
for recurrent gout, confirming the direct causal relation-
ship between serum uric acid levels and risk for gouty ar-
500 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
Glossary
Adenosine: A condensation product of adenine and D-ribose; a nucleoside
found among the hydrolysis products of all nucleic acids and of the
various adenine nucleotides.
Adenosine triphosphate: A phosphorylated nucleoside C10H16N5O13P3 of
adenine that supplies energy for many biochemical cellular processes by
undergoing enzymatic hydrolysis (especially to adenosine diphosphate).
Anion exchanger: A transport protein that mediates movement of an anion
across the plasma membrane by exchanging it with another anion on the
opposite side of the membrane. Urate–anion exchange plays a key role in
the transport of urate across cell membranes.
Antiuricosuric agent: A chemical or drug that results in reduced renal
excretion of urate and hyperuricemia; pyrazinamide, the classic
antiuricosuric drug, exerts its effect by promoting proximal tubular
reabsorption of urate.
Apolipoprotein: The protein component of any lipoprotein complexes that is
a normal constituent of plasma chylomicrons, high-density lipoproteins,
low-density lipoproteins, and very low-density lipoproteins in humans.
Apoptosis: Disintegration of cells into membrane-bound particles that are
then phagocytosed by other cells.
Brush-border membrane vesicles (BBMV): Purified from superficial renal
cortex, BBMV are predominantly derived from the renal proximal tubule;
urate transporter-1 was initially defined as an anion exchanger activity
present in renal BBMV preparations.
Calcium-binding cytoplasmic proteins S100A8, S100A9: Chemotactic factor
that stimulates neutrophil adhesion and migration by activating the
␤2-integrin CD11b/CD18.
Chemokines: A class of polypeptide cytokines, usually 8–10 kDa, that are
chemokinetic and chemotactic, stimulating leukocyte movement and
attraction.
Cis-inhibition: Competitive inhibition of urate exchange by a urate
transporter-1 substrate present at the same side of the plasma membrane.
Chondroitin: A mucopolysaccharide occurring in sulfated form; present
among the ground substance materials in the extracellular matrix of
connective tissue (for example, cartilage).
c-Jun N-terminal kinase: Downstream kinase activated by ERK-1/ERRK-2
and p38 cascades, leading to autophosphorylation and regulation of
complex biological responses.
Cyclooxygenase-2 (COX-2): An enzyme that makes the prostaglandins that
cause inflammation, pain, and fever; nonsteroidal anti-inflammatory drugs
relieve symptoms as result of their ability to block COX-2 enzymes.
Cytokines: Intercellular messenger proteins; hormone-like products of many
different cell types that are usually active within a small radius of the cells
producing them.
Docosahexaenoic acid (DHA): All-cis-4,7,10,13,16,19-docosahexaenoic acid,
an ␻-3, polyunsaturated, 22-carbon fatty acid found almost exclusively in
fish and marine animal oils; a substrate for cyclooxygenase.
Eicosapentaenoic acid (EPA): All-cis-5,8,11,14,17-eicosapentaenoic acid, an
␻-3, polyunsaturated, 20-carbon fatty acid found almost exclusively in
fish and marine animal oils; a substrate for cyclooxygenase.
E-selectin: Endothelial cell adhesion molecules consisting of a lectin-like
domain, an epidermal growth factor–like domain, and a variable number
of domains that encode proteins homologous to complement-binding
proteins; their function is to mediate the binding of leukocytes to the
vascular endothelium.
Familial renal hypouricemia: A recessive genetic disorder caused by
homozygous loss-of-function mutations in the SLC22A12 gene encoding
urate transporter-1. Patients with this disorder have hypouricemia that
does not respond to uricosuric or antiuricosuric agents.
G proteins: A family of similar heterotrimeric proteins found in the
intracellular portion of the plasma membrane; bind activated receptor
complexes and, through conformational changes and cyclic binding and
hydrolysis of guanosine triphosphate, directly or indirectly effect
alterations in channel gating and couple cell surface receptors to
intracellular responses.
Interleukins: A large family of hormone-like messenger proteins produced
by immune cells that act on leukocytes and other cells.
Kinase: An enzyme catalyzing the conversion of a proenzyme to an active
enzyme (for example, enteropeptidase [enterokinase]) or catalyzing the
transfer of phosphate groups.
Kinin: One of a number of widely differing substances having pronounced
and dramatic physiologic effects; kallidin and bradykinin are polypeptides,
formed in blood by proteolysis secondary to some pathologic process
producing vasodilation.
Continued
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Glossary—Continued
Leptin: A helical protein secreted by adipose tissue; acts on a receptor site in
the ventromedial nucleus of the hypothalamus to curb appetite and
increase energy expenditure as body fat stores increase.
Leukotriene: Substance produced from arachidonic acid by the lipoxygenase
pathway; functions as a regulator of allergic and inflammatory reactions;
stimulates the movement of leukocytes; identified by the letters A, B, C,
D, and E, with subscripts indicating the number of double bonds in the
molecule (for example, LTB4).
Lipoxins: Any of several conjugated tetraene derivatives of arachidonic acid
that oppose the actions of leukotrienes, have potent vasodilating effects,
and appear to be toxic to natural killer cells.
Matrix metalloproteinases: A family of protein-hydrolyzing endopeptidases
that hydrolyze extracellular proteins, especially collagens and elastin.
Mitogen-activated protein kinases ERK1/ERK: One of the mitogen-activated
protein kinases that signals transduction pathways in eukaryotic cells and
integrates diverse extracellular signals; regulates complex biological
responses, such as growth, differentiation, and death.
Multidrug resistance protein-4 (MRP4): An anion transporter capable of
adenosine triphosphate–driven urate efflux, expressed at the apical
membrane of the proximal tubule.
Nucleotide: A combination of a nucleic acid (purine or pyrimidine), 1 sugar
(ribose or deoxyribose), and a phosphoric group.
Organic anion transporter-1 (OAT1): A basolateral anion exchanger
involved in proximal tubular transport of multiple organic anions,
including urate; OAT1 is encoded by the SLC22A6 gene.
Organic anion transporter-3 (OAT3): A basolateral anion exchanger
involved in proximal tubular transport of multiple organic anions,
including urate; OAT3 is encoded by the SLC22A8 gene.
␻-3 fatty acids: Polyunsaturated fatty acids that have the final double bond
in the hydrocarbon chain between the third and fourth carbon atoms
from 1 end of the molecule; found especially in fish, fish oils, vegetable
oils, and green leafy vegetables.
Osteocalcin: A vitamin K–dependent, calcium-binding bone protein, the
most abundant noncollagen protein in bone; increased serum
concentrations are a marker of increased bone turnover in disease states.
p38 mitogen–activated protein kinase: One of the mitogen-activated
protein kinases that signals transduction pathways in eukaryotic cells and
integrates diverse extracellular signals; regulates complex biological
responses such as growth, differentiation, and death.
Peroxisome proliferator-activated receptor-␥ receptor (PPAR-␥): A nuclear
receptor regulating an array of diverse functions in a variety of cell types,
including regulation of genes associated with growth and differentiation.
Phospholipase: An enzyme that catalyzes the hydrolysis of a phospholipid.
Prostaglandin: Any of a class of physiologically active substances present in
many tissues; causes vasodilation, vasoconstriction, and antagonism to
hormones that influence lipid metabolism.
Proteoglycan: Any of a class of glycoproteins of high molecular weight that
are found especially in the extracellular matrix of connective tissue.
Proximal tubule: The earliest segment of the renal tubule, responsible for
the reabsorption of urate and other solutes from the glomerular
ultrafiltrate.
Purine: A double-ringed, crystalline organic base, C5H4N4, from which the
nitrogen bases adenine and guanine are derived; uric acid is a metabolic
end product.
SLC22 gene family: The “Solute Carrier-22” gene family encompasses more
than 20 different genes encoding organic anion and cation transporters,
including the urate transporter-1 (URAT1, SLC22A12), organic anion
transporter-1 (OAT1, SLC22A6), and organic anion transporter-3 (OAT3,
SLC22A8).
SLC5A8: A member of the SLC5 gene family of sodium-coupled
transporters; a leading candidate for the sodium-dependent
lactate/butyrate/pyrazinoate/nicotinate transporter that collaborates with
urate transporter-1 in proximal tubular reabsorption of urate.
Src tyrosine kinase: One of a group of enzymes of the transferase class that
catalyze the phosphorylation of tyrosine residues in specific membrane
vesicle–associated proteins.
Stop codon: Trinucleotide sequence (UAA, UGA, or UAG) that specifies the
end of translation or transcription.
Synovitis: Inflammation of a synovial membrane, especially that of a joint;
in general, when unqualified, the same as arthritis.
Transcription: Transfer of genetic code information from one kind of nucleic
acid to another; commonly used to refer to transfer of genetic
information from DNA to RNA.
Continued
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Pathogenesis of Gout Review
Glossary—Continued
Transforming growth factor-␤ (TGF-␤): A regulatory cytokine that has
multifunctional properties and can enhance or inhibit many cellular
functions, including interfering with the production of other cytokines and
enhancing collagen deposition.
Trans-stimulation: Stimulation of urate exchange by a urate transporter-1
substrate when present at the opposite side of the plasma membrane;
antiuricosuria apparently results from trans-stimulation of urate
reabsorption by anions within the cytoplasm of proximal tubular epithelial
cells.
Tumor necrosis factor (TNF): A polypeptide cytokine, produced by
endotoxin-activated macrophages, that has the ability to modulate
adipocyte metabolism, lyse tumor cells in vitro, and induce hemorrhagic
necrosis of certain transplantable tumors in vivo.
Urate transporter-1 (URAT1): The urate–anion exchanger expressed at the
apical brush-border membrane of proximal tubular epithelial cells; URAT1
is encoded by the SLC22A12 gene.
Urate transporter/channel (UAT): Also known as galectin-9; may also be
involved in proximal tubular urate secretion.
Uricosuric agent: A chemical or drug that results in increased renal excretion
of urate; urate transporter-1 appears to be the major target for uricosuric
drugs.
Voltage-driven organic anion transporter-1 (OATV1): A voltage-sensitive
organic anion transporter capable of transporting urate and expressed at
the apical membrane of the proximal tubule.
thritis (15). The solubility of urate in joint fluids, however,
is influenced by other factors in the joint, as shown in
Figure 3. Such factors include temperature, pH, concen-
tration of cations, level of articular dehydration, and the
presence of such nucleating agents as nonaggregated pro-
teoglycans, insoluble collagens, and chondroitin sulfate (see
Glossary) (16 –18). Variation in these factors may account
for some of the difference in the risk for gout associated
with a given elevation in serum urate level (13, 14). Fur-
thermore, these factors may explain the predilection of
gout in the first metatarsal phalangeal joint (a peripheral
joint with a lower temperature) and osteoarthritic joints
(18) (degenerative joints with nucleating debris) and the
nocturnal onset of pain (because of intra-articular dehydra-
tion) (19).
Urate Balance
The amount of urate in the body depends on the bal-
ance between dietary intake, synthesis, and the rate of ex-
cretion (20), as shown in Figure 1. Hyperuricemia results
from urate overproduction (10%), underexcretion (90%),
or often a combination of the two. The purine precursors
come from exogenous (dietary) sources or endogenous me-
tabolism (synthesis and cell turnover).
The Relationship between Purine Intake and Urate
Levels
The dietary intake of purines contributes substantially
to the blood uric acid. For example, the institution of an
entirely purine-free diet over a period of days can reduce
blood uric acid levels of healthy men from an average of
297 ␮mol/L to 178 ␮mol/L (21, 22). The bioavailable
purine content of particular foods would depend on their
relative cellularity and the transcriptional (see Glossary)
and metabolic activity of the cellular content (20). Little
is known, however, about the precise identity and quantity
4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 501
Review Pathogenesis of Gout
Figure 1. Overview of the pathogenesis of gout.
Gout is mediated by the supersaturation and crystallization of uric acid
within the joints. The amount of urate in the body depends on the
balance between dietary intake, synthesis, and excretion. Hyperuricemia
results from the overproduction of urate (10%), from underexcretion of
urate (90%), or often a combination of the two. Approximately one third
of urate elimination in humans occurs in the gastrointestinal tract, with
the remainder excreted in the urine.
of individual purines in most foods, especially when
cooked or processed (23). When a purine precursor is in-
gested, pancreatic nucleases break its nucleic acids into nu-
cleotides (see Glossary), phosphodiesterases break oligonu-
cleotides into simple nucleotides, and pancreatic and
mucosal enzymes remove phosphates and sugars from nu-
cleotides (20). The addition of dietary purines to purine-
free dietary protocols has revealed a variable increase in
blood uric acid levels, depending on the formulation and
dose of purines administered (21). For example, RNA has
a greater effect than an equivalent amount of DNA (24),
ribomononucleotides have a greater effect than nucleic acid
(21), and adenine has a greater effect than guanine (25, 26).
A recent large prospective study showed that men in
the highest quintile of meat intake had a 41% higher risk
for gout compared with the lowest quintile, and men in the
highest quintile of seafood intake had a 51% higher risk
compared with the lowest quintile (27). Correspondingly,
in a nationally representative sample of men and women in
the United States, higher levels of meat and seafood con-
sumption were associated with higher serum uric acid lev-
els (28). However, consumption of oatmeal and purine-
rich vegetables (for example, peas, beans, lentils, spinach,
mushrooms, and cauliflower) was not associated with an
502 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
increased risk for gout (27). The variation in the risk for
gout associated with different purine-rich foods may be
explained by varying amounts and type of purine content
and their bioavailability for metabolizing purine to uric
acid (28). At the practical level, these data suggest that
dietary purine restriction in patients with gout or hyper-
uricemia (29, 30) may be applicable to purines of animal
origin but not to purine-rich vegetables, which are excel-
lent sources of protein, fiber, vitamins, and minerals. Sim-
ilarly, implications of the recent findings (27, 28, 31) in
the management of hyperuricemia or gout were consistent
with the new dietary recommendations for the general
public (32), with the exception of the guidelines for fish
intake (Figure 4). Thus, among patients with gout or hy-
peruricemia, the use of plant-derived ␻-3 fatty acids or
supplements of eicosapentaenoic acid and docosahexaenoic
acid (see Glossary) instead of fish consumption could be
considered to provide the benefit of these fatty acids with-
out increasing the risk for gout.
PURINE METABOLISM AND GOUT
The steps in the urate production pathways implicated
in the pathogenesis of gout are displayed in Figure 5. The
vast majority of patients with endogenous overproduction
of urate have the condition as a result of salvaged purines
arising from increased cell turnover in proliferative and
inflammatory disorders (for example, hematologic cancer
Figure 2. The relationship between serum uric acid levels and
the incidence of gout.
Annual incidence of gout was less than 0.1% for men with serum uric
acid levels less than 416 ␮mol/L, 0.4% for men with levels of 416 to 475
␮mol/L, 0.8% for men with levels of 476 to 534 ␮mol/L, 4.3% for men
with levels of 535 to 594 ␮mol/L, and 7.0% for men with levels greater
than 595 ␮mol/L, according to the Normative Aging Study (13). The
solid line denotes these data points; the dotted line shows an exponential
projection of the data points.
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 Pathogenesis of Gout Review
Figure 3. Mechanisms of monosodium urate crystal formation and induction of crystal-induced inflammation.

Urate crystallizes as a monosodium salt in oversaturated tissue fluids. Its crystallization depends on the concentrations of both urate and cation levels.
Several other factors contribute to the decreased solubility of sodium urate and crystallization. Alteration in the extracellular matrix leading to an increase
in nonaggregated proteoglycans, chondroitin sulfate, insoluble collagen fibrils, and other molecules in the affected joint may serve as nucleating agents.
Furthermore, monosodium urate (MSU) crystals can undergo spontaneous dissolution depending on their physiochemical environments. Chronic
cumulative urate crystal formation in tissue fluids leads to MSU crystal deposition (tophus) in the synovium and cell surface layer of cartilage. Synovial
tophi are usually walled off, but changes in the size and packing of the crystal from microtrauma or from changes in uric acid levels may loosen them
from the organic matrix. This activity leads to “crystal shedding” and facilitates crystal interaction with synovial cell lining and residential inflammatory
cells, leading to an acute gouty flare.

and psoriasis), from pharmacologic intervention resulting
in increased urate production (such as chemotherapy), or
from tissue hypoxia. Only a small proportion of those with
urate overproduction (10%) have the well-characterized in-
born errors of metabolism (for example, superactivity of
5’-phosphoribosyl-1-pyrophosphate synthetase and defi-
ciency of hypoxanthine– guanine phosphoribosyl trans-
ferase). These genetic disorders have been extensively re-
viewed in textbooks (20, 33, 34), and the involved
pathways are depicted in Figure 5.
Conditions associated with net adenosine triphosphate
(ATP) (see Glossary) degradation lead to accumulation of
adenosine diphosphate (ADP) and adenosine monophos-
phate (AMP), which can be rapidly degraded to uric acid
(35– 44), as shown in Figure 5. For example, ethanol ad-
ministration has been shown to increase uric acid produc-
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tion by net ATP degradation to AMP (41, 44). In addi-
tion, decreased urinary excretion as a result of dehydration
and metabolic acidosis may contribute to the hyperurice-
mia that is associated with ethanol ingestion, as discussed
later in this review (34, 45).
Recently, a large-scale prospective study confirmed
that the effect of ethanol on urate levels can be translated
into the risk for gout (31). Compared with abstinence,
daily alcohol consumption of 10 to 14.9 g increased the
risk for gout by 32%; daily consumption of 15 to 29.9 g,
30 to 49.9 g, and 50 g or greater increased the risk by 49%,
96%, and 153%, respectively. Furthermore, the study also
found that this risk varied according to type of alcoholic
beverage: Beer conferred a larger risk than liquor, whereas
moderate wine drinking did not increase risk (31). Corre-
spondingly, a national U.S. survey demonstrated parallel
4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 503
Review Pathogenesis of Gout

Figure 4. Dietary influences on the risk for gout and their implications within the Harvard Healthy Eating Pyramid.

Data on the relationship between diet and the risk for gout are primarily derived from the recent Health Professionals Follow-Up Study (27, 28, 31).
Implications of these findings in the management of hyperuricemia or gout are generally consistent with the new Healthy Eating Pyramid (32), except
for fish intake. The use of plant-derived ␻-3 fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid in place of fish consumption
could be considered to provide patients the benefit of these fatty acids without increasing the risk for gout. Use of ␻-3 fatty acids may have
anti-inflammatory effect against gouty flares. Vitamin C intake exerts a uricosuric effect. (Adapted with permission from reference 32: Willett WC,
Stampfer MJ. Rebuilding the food pyramid. Sci Am. 2003;288:64-71.) Red arrows denote an increased risk for gout, solid green arrows denote a
decreased risk, and yellow arrows denote no influence on risk. Broken green arrows denote potential effect but without prospective evidence for the
outcome of gout.

associations between these alcoholic beverages and serum
urate levels (46). These findings suggest that certain non-
alcoholic components that vary among these alcoholic bev-
erages play an important role in urate metabolism. Ingested
purines in beer, such as highly absorbable guanosine (23,
47), may produce an effect on blood uric acid levels that is
sufficient to augment the hyperuricemic effect of alcohol
itself, thereby producing a greater risk for gout than liquor
or wine. Whether other nonalcoholic offending factors ex-
ist remains unclear, particularly in regard to beer; instead,
protective factors in wine may be mitigating the alcohol
effect on the risk for gout (28).
Fructose is the only carbohydrate that has been shown
to exert a direct effect on uric acid metabolism (23). Fruc-
tose phosphorylation in the liver uses ATP, and the accom-
504 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
panying phosphate depletion limits regeneration of ATP
from ADP. The subsequent catabolism of AMP serves as a
substrate for uric acid formation (48). Thus, within min-
utes after fructose infusion, plasma (and later urinary) uric
acid concentrations are increased (42). In conjunction with
purine nucleotide depletion, rates of purine synthesis de
novo are accelerated, thus potentiating uric acid produc-
tion (43). Oral fructose may also increase blood uric acid
levels, especially in patients with hyperuricemia (49) or a
history of gout (50). Fructose has also been implicated in
the risk for the insulin resistance syndrome and obesity, which
are closely associated with gout (51, 52). Furthermore, hyper-
uricemia resulting from ATP degradation can occur in acute,
severe illnesses, such as the adult respiratory distress syndrome,
myocardial infarction, or status epilepticus (34 –36).
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 Pathogenesis of Gout Review

ADIPOSITY, INSULIN RESISTANCE, AND GOUT
Increased adiposity and the insulin resistance syn-
drome are both associated with hyperuricemia (53–56).
Body mass index, waist-to-hip ratio, and weight gain have
all been associated with the risk for incident gout in men
(28, 57). Conversely, small, open-label interventional stud-
ies showed that weight reduction was associated with a
decline in urate levels and risk for gout (58, 59).
Reduced de novo purine synthesis was observed in pa-
tients after weight loss, resulting in decreased serum urate
levels (60). Exogenous insulin can reduce the renal excre-
tion of urate in both healthy and hypertensive persons (54,
61, 62). Insulin may enhance renal urate reabsorption
through stimulation of the urate–anion exchanger urate
transporter-1 (URAT1) (see Glossary) (63) or through the
sodium-dependent anion cotransporter in brush-border
membranes of the renal proximal tubule (discussed later in
this review). Because serum levels of leptin (see Glossary)
and urate tend to increase together (64, 65), some investi-
gators have also suggested that leptin may affect renal re-
absorption. Finally, in the insulin resistance syndrome, im-
paired oxidative phosphorylation may increase systemic
adenosine (see Glossary) concentrations by increasing the
intracellular levels of coenzyme A esters of long-chain fatty
acids. Increased adenosine, in turn, can result in renal re-
tention of sodium, urate, and water (66 – 69). Some re-
searchers have speculated that increased extracellular aden-
osine concentrations over the long term may also
contribute to hyperuricemia by increasing urate production
(66). The growing “epidemic” of obesity (70, 71) and the
insulin resistance syndrome (72) present a substantial chal-
lenge in the prevention and management of gout.
HYPERTENSION, CARDIOVASCULAR DISORDERS, AND
GOUT
Associations between hypertension and the incidence
of gout have been observed (13, 57), but researchers were
previously unable to determine whether hypertension was
independently associated or if it only served as a marker for

Figure 5. Urate production pathways implicated in the pathogenesis of gout.

The de novo synthesis starts with 5’-phosphoribosyl 1-pyrophosphate (PRPP), which is produced by addition of a further phosphate group from
adenosine triphosphate (ATP) to the modified sugar ribose-5-phosphate. This step is performed by the family of PRPP synthetase (PRS) enzymes. In
addition, purine bases derived from tissue nucleic acids are reutilized through the salvage pathway. The enzyme hypoxanthine– guanine phosphoribosyl
transferase (HPRT) salvages hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP). Only a small proportion
of patients with urate overproduction have the well-characterized inborn errors of metabolism, such as superactivity of PRS and deficiency of HPRT.
Furthermore, conditions associated with net ATP degradation lead to the accumulation of adenosine diphosphate (ADP) and adenosine monophosphate
(AMP), which can be rapidly degraded to uric acid. These conditions are displayed in left upper corner. Plus sign denotes stimulation, and minus sign
denotes inhibition. APRT ⫽ adenine phosphoribosyl transferase; PNP ⫽ purine nucleotide phosphorylase.
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Review Pathogenesis of Gout

Table. Substances Affecting Urate Levels and Their Underlying Mechanisms*

Substance Implicated Mechanism

Urate-increasing agents
Pyrazinamide Trans-stimulation of URAT1 (63)
Nicotinate Trans-stimulation of URAT1 (63)
Lactate, ␤-hydroxybutyrate, acetoacetate Trans-stimulation of URAT1 (63)
Salicylate (low dose) Decreased renal urate excretion (78)
Diuretics Increased renal tubular reabsorption associated with volume depletion (79, 80), may
stimulate URAT1 (63)
Cyclosporine Increased renal tubular reabsorption associated with decreased glomerular filtration (81–85),
hypertension (86), interstitial nephropathy
Tacrolimus Similar to cyclosporine (87, 88)
Ethambutol Decreased renal urate excretion
␤-Blockers Unknown (no change in renal urate excretion) (89)

Urate-decreasing agents
Uricosurics
Probenecid Inhibition of URAT1 (63, 90)
Sulfinpyrazone Inhibition of URAT1 (63, 90)
Benzbromarone Inhibition of URAT1 (63, 90)
Losartan Inhibition of URAT1 (63)
Salicylate (high-dose) Inhibition of URAT1 (63)
Fenofibrate May inhibit URAT1
Amlodipine Increased renal urate excretion (86)
Xanthine oxidase inhibitors
Allopurinol Inhibition of xanthine oxidase
Febuxostat Inhibition of xanthine oxidase
Uricase Oxidation of urate to allantoin

* Numbers in parentheses are reference numbers. URAT1 ⫽ urate transporter-1.

associated risk factors, such as dietary factors, obesity, di-
uretic use, and renal failure. A recent prospective study,
however, has confirmed that hypertension is associated
with an increased risk for gout independent of these po-
tential confounders (28). Renal urate excretion was found
to be inappropriately low relative to glomerular filtration
rates in patients with essential hypertension (73, 74). Re-
duced renal blood flow with increased renal and systemic
vascular resistance may also contribute to elevated serum
uric acid levels (75). Hyperuricemia in patients with essen-
tial hypertension may reflect early nephrosclerosis, thus im-
plying renal morbidity in these patients. Furthermore,
studies have suggested that hyperuricemia may be associ-
ated with incident hypertension or cardiovascular disor-
ders. The proposed role of urate in the pathogenesis of
these disorders has recently been reviewed in the Physiol-
ogy in Medicine series (12).
RENAL TRANSPORT OF URATE
Renal urate transport is typically explained by a
4-component model: glomerular filtration, a near-complete
reabsorption of filtered urate, subsequent secretion, and
postsecretory reabsorption in the remaining proximal tu-
bule (see Glossary) (76, 77). This model evolved from an
interpretation of the effects of “uricosuric” and “antiurico-
suric” agents; drugs and compounds known to affect serum
urate levels are summarized in the Table. The urate secre-
tion step was incorporated into the model to explain the
potent antiuricosuric effect of pyrazinamide (91). How-
ever, direct inhibition of proximal tubular urate secretion
506 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
by pyrazinoate, the relevant metabolite, has never been
demonstrated. Indeed, pyrazinamide has no effect in ani-
mal species that eliminate urate through net secretion (92),
and direct effects of the drug on human urate secretion are
largely unsubstantiated (91). Rather, studies utilizing renal
brush-border membrane vesicles (see Glossary) (93, 94)
have shown that pyrazinoate activates the reabsorption of
urate through indirect stimulation of apical urate exchange
(Figure 5). Similar mechanisms underlie the clinically rel-
evant hyperuricemic effects of lactate (45), ketoacids (95),
and nicotinate (96), as shown in the Table. Recent ad-
vances in the understanding of the relevant physiology are
reviewed in the following sections.
The Renal Urate–Anion Exchanger URAT1
Enomoto and colleagues (63) recently identified the
molecular target for uricosuric agents (see Glossary), an
anion exchanger responsible for the reabsorption of filtered
urate by the renal proximal tubule (Table). The authors
searched the human genome database for novel gene se-
quences within the organic anion transporter (OAT) gene
family and identified URAT1 (SLC22A12) (see Glossary),
a novel transporter expressed at the apical brush border of
the proximal nephron (63). Urate–anion exchange activity
similar to that of URAT1 was initially described in brush-
border membrane vesicles from urate-reabsorbing species,
such as rats and dogs (97–100), and was subsequently con-
firmed in human kidneys (101). Frog eggs (Xenopus oo-
cytes) injected with URAT1-encoding RNA transport
urate and exhibit pharmacologic properties consistent with
data from human brush-border membrane vesicles (63,
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 Pathogenesis of Gout Review

101). These and other experiments indicate that uricosuric
compounds (for example, probenecid, benzbromarone,
sulfinpyrazone, and losartan) directly inhibit URAT1 from
the apical side of tubular cells (“cis-inhibition” [see Glos-
sary]). Conversely, antiuricosuric substances (for example,
pyrazinoate, nicotinate, and lactate) serve as the exchang-
ing anion from inside cells (Figure 6 and Table), thereby
stimulating anion exchange and urate reabsorption (“trans-
stimulation” [see Glossary]) (9, 63). In addition to urate,
URAT1 has particular affinity for aromatic organic anions,
such as nicotinate and pyrazinoate, followed by lactate,
␤-hydroxybutyrate, acetoacetate, and inorganic anions,
such as chloride and nitrate (63).
Enomoto and colleagues (63) provided unequivocal
genetic proof that URAT1 is crucial for urate homeostasis:
A handful of patients with “familial renal hypouricemia”
(OMIM [Online Mendelian Inheritance in Man] accession
number 220150; see Glossary) were shown to carry loss-
of-function mutations in the human SLC22A12 gene en-
coding URAT1, indicating that this exchanger is essential
for proximal tubular reabsorption. Furthermore, pyrazin-
amide, benzbromarone, and probenecid failed to affect
urate clearance in patients with homozygous loss-of-func-
tion mutations in SLC22A12, indicating that URAT1 is
essential for the effect of both uricosuric and antiuricosuric
agents (see Glossary) (90).
Secondary Sodium Dependency of Urate Reabsorption
Antiuricosuric agents exert their effect by stimulating re-
nal reabsorption rather than inhibiting tubular secretion (91).
The mechanism appears to involve a “priming” of renal urate
reabsorption through the sodium-dependent loading of prox-
imal tubular epithelial cells with anions capable of a trans-
stimulation of urate reabsorption (Figure 6). Studies from sev-
eral laboratories have indicated that a transporter in the
proximal tubule brush border mediates sodium-dependent
reabsorption of pyrazinoate, nicotinate, lactate, pyruvate,
␤-hydroxybutyrate, and acetoacetate (102–104), monovalent
anions that are also substrates for URAT1 (63). Increased
plasma concentrations of these antiuricosuric anions result in
their increased glomerular filtration and greater reabsorption
by the proximal tubule. The augmented intraepithelial con-
centrations in turn induce the reabsorption of urate by pro-
moting the URAT1-dependent anion exchange of filtered
urate (trans-stimulation) (Figure 6).
Urate reabsorption by the proximal tubule thus exhib-
its a form of secondary sodium dependency, in that sodium-
dependent loading of proximal tubular cells stimulates

Figure 6. Urate transport mechanisms in human proximal tubule.

Urate transporter-1 (URAT1) is located in the apical membrane of proximal tubular cells in human kidneys and transports urate from lumen to proximal
tubular cells in exchange for anions in order to maintain electrical balance. This exchanger is essential for proximal tubular reabsorption of urate and is
targeted by both uricosuric and antiuricosuric agents. Sodium-dependent entry of monovalent anions (such as pyrazinoate, nicotinate, lactate, pyruvate,
␤-hydroxybutyrate, and acetoacetate), presumptively through the sodium–anion cotransporter, fuels the absorption of luminal urate via the anion
exchanger URAT1. Basolateral entry of urate during urate secretion by the proximal tubule is stimulated by sodium-dependent uptake of the divalent
anion ␣-ketoglutarate, leading to urate-␣-ketoglutarate exchange via organic anion transporter-1 (OAT1) or organic anion transporter-3 (OAT3). These
proteins or similar transporters may facilitate the basolateral influx or efflux of urate. As discussed in the text, although the quantitative role of human
urate secretion remains unclear, several molecular candidates have been proposed for the electrogenic urate secretion pathway in apical membrane of
proximal tubules, including URAT1, ATP-driven efflux pathway (MRP4), and voltage-driven organic anion transporter-1 (OATV1). FEu ⫽ renal
clearance of urate/glomerular filtration rate.
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Review Pathogenesis of Gout
Figure 7. Dual effects of pyrazinoate on urate transport.
The anti-uricosuric agent pyrazinoate (PZA), a metabolite of pyrazin-
amide, has dual effects on urate transport by the proximal tubule. Urate
uptake by brush-border membrane vesicles isolated from canine kidney
cortex is shown, in the presence of 100 mM sodium (Na⫹) with 0.1 mM
PZA, 0 PZA, or 5 mM PZA. The concentration results in Na⫹-depen-
dent uptake of PZA and a potentiation of urate uptake via urate trans-
porter-1 (URAT1); in contrast, the higher concentration cis-inhibits
URAT1, thus reducing urate uptake by the membrane vesicles. (Repro-
duced with permission from reference 93: Guggino SE, Aronson PS.
Paradoxical effects of pyrazinoate and nicotinate on urate transport in
dog renal microvillus membranes. J Clin Invest. 1985;76:543-7.)
brush-border urate exchange; urate itself is not a substrate
for the sodium–anion transporter. The molecular identity
of the relevant sodium-dependent anion cotransporter or
cotransporters remains unclear; however, a leading candi-
date gene is SLC5A8 (see Glossary), which encodes a sodi-
um-dependent lactate and butyrate cotransporter (105).
Preliminary data indicate that the SLC5A8 protein can also
transport both pyrazinoate and nicotinate, potentiating
urate transport in Xenopus oocytes that co-express URAT1
(106).
The antiuricosuric mechanism explains the long-
standing clinical observation that hyperuricemia is induced
by increased ␤-hydroxybutyrate and acetoacetate levels in
diabetic ketoacidosis (95), increased lactic acid levels in
alcohol intoxication (45), or increased nicotinate and
pyrazinoate levels in niacin and pyrazinamide therapy, re-
spectively (96). Urate retention is also known to be pro-
voked by a reduction in extracellular fluid volume (107)
and by excesses of angiotensin II (108, 109), insulin (62,
508 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
110), and parathyroid hormone (111); URAT1 and the
sodium-dependent anion cotransporter or cotransporters
may be targets for these stimuli.
Dose-Dependent Dual Response in Urate Excretion
A conundrum in the pathophysiology of gout has been
how certain anions can exhibit either uricosuric or antiuri-
cosuric properties, depending on the dose administered.
Monovalent anions that interact with URAT1 have the
dual potential to increase or decrease renal urate excretion
(93, 112) because they can both trans-stimulate and cis-
inhibit apical urate exchange in the proximal tubule (101).
For example, a low concentration of pyrazinoate stimulates
urate reabsorption as a consequence of trans-stimulation,
whereas a higher concentration reduces urate reabsorption
through extracellular cis-inhibition of URAT1 (63, 93,
113) (Figure 7). Dissenting opinions notwithstanding
(114), these observations remain consistent with the basic
scheme of apical urate transport shown in Figure 6. Bipha-
sic effects on urate excretion (that is, antiuricosuria at low
doses and uricosuria at high doses) are particularly well
described for salicylate (115). Salicylate cis-inhibits
URAT1 (63, 116), explaining the high-dose uricosuric ef-
fect; low antiuricosuria reflects a trans-stimulation of
URAT1 by intracellular salicylate, which is evidently a sub-
strate for the sodium–pyrazinoate transporter (103). Min-
imal doses of salicylate—75, 150, and 325 mg daily—were
shown to increase serum uric acid levels by 16, 12, and 2
␮mol/L, respectively (78). However, the effect on the risk
for gout of this salicylate-induced increase in the serum
uric acid level has not been determined.
Other Renal Urate Transporters
At the basolateral membrane of proximal tubular cells,
the entry of urate from the surrounding interstitium ap-
pears to be driven by sodium-dependent uptake of divalent
anions, such as ␣-ketoglutarate, rather than monovalent
carboxylates, such as pyrazinoate and lactate (117, 118)
(Figure 6). Candidate proteins for this basolateral urate
exchange activity include both OAT1 (119) and OAT3
(120,⫺ 121) (see Glossary),
⫺
each of which function as an-
ion1 – dicarboxylate2 exchangers (121–123) at the baso-
lateral membrane of the proximal tubule. These proteins
(or similar transporters) conceivably facilitate the basolat-
eral influx or efflux of urate.
As mentioned previously, the quantitative role of hu-
man urate secretion remains unclear. Nonetheless, several
molecular candidates have been proposed for the electro-
genic urate secretion pathway across the apical membrane
of proximal tubules, including the urate transporter/chan-
nel (UAT, also known as galectin-9) (124) and the voltage-
driven organic anion transporter-1 (OATV1) (125). The
apical ATP-driven anion transporter multidrug resistance
protein 4 (MRP4) (see Glossary) has also been shown to
mediate urate efflux (126).
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 Pathogenesis of Gout Review
Figure 8. Putative mechanisms for initiation, perpetuation, and termination of an acute monosodium urate crystal–induced gouty
inflammation.

Recent advances in the understanding of acute gouty attack are illustrated (left). The attack is primarily neutrophil-dependent and initiated by the
capacity of urate crystals to activate complements and to stimulate synovial lining cells and resident inflammatory cells to induce a variety of inflammatory
mediators. As depicted (right), self-resolution of acute gout is mediated by several mechanisms, including coating of monosodium urate crystals with
proteins and clearance by differentiated macrophages, neutrophil apoptosis, clearance of apoptotic cells, inactivation of inflammatory mediators, and the
release of anti-inflammatory mediators. Dots represent humoral inflammatory mediators, including cytokines and chemokines. Apo B ⫽ apolipoprotein
B; Apo E ⫽ apolipoprotein E; C1q, C3a, C3b, C5a, C5b-9 ⫽ complement membrane attack complex; IL ⫽ interleukin; LDL ⫽ low-density
lipoprotein; LTB4 ⫽ leukotriene B4; MCP-1 ⫽ monocyte chemoattractant protein-1/CCL2; MIP-1 ⫽ macrophage inflammatory protein-1/CCL3;
MMP-3 ⫽ matrix metalloproteinase-3; NO ⫽ nitrous oxide; PAF ⫽ platelet-activating factor; PGE2 ⫽ prostaglandin E2; PLA2 ⫽ phospholipase A2;
PPAR-␣ ⫽ peroxisome proliferator-activated receptor-␣ ligand; PPAR␥ ⫽ peroxisome proliferator-activated receptor-␥ ligand; TGF-␤ ⫽ transcription
growth factor-␤; TNF-␣ ⫽ tumor necrosis factor-␣; S100A8/A9 ⫽ myeloid-related protein; sTNFr ⫽ soluble tumor necrosis factor receptor.

URATE CRYSTAL–INDUCED INFLAMMATION
Urate crystals are directly able to initiate, to amplify,
and to sustain an intense inflammatory attack because of
their ability to stimulate the synthesis and release of hu-
moral and cellular inflammatory mediators (Figure 8).
Urate Crystal–Induced Cell Activation and Signaling
Urate crystals interact with the phagocyte through 2
broad mechanisms. First, they activate the cells through
the conventional route as opsonized and phagocytosed
particles, eliciting the stereotypical phagocyte response of
lysosomal fusion, respiratory burst, and release of inflam-
matory mediators. The other mechanism involves the par-
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ticular properties of the urate crystal to interact directly
with lipid membranes and proteins through cell membrane
perturbation and cross-linking of membrane glycoproteins
in the phagocyte. This interaction leads to the activation of
several signal transduction pathways, including G proteins,
phospholipase C and D, Src tyrosine kinases, the mitogen-
activated protein kinases ERK1/ERK2, c-Jun N-terminal
kinase, and p38 mitogen-activated protein kinase (see
Glossary) (127–130). These steps are critical for crystal-
induced interleukin (IL)– 8 (see Glossary) expression in
monocytic cells (130 –132), which plays a key role in the
neutrophil accumulation that is discussed later in this re-
view (133).
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Review Pathogenesis of Gout
Crystal-Induced Cellular Response
Cellular kinetic analyses using experimental animal
models of gout (134, 135) indicate that monocytes and
mast cells participate during the early phase of inflamma-
tion, whereas neutrophil infiltrates occur later during in-
flammation (Figure 8). Phagocytes from noninflamed
joints may contain urate crystals (136), and most of these
phagocytes are macrophages (137). The state of differenti-
ation of mononuclear phagocytes determines whether the
crystals will trigger an inflammatory response. In less dif-
ferentiated cell lines, synthesis of tumor necrosis factor–␣
(TNF-␣) (see Glossary) and endothelial cell activation oc-
curred after urate crystal phagocytosis, whereas well-differ-
entiated macrophages failed to induce TNF-␣ synthesis or
to activate endothelial cells (137). Similarly, freshly isolated
human monocytes lead to a vigorous response by induction
of TNF-␣, IL-1␤, IL-6, IL-8, and cyclooxygenase-2 secre-
tion (see Glossary), whereas human macrophages differen-
tiated in vitro for 7 days failed to secrete cytokines (see
Glossary) or to induce endothelial cell activation (138).
These findings indicate that monocytes play a central role
in stimulating an acute attack of gout, whereas differenti-
ated macrophages play an anti-inflammatory role in termi-
nating an acute attack and preserving the asymptomatic
state (Figure 8).
Experimental animal models suggest that mast cells are
involved in the early phase of crystal-induced inflammation
(134), and they also release inflammatory mediators, such
as histamine (139), in response to C3a, C5a, and IL-1. The
vasodilatation, increased vascular permeability, and pain
are also mediated by kinins, complement cleavage peptides,
and other vasoactive prostaglandins (see Glossary) (140).
Neutrophilic Influx and Amplification
Neutrophilic synovitis (see Glossary) is the hallmark
of an acute gouty attack (Figure 8). Neutrophilic– endo-
thelial cell interaction leading to neutrophilic influx ap-
pears to be an important event in this inflammation and
represents a major locus for the pharmacologic effect of
colchicine. Neutrophil influx is believed to be promoted by
the endothelial–neutrophil adhesion that is triggered by
IL-1, TNF-␣, and several chemokines (see Glossary), such
as IL-8 and neutrophil chemoattractant protein-1 (MCP-
1). Neutrophil migration involves neutrophilic– endothe-
lial interaction mediated by cytokine-induced clustering of
E-selectin (see Glossary) on endothelial cells. Colchicine
interferes with the interactions by altering the number and
distribution of selectins on endothelial cells and neutro-
phils in response to IL-1 or TNF-␣ (141).
Once in the synovial tissue, the neutrophils follow
concentration gradients of chemoattractants such as C5a,
leukotriene B4 (see Glossary), platelet-activating factor,
IL-1, and IL-8 (142). Among these factors, IL-8 and
growth-related gene chemokines play a central role in neu-
trophil invasion in experimental models of acute gout
(143–147). For example, IL-8 alone accounts for approxi-
510 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
mately 90% of the neutrophil chemotactic activity of hu-
man monocytes in response to urate crystals (133). Neu-
tralization of IL-8 or its receptor may substantially reduce
the IL-8 –induced neutrophilic inflammatory process (148)
and provide a potential therapeutic target in gout. Several
other neutrophil chemotactic factors, including the calci-
um-binding proteins (calgranulins) S100A8 and S100A9
(see Glossary) (149, 150), have also been shown to be
involved in neutrophil migration induced by urate crystals
(Figure 8).
SPONTANEOUS RESOLUTION OF ACUTE GOUT
The self-limited nature of acute gout is thought to
involve several mechanisms (151), as shown in Figure 8.
Clearance of urate crystals by differentiated macrophages
in vitro has been linked to inhibition of leukocyte and
endothelial activation (137, 138, 152). Neutrophil apopto-
sis (see Glossary) and other apoptotic cell clearance repre-
sent a fundamental mechanism in the resolution of acute
inflammation. Furthermore, transforming growth factor–␤
(see Glossary) becomes abundant in acute gouty synovial
fluid and inhibits IL-1 receptor expression and IL-1–
driven cellular inflammatory responses (153, 154).
Upregulation of IL-10 expression has been shown to
limit experimental urate-induced inflammation and may
function as a native inhibitor of gouty inflammation (155).
Similarly, urate crystals induce peroxisome proliferator–ac-
tivated receptor-␥ (PPAR-␥) (see Glossary) expression in
human monocytes and promote neutrophil and macro-
phage apoptosis (156). Research has yet to determine if the
PPAR-␥– based therapy currently available for type 2 dia-
betes would also be useful in gout management.
Inactivation of inflammatory mediators by proteolytic
cleavage, cross-desensitization of receptors for chemokines,
release of lipoxins (see Glossary), IL-1 receptor antagonist,
and other anti-inflammatory mediators all facilitate the res-
olution of acute gout. As shown in Figure 8, increased
vascular permeability allows the entry of large molecules
(such as apolipoproteins B and E [see Glossary]) and other
plasma proteins into the synovial cavity, which also con-
tributes to the spontaneous resolution of acute flares (157,
158).
CHRONIC GOUTY ARTHRITIS
Chronic gouty arthritis typically develops in patients
who have had gout for years (Figure 9). Cytokines, che-
mokines, proteases, and oxidants involved in acute urate
crystal–induced inflammation also contribute to the
chronic inflammation, leading to chronic synovitis, carti-
lage loss, and bone erosion. Even during remissions of
acute flares, low-grade synovitis in involved joints may per-
sist with ongoing intra-articular phagocytosis of crystals
by leukocytes (136). Tophi on the cartilage surface, which
can be observed through arthroscopy (159), may contrib-
ute to chondrolysis despite adequate treatment of both
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 Pathogenesis of Gout Review
Figure 9. Putative mechanisms for chronic monosodium urate–induced inflammation and cartilage and bone destruction.

Low-level inflammation persists during the remissions of acute flares. Cytokines, chemokines, proteases, and oxidants involved in acute inflammation
contribute to chronic inflammation leading to chronic synovitis, cartilage loss, and bone erosion. Monosodium urate (MSU) crystals are able to activate
chondrocytes to release interleukin-1, inducible nitric oxide synthetase, and matrix metalloproteinases, leading to cartilage destruction. Similarly, MSU
crystal activation of osteoblasts, release of cytokines by activated osteoblast, and decreased anabolic function contribute to the juxta-articular bone damage
seen in chronic MSU inflammation. IL ⫽ interleukin; iNOs ⫽ inducible nitrous oxide synthase; MMP-9 ⫽ matrix metalloproteinase-9; PGE2 ⫽
prostaglandin E2.

hyperuricemia and acute gouty attacks (160). Adherent
chondrocytes phagocytize microcrystals and produce active
metalloproteinases. Furthermore, crystal– chondrocyte cell
membrane interactions can trigger chondrocyte activation,
gene expression of IL-1␤ and inducible nitric oxide synthase,
nitric oxide release, and the overexpression of matrix metallo-
proteinases (see Glossary) that leads to cartilage destruction
(161). The crystals can also suppress the 1,25-dihydroxychole-
calciferol–induced activity of alkaline phosphatase and osteo-
calcin (see Glossary). Thus, crystals can reduce the anabolic
effects of osteoblasts, thereby contributing to damage to the
juxta-articular bone (162) (Figure 9).
SUMMARY
The disease burden of gout remains substantial and
may be increasing. As more scientific data on modifiable
risk factors and comorbidities of gout become available,
integration of these data into gout care strategy may be-
come essential, similar to the current care strategies for
hypertension (163) and type 2 diabetes (164). Recommen-
dations for lifestyle modification to treat or to prevent gout
are generally in line with those for the prevention or treat-
ment of other major chronic disorders (32). Thus, the net
health benefits from these general healthy lifestyle recom-
mendations (32) are expected to be even larger among
many patients with gout, particularly those with coexisting
insulin resistance syndrome, diabetes, obesity, and hyper-
tension.
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Weight control, limits on red meat consumption, and
daily exercise are important foundations of lifestyle modi-
fication recommendations for patients with gout or hyper-
uricemia and parallel recommendations related to preven-
tion of coronary heart disease, diabetes, and certain types
of cancer. Patients with gout could consider using plant-
derived ␻-3 fatty acids or supplements of eicosapentaenoic
acid and docosahexanoic acid instead of consuming fish for
cardiovascular benefits. The recent recommendation on
dairy consumption for the general public would also be
applicable for most patients with gout or hyperuricemia
and may offer added benefit to individuals with hyperten-
sion, diabetes, and cardiovascular disorders. Further risk–
benefit assessments in each specific clinical context would
be helpful. Daily consumption of nuts and legumes as rec-
ommended by the Harvard Healthy Eating Pyramid (32)
may also provide important health benefits without in-
creasing the risk for gout. Similarly, a daily glass of wine
may benefit health without imposing an elevated risk for
gout, especially in contrast to beer or liquor consumption.
These lifestyle modifications are inexpensive and safe and,
when combined with drug therapy, may result in better
control of gout.
Effective management of gout risk factors (for exam-
ple, hypertension) and the strategic choice of certain ther-
apies for comorbid conditions may also aid gout care. For
example, antihypertensive agents with uricosuric properties
(for example, losartan [165] or amlodipine [86]) could
4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 511
Review Pathogenesis of Gout
have a better risk– benefit ratio than diuretics for hyperten-
sion in hypertensive patients with gout. Similarly, the uri-
cosuric property of fenofibrate (165) may be associated
with a favorable risk– benefit ratio among patients with
gout and the metabolic syndrome.
The recently elucidated molecular mechanism of renal
urate transport has several important implications in con-
ditions that are associated with high urate levels. In partic-
ular, the molecular characterization of the URAT1 anion
exchanger has provided a specific target of action for well-
known substances affecting urate levels. Genetic variation
in these renal transporters or upstream regulatory factors
may explain the genetic tendency to develop conditions
associated with high urate levels and a patient’s particular
response to medications. Furthermore, the transporters
themselves may serve as targets for future drug develop-
ment.
Finally, advances in our understanding of crystal-in-
duced inflammation indicate that gout shares many patho-
genetic features with other chronic inflammatory disorders.
Some newly available potent anti-inflammatory medica-
tions (including biological agents that are indicated for
other conditions) may have therapeutic potential in se-
lected subsets of patients with gout, although the high costs
of biological agents would probably prevent their wide-
spread use in gout. Anti-inflammatory agents for gout (in-
cluding colchicine) are typically used to treat acute gout or
to reduce the risk for rebound gout attacks during the
initiation of urate-lowering therapy but do not lower se-
rum levels of uric acid. The long-term safety profile of
these agents needs to be clarified, including the potential
consequences of chronic hyperuricemia with such anti-in-
flammatory treatment.
From Arthritis Research Centre of Canada, University of British Colum-
bia, Vancouver, British Columbia, Canada; Massachusetts General Hos-
pital, Brigham and Women’s Hospital, Harvard Medical School, and VA
Boston Healthcare System, Boston, Massachusetts.
Acknowledgments: The authors thank Dr. John Seeger for his critical
review of the manuscript.
Potential Financial Conflicts of Interest: Consultancies: H.K. Choi
(TAP Pharmaceutical Products); Honoraria: H.K. Choi (TAP Pharma-
ceutical Products); Grants received: H.K. Choi (TAP Pharmaceutical
Products).
Requests for Single Reprints: Hyon K. Choi, MD, DrPH, Division of
Rheumatology, Department of Medicine, University of British Colum-
bia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Van-
couver, BC V5Z 1L7; e-mail, hchoi@partners.org.
Current author addresses are available at www.annals.org.
512 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7
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Annals of Internal Medicine
Current Author Addresses: Dr. Choi: Division of Rheumatology, De-
partment of Medicine, University of British Columbia, Arthritis Re-
search Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z
1L7.
www.annals.org
Dr. Mount: Brigham and Women’s Hospital, Renal Division, Room
540, 4 Blackfan Circle, Boston, MA 02115.
Dr. Reginato: Massachusetts General Hospital, 55 Fruit Street, Boston,
MA 02114.
4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 W-121