Review arthritis by mikesanye

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									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
                                                                                                                                      Review
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                                                 Pathophysiologic Principles

      The overall disease burden of gout is substantial and may be        A direct causal relationship exists between serum urate levels
        increasing.                                                         and the risk for gout.

      As more scientific data on the modifiable risk factors and          Lifestyle factors, including adiposity and dietary habits,
        comorbidities of gout become available, integration of               appear to contribute to serum uric acid levels and the risk
        these data into gout care strategies may become essential.           for gout.

      Hyperuricemia and gout are associated with the insulin              Urate is extensively reabsorbed from the glomerular
        resistance syndrome and related comorbid conditions.                ultrafiltrate in the proximal tubule via the brush-border
                                                                            urate–anion exchanger URAT1.
      Lifestyle modifications that are recommended for gout
         generally align with those for major chronic disorders (such     Sodium-dependent reabsorption of anions increases their
         as the insulin resistance syndrome, hypertension, and              concentration in proximal tubule cells, resulting in increased
         cardiovascular disorders); thus, these measures may be             urate exchange via URAT1, increased urate reabsorption by
         doubly beneficial for many patients with gout and                  the kidney, and hyperuricemia.
         particularly for individuals with these comorbid conditions.
                                                                          Genetic variation in renal urate transporters or upstream
      Effective management of risk factors for gout and careful             regulatory factors may explain the hereditary susceptibility
         selection of certain therapies for comorbid conditions (such       to conditions associated with high urate levels and a
         as hypertension or the insulin resistance syndrome) may            patient’s particular response to medications; these
         also aid gout care.                                                transporters may also serve as targets for future drug
                                                                            development.
      The urate–anion exchanger URAT1 (urate transporter-1) is a
        specific target of action for both antiuricosuric and             Urate crystals are able to directly initiate, to amplify, and to
        uricosuric agents.                                                  sustain an intense inflammatory attack because of their
                                                                            ability to stimulate the synthesis and release of humoral
      The long-term health effect of hyperuricemia (beyond the              and cellular inflammatory mediators.
        increased risk for gout) needs to be clarified, including any
        potential consequences associated with the chronic                Cytokines, chemokines, proteases, and oxidants involved in
        hyperuricemia that anti-inflammatory treatment does not             acute urate crystal–induced inflammation also contribute to
        correct.                                                            the chronic inflammation that leads to chronic gouty
                                                                            synovitis, cartilage loss, and bone erosion.




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
                                                                            The overall disease burden of gout remains substantial
                                                                        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-               See also:
though tophi occasionally can be part of the initial presenta-             Print
tion. In addition to the morbidity that is attributable to gout            Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
itself, the disease is associated with such conditions as the
insulin resistance syndrome, hypertension, nephropathy, and                Web-Only
disorders associated with increased cell turnover (1, 2).                  Conversion of figures and table into slides




Ann Intern Med. 2005;143:499-516.
For author affiliations, see end of text.
For definition of terms used, see Glossary.


                                                                                                                 © 2005 American College of Physicians 499
Review           Pathogenesis of Gout


and Nutrition Examination Survey was found to be greater               Glossary
than 2% in men older than 30 years of age and in women
                                                                        Adenosine: A condensation product of adenine and D-ribose; a nucleoside
older than 50 years of age (3). The prevalence increased                  found among the hydrolysis products of all nucleic acids and of the
with increasing age and reached 9% in men and 6% in                       various adenine nucleotides.
women older than 80 years of age (4). Furthermore, the                  Adenosine triphosphate: A phosphorylated nucleoside C10H16N5O13P3 of
                                                                          adenine that supplies energy for many biochemical cellular processes by
incidence of primary gout (that is, patients without di-                  undergoing enzymatic hydrolysis (especially to adenosine diphosphate).
uretic exposure) doubled over the past 20 years, according              Anion exchanger: A transport protein that mediates movement of an anion
                                                                          across the plasma membrane by exchanging it with another anion on the
to the Rochester Epidemiology Project (4). Dietary and                    opposite side of the membrane. Urate–anion exchange plays a key role in
lifestyle trends and the increasing prevalence of obesity and             the transport of urate across cell membranes.
the metabolic syndrome may explain the increasing inci-                 Antiuricosuric agent: A chemical or drug that results in reduced renal
                                                                          excretion of urate and hyperuricemia; pyrazinamide, the classic
dence of gout.                                                            antiuricosuric drug, exerts its effect by promoting proximal tubular
      Researchers have recently made great advances in de-                reabsorption of urate.
                                                                        Apolipoprotein: The protein component of any lipoprotein complexes that is
fining the pathogenesis of gout, including elucidating its                 a normal constituent of plasma chylomicrons, high-density lipoproteins,
risk factors and tracing the molecular mechanisms of renal                low-density lipoproteins, and very low-density lipoproteins in humans.
urate transport and crystal-induced inflammation. This ar-               Apoptosis: Disintegration of cells into membrane-bound particles that are
                                                                          then phagocytosed by other cells.
ticle reviews key aspects of the pathogenesis of gout with a            Brush-border membrane vesicles (BBMV): Purified from superficial renal
focus on the recent advances.                                             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.
ABSENCE     OF   URICASE     IN   HUMANS                                Calcium-binding cytoplasmic proteins S100A8, S100A9: Chemotactic factor
                                                                          that stimulates neutrophil adhesion and migration by activating the
     Humans are the only mammals in whom gout is                             2-integrin CD11b/CD18.
known to develop spontaneously, probably because hyper-                 Chemokines: A class of polypeptide cytokines, usually 8–10 kDa, that are
                                                                          chemokinetic and chemotactic, stimulating leukocyte movement and
uricemia only commonly develops in humans (5). In most                    attraction.
fish, amphibians, and nonprimate mammals, uric acid that                 Cis-inhibition: Competitive inhibition of urate exchange by a urate
                                                                          transporter-1 substrate present at the same side of the plasma membrane.
has been generated from purine (see Glossary) metabolism
                                                                        Chondroitin: A mucopolysaccharide occurring in sulfated form; present
undergoes oxidative degradation through the uricase en-                   among the ground substance materials in the extracellular matrix of
zyme, producing the more soluble compound allantoin. In                   connective tissue (for example, cartilage).
                                                                        c-Jun N-terminal kinase: Downstream kinase activated by ERK-1/ERRK-2
humans, the uricase gene is crippled by 2 mutations that                  and p38 cascades, leading to autophosphorylation and regulation of
introduce premature stop codons (see Glossary) (6). The                   complex biological responses.
absence of uricase, combined with extensive reabsorption                Cyclooxygenase-2 (COX-2): An enzyme that makes the prostaglandins that
                                                                          cause inflammation, pain, and fever; nonsteroidal anti-inflammatory drugs
of filtered urate, results in urate levels in human plasma                 relieve symptoms as result of their ability to block COX-2 enzymes.
that are approximately 10 times those of most other mam-                Cytokines: Intercellular messenger proteins; hormone-like products of many
                                                                          different cell types that are usually active within a small radius of the cells
mals (30 to 59 mol/L) (7). The evolutionary advantage of                  producing them.
these findings is unclear, but urate may serve as a primary              Docosahexaenoic acid (DHA): All-cis-4,7,10,13,16,19-docosahexaenoic acid,
antioxidant in human blood because it can remove singlet                  an -3, polyunsaturated, 22-carbon fatty acid found almost exclusively in
                                                                           fish and marine animal oils; a substrate for cyclooxygenase.
oxygen and radicals as effectively as vitamin C (8). Of note,           Eicosapentaenoic acid (EPA): All-cis-5,8,11,14,17-eicosapentaenoic acid, an
levels of plasma uric acid (about 300 M) are approxi-                        -3, polyunsaturated, 20-carbon fatty acid found almost exclusively in
                                                                          fish and marine animal oils; a substrate for cyclooxygenase.
mately 6 times those of vitamin C in humans (8, 9). Other
                                                                        E-selectin: Endothelial cell adhesion molecules consisting of a lectin-like
potential advantages of the relative hyperuricemia in pri-                domain, an epidermal growth factor–like domain, and a variable number
mate species have been speculated (8, 10, 11). However,                   of domains that encode proteins homologous to complement-binding
                                                                          proteins; their function is to mediate the binding of leukocytes to the
hyperuricemia can be detrimental in humans, as demon-                     vascular endothelium.
strated by its proven pathogenetic roles in gout and neph-              Familial renal hypouricemia: A recessive genetic disorder caused by
rolithiasis and by its putative roles in hypertension and                 homozygous loss-of-function mutations in the SLC22A12 gene encoding
                                                                          urate transporter-1. Patients with this disorder have hypouricemia that
other cardiovascular disorders (12).                                      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
THE ROLE      OF   URATE LEVELS                                           complexes and, through conformational changes and cyclic binding and
                                                                          hydrolysis of guanosine triphosphate, directly or indirectly effect
     Uric acid is a weak acid (pKa, 5.8) that exists largely as           alterations in channel gating and couple cell surface receptors to
urate, the ionized form, at physiologic pH. As urate con-                 intracellular responses.
                                                                        Interleukins: A large family of hormone-like messenger proteins produced
centration increases in physiologic fluids, the risk for su-               by immune cells that act on leukocytes and other cells.
persaturation and crystal formation generally increases.                Kinase: An enzyme catalyzing the conversion of a proenzyme to an active
Population studies indicate a direct positive association be-             enzyme (for example, enteropeptidase [enterokinase]) or catalyzing the
                                                                          transfer of phosphate groups.
tween serum urate levels and a future risk for gout (13, 14),           Kinin: One of a number of widely differing substances having pronounced
as shown in Figure 2. Conversely, the use of antihyperuri-                and dramatic physiologic effects; kallidin and bradykinin are polypeptides,
cemic medication is associated with an 80% reduced risk                   formed in blood by proteolysis secondary to some pathologic process
                                                                          producing vasodilation.
for recurrent gout, confirming the direct causal relation-
ship between serum uric acid levels and risk for gouty ar-                                                                                  Continued

500 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                                       www.annals.org
                                                                                                                          Pathogenesis of Gout      Review
  Glossary—Continued                                                                  Glossary—Continued

  Leptin: A helical protein secreted by adipose tissue; acts on a receptor site in    Transforming growth factor- (TGF- ): A regulatory cytokine that has
     the ventromedial nucleus of the hypothalamus to curb appetite and                  multifunctional properties and can enhance or inhibit many cellular
     increase energy expenditure as body fat stores increase.                           functions, including interfering with the production of other cytokines and
  Leukotriene: Substance produced from arachidonic acid by the lipoxygenase             enhancing collagen deposition.
     pathway; functions as a regulator of allergic and inflammatory reactions;        Trans-stimulation: Stimulation of urate exchange by a urate transporter-1
     stimulates the movement of leukocytes; identified by the letters A, B, C,          substrate when present at the opposite side of the plasma membrane;
     D, and E, with subscripts indicating the number of double bonds in the             antiuricosuria apparently results from trans-stimulation of urate
     molecule (for example, LTB4).                                                      reabsorption by anions within the cytoplasm of proximal tubular epithelial
  Lipoxins: Any of several conjugated tetraene derivatives of arachidonic acid          cells.
     that oppose the actions of leukotrienes, have potent vasodilating effects,       Tumor necrosis factor (TNF): A polypeptide cytokine, produced by
     and appear to be toxic to natural killer cells.                                    endotoxin-activated macrophages, that has the ability to modulate
  Matrix metalloproteinases: A family of protein-hydrolyzing endopeptidases             adipocyte metabolism, lyse tumor cells in vitro, and induce hemorrhagic
     that hydrolyze extracellular proteins, especially collagens and elastin.           necrosis of certain transplantable tumors in vivo.
  Mitogen-activated protein kinases ERK1/ERK: One of the mitogen-activated            Urate transporter-1 (URAT1): The urate–anion exchanger expressed at the
     protein kinases that signals transduction pathways in eukaryotic cells and         apical brush-border membrane of proximal tubular epithelial cells; URAT1
     integrates diverse extracellular signals; regulates complex biological             is encoded by the SLC22A12 gene.
     responses, such as growth, differentiation, and death.                           Urate transporter/channel (UAT): Also known as galectin-9; may also be
  Multidrug resistance protein-4 (MRP4): An anion transporter capable of                involved in proximal tubular urate secretion.
     adenosine triphosphate–driven urate efflux, expressed at the apical              Uricosuric agent: A chemical or drug that results in increased renal excretion
     membrane of the proximal tubule.                                                   of urate; urate transporter-1 appears to be the major target for uricosuric
  Nucleotide: A combination of a nucleic acid (purine or pyrimidine), 1 sugar           drugs.
     (ribose or deoxyribose), and a phosphoric group.                                 Voltage-driven organic anion transporter-1 (OATV1): A voltage-sensitive
  Organic anion transporter-1 (OAT1): A basolateral anion exchanger                     organic anion transporter capable of transporting urate and expressed at
     involved in proximal tubular transport of multiple organic anions,                 the apical membrane of the proximal tubule.
     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
                                                                                     thritis (15). The solubility of urate in joint fluids, however,
     in the hydrocarbon chain between the third and fourth carbon atoms              is influenced by other factors in the joint, as shown in
     from 1 end of the molecule; found especially in fish, fish oils, vegetable      Figure 3. Such factors include temperature, pH, concen-
     oils, and green leafy vegetables.
  Osteocalcin: A vitamin K–dependent, calcium-binding bone protein, the              tration of cations, level of articular dehydration, and the
     most abundant noncollagen protein in bone; increased serum                      presence of such nucleating agents as nonaggregated pro-
     concentrations are a marker of increased bone turnover in disease states.
                                                                                     teoglycans, insoluble collagens, and chondroitin sulfate (see
  p38 mitogen–activated protein kinase: One of the mitogen-activated
     protein kinases that signals transduction pathways in eukaryotic cells and      Glossary) (16 –18). Variation in these factors may account
     integrates diverse extracellular signals; regulates complex biological          for some of the difference in the risk for gout associated
     responses such as growth, differentiation, and death.
  Peroxisome proliferator-activated receptor- receptor (PPAR- ): A nuclear
                                                                                     with a given elevation in serum urate level (13, 14). Fur-
     receptor regulating an array of diverse functions in a variety of cell types,   thermore, these factors may explain the predilection of
     including regulation of genes associated with growth and differentiation.       gout in the first metatarsal phalangeal joint (a peripheral
  Phospholipase: An enzyme that catalyzes the hydrolysis of a phospholipid.
  Prostaglandin: Any of a class of physiologically active substances present in      joint with a lower temperature) and osteoarthritic joints
     many tissues; causes vasodilation, vasoconstriction, and antagonism to          (18) (degenerative joints with nucleating debris) and the
     hormones that influence lipid metabolism.
  Proteoglycan: Any of a class of glycoproteins of high molecular weight that
                                                                                     nocturnal onset of pain (because of intra-articular dehydra-
     are found especially in the extracellular matrix of connective tissue.          tion) (19).
  Proximal tubule: The earliest segment of the renal tubule, responsible for
     the reabsorption of urate and other solutes from the glomerular
                                                                                     Urate Balance
     ultrafiltrate.                                                                       The amount of urate in the body depends on the bal-
  Purine: A double-ringed, crystalline organic base, C5H4N4, from which the
     nitrogen bases adenine and guanine are derived; uric acid is a metabolic
                                                                                     ance between dietary intake, synthesis, and the rate of ex-
     end product.                                                                    cretion (20), as shown in Figure 1. Hyperuricemia results
  SLC22 gene family: The “Solute Carrier-22” gene family encompasses more            from urate overproduction (10%), underexcretion (90%),
     than 20 different genes encoding organic anion and cation transporters,
     including the urate transporter-1 (URAT1, SLC22A12), organic anion              or often a combination of the two. The purine precursors
     transporter-1 (OAT1, SLC22A6), and organic anion transporter-3 (OAT3,           come from exogenous (dietary) sources or endogenous me-
     SLC22A8).
                                                                                     tabolism (synthesis and cell turnover).
  SLC5A8: A member of the SLC5 gene family of sodium-coupled
     transporters; a leading candidate for the sodium-dependent                      The Relationship between Purine Intake and Urate
     lactate/butyrate/pyrazinoate/nicotinate transporter that collaborates with
     urate transporter-1 in proximal tubular reabsorption of urate.
                                                                                     Levels
  Src tyrosine kinase: One of a group of enzymes of the transferase class that            The dietary intake of purines contributes substantially
     catalyze the phosphorylation of tyrosine residues in specific membrane          to the blood uric acid. For example, the institution of an
     vesicle–associated proteins.
  Stop codon: Trinucleotide sequence (UAA, UGA, or UAG) that specifies the           entirely purine-free diet over a period of days can reduce
     end of translation or transcription.                                            blood uric acid levels of healthy men from an average of
  Synovitis: Inflammation of a synovial membrane, especially that of a joint;
     in general, when unqualified, the same as arthritis.
                                                                                     297 mol/L to 178 mol/L (21, 22). The bioavailable
  Transcription: Transfer of genetic code information from one kind of nucleic       purine content of particular foods would depend on their
     acid to another; commonly used to refer to transfer of genetic                  relative cellularity and the transcriptional (see Glossary)
     information from DNA to RNA.
                                                                                     and metabolic activity of the cellular content (20). Little
                                                                     Continued       is known, however, about the precise identity and quantity
www.annals.org                                                                            4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 501
Review          Pathogenesis of Gout


Figure 1. Overview of the pathogenesis of gout.                             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
Gout is mediated by the supersaturation and crystallization of uric acid
within the joints. The amount of urate in the body depends on the           of urate have the condition as a result of salvaged purines
balance between dietary intake, synthesis, and excretion. Hyperuricemia     arising from increased cell turnover in proliferative and
results from the overproduction of urate (10%), from underexcretion of      inflammatory disorders (for example, hematologic cancer
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.
                                                                            Figure 2. The relationship between serum uric acid levels and
                                                                            the incidence of gout.

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
                                                                            Annual incidence of gout was less than 0.1% for men with serum uric
the United States, higher levels of meat and seafood con-                   acid levels less than 416 mol/L, 0.4% for men with levels of 416 to 475
sumption were associated with higher serum uric acid lev-                     mol/L, 0.8% for men with levels of 476 to 534 mol/L, 4.3% for men
els (28). However, consumption of oatmeal and purine-                       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
rich vegetables (for example, peas, beans, lentils, spinach,                solid line denotes these data points; the dotted line shows an exponential
mushrooms, and cauliflower) was not associated with an                       projection of the data points.
502 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                                     www.annals.org
                                                                                                                       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                          tion by net ATP degradation to AMP (41, 44). In addi-
in increased urate production (such as chemotherapy), or                           tion, decreased urinary excretion as a result of dehydration
from tissue hypoxia. Only a small proportion of those with                         and metabolic acidosis may contribute to the hyperurice-
urate overproduction (10%) have the well-characterized in-                         mia that is associated with ethanol ingestion, as discussed
born errors of metabolism (for example, superactivity of                           later in this review (34, 45).
5’-phosphoribosyl-1-pyrophosphate synthetase and defi-                                   Recently, a large-scale prospective study confirmed
ciency of hypoxanthine– guanine phosphoribosyl trans-                              that the effect of ethanol on urate levels can be translated
ferase). These genetic disorders have been extensively re-                         into the risk for gout (31). Compared with abstinence,
viewed in textbooks (20, 33, 34), and the involved                                 daily alcohol consumption of 10 to 14.9 g increased the
pathways are depicted in Figure 5.                                                 risk for gout by 32%; daily consumption of 15 to 29.9 g,
     Conditions associated with net adenosine triphosphate                         30 to 49.9 g, and 50 g or greater increased the risk by 49%,
(ATP) (see Glossary) degradation lead to accumulation of                           96%, and 153%, respectively. Furthermore, the study also
adenosine diphosphate (ADP) and adenosine monophos-                                found that this risk varied according to type of alcoholic
phate (AMP), which can be rapidly degraded to uric acid                            beverage: Beer conferred a larger risk than liquor, whereas
(35– 44), as shown in Figure 5. For example, ethanol ad-                           moderate wine drinking did not increase risk (31). Corre-
ministration has been shown to increase uric acid produc-                          spondingly, a national U.S. survey demonstrated parallel
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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                     panying phosphate depletion limits regeneration of ATP
urate levels (46). These findings suggest that certain non-                   from ADP. The subsequent catabolism of AMP serves as a
alcoholic components that vary among these alcoholic bev-                    substrate for uric acid formation (48). Thus, within min-
erages play an important role in urate metabolism. Ingested                  utes after fructose infusion, plasma (and later urinary) uric
purines in beer, such as highly absorbable guanosine (23,                    acid concentrations are increased (42). In conjunction with
47), may produce an effect on blood uric acid levels that is                 purine nucleotide depletion, rates of purine synthesis de
sufficient to augment the hyperuricemic effect of alcohol                     novo are accelerated, thus potentiating uric acid produc-
itself, thereby producing a greater risk for gout than liquor                tion (43). Oral fructose may also increase blood uric acid
or wine. Whether other nonalcoholic offending factors ex-                    levels, especially in patients with hyperuricemia (49) or a
ist remains unclear, particularly in regard to beer; instead,                history of gout (50). Fructose has also been implicated in
protective factors in wine may be mitigating the alcohol                     the risk for the insulin resistance syndrome and obesity, which
effect on the risk for gout (28).                                            are closely associated with gout (51, 52). Furthermore, hyper-
      Fructose is the only carbohydrate that has been shown                  uricemia resulting from ATP degradation can occur in acute,
to exert a direct effect on uric acid metabolism (23). Fruc-                 severe illnesses, such as the adult respiratory distress syndrome,
tose phosphorylation in the liver uses ATP, and the accom-                   myocardial infarction, or status epilepticus (34 –36).
504 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                                    www.annals.org
                                                                                                                 Pathogenesis of Gout    Review

ADIPOSITY, INSULIN RESISTANCE,            AND   GOUT                          absorption. Finally, in the insulin resistance syndrome, im-
     Increased adiposity and the insulin resistance syn-                      paired oxidative phosphorylation may increase systemic
drome are both associated with hyperuricemia (53–56).                         adenosine (see Glossary) concentrations by increasing the
Body mass index, waist-to-hip ratio, and weight gain have                     intracellular levels of coenzyme A esters of long-chain fatty
all been associated with the risk for incident gout in men                    acids. Increased adenosine, in turn, can result in renal re-
(28, 57). Conversely, small, open-label interventional stud-                  tention of sodium, urate, and water (66 – 69). Some re-
ies showed that weight reduction was associated with a                        searchers have speculated that increased extracellular aden-
decline in urate levels and risk for gout (58, 59).                           osine concentrations over the long term may also
     Reduced de novo purine synthesis was observed in pa-                     contribute to hyperuricemia by increasing urate production
tients after weight loss, resulting in decreased serum urate                  (66). The growing “epidemic” of obesity (70, 71) and the
levels (60). Exogenous insulin can reduce the renal excre-                    insulin resistance syndrome (72) present a substantial chal-
tion of urate in both healthy and hypertensive persons (54,                   lenge in the prevention and management of gout.
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                      HYPERTENSION, CARDIOVASCULAR DISORDERS,                       AND
sodium-dependent anion cotransporter in brush-border                          GOUT
membranes of the renal proximal tubule (discussed later in                        Associations between hypertension and the incidence
this review). Because serum levels of leptin (see Glossary)                   of gout have been observed (13, 57), but researchers were
and urate tend to increase together (64, 65), some investi-                   previously unable to determine whether hypertension was
gators have also suggested that leptin may affect renal re-                   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.
www.annals.org                                                                      4 October 2005 Annals of Internal Medicine Volume 143 • Number 7 505
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-                       by pyrazinoate, the relevant metabolite, has never been
uretic use, and renal failure. A recent prospective study,                           demonstrated. Indeed, pyrazinamide has no effect in ani-
however, has confirmed that hypertension is associated                                mal species that eliminate urate through net secretion (92),
with an increased risk for gout independent of these po-                             and direct effects of the drug on human urate secretion are
tential confounders (28). Renal urate excretion was found                            largely unsubstantiated (91). Rather, studies utilizing renal
to be inappropriately low relative to glomerular filtration                           brush-border membrane vesicles (see Glossary) (93, 94)
rates in patients with essential hypertension (73, 74). Re-                          have shown that pyrazinoate activates the reabsorption of
duced renal blood flow with increased renal and systemic                              urate through indirect stimulation of apical urate exchange
vascular resistance may also contribute to elevated serum                            (Figure 5). Similar mechanisms underlie the clinically rel-
uric acid levels (75). Hyperuricemia in patients with essen-                         evant hyperuricemic effects of lactate (45), ketoacids (95),
tial hypertension may reflect early nephrosclerosis, thus im-                         and nicotinate (96), as shown in the Table. Recent ad-
plying renal morbidity in these patients. Furthermore,                               vances in the understanding of the relevant physiology are
studies have suggested that hyperuricemia may be associ-                             reviewed in the following sections.
ated with incident hypertension or cardiovascular disor-
                                                                                     The Renal Urate–Anion Exchanger URAT1
ders. The proposed role of urate in the pathogenesis of
                                                                                          Enomoto and colleagues (63) recently identified the
these disorders has recently been reviewed in the Physiol-
                                                                                     molecular target for uricosuric agents (see Glossary), an
ogy in Medicine series (12).
                                                                                     anion exchanger responsible for the reabsorption of filtered
                                                                                     urate by the renal proximal tubule (Table). The authors
RENAL TRANSPORT            OF     URATE                                              searched the human genome database for novel gene se-
     Renal urate transport is typically explained by a                               quences within the organic anion transporter (OAT) gene
4-component model: glomerular filtration, a near-complete                             family and identified URAT1 (SLC22A12) (see Glossary),
reabsorption of filtered urate, subsequent secretion, and                             a novel transporter expressed at the apical brush border of
postsecretory reabsorption in the remaining proximal tu-                             the proximal nephron (63). Urate–anion exchange activity
bule (see Glossary) (76, 77). This model evolved from an                             similar to that of URAT1 was initially described in brush-
interpretation of the effects of “uricosuric” and “antiurico-                        border membrane vesicles from urate-reabsorbing species,
suric” agents; drugs and compounds known to affect serum                             such as rats and dogs (97–100), and was subsequently con-
urate levels are summarized in the Table. The urate secre-                           firmed in human kidneys (101). Frog eggs (Xenopus oo-
tion step was incorporated into the model to explain the                             cytes) injected with URAT1-encoding RNA transport
potent antiuricosuric effect of pyrazinamide (91). How-                              urate and exhibit pharmacologic properties consistent with
ever, direct inhibition of proximal tubular urate secretion                          data from human brush-border membrane vesicles (63,
506 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                                                   www.annals.org
                                                                                                                     Pathogenesis of Gout    Review

101). These and other experiments indicate that uricosuric                       essential for the effect of both uricosuric and antiuricosuric
compounds (for example, probenecid, benzbromarone,                               agents (see Glossary) (90).
sulfinpyrazone, and losartan) directly inhibit URAT1 from
the apical side of tubular cells (“cis-inhibition” [see Glos-                    Secondary Sodium Dependency of Urate Reabsorption
sary]). Conversely, antiuricosuric substances (for example,                            Antiuricosuric agents exert their effect by stimulating re-
pyrazinoate, nicotinate, and lactate) serve as the exchang-                      nal reabsorption rather than inhibiting tubular secretion (91).
ing anion from inside cells (Figure 6 and Table), thereby                        The mechanism appears to involve a “priming” of renal urate
stimulating anion exchange and urate reabsorption (“trans-                       reabsorption through the sodium-dependent loading of prox-
stimulation” [see Glossary]) (9, 63). In addition to urate,                      imal tubular epithelial cells with anions capable of a trans-
URAT1 has particular affinity for aromatic organic anions,                        stimulation of urate reabsorption (Figure 6). Studies from sev-
such as nicotinate and pyrazinoate, followed by lactate,                         eral laboratories have indicated that a transporter in the
  -hydroxybutyrate, acetoacetate, and inorganic anions,                          proximal tubule brush border mediates sodium-dependent
such as chloride and nitrate (63).                                               reabsorption of pyrazinoate, nicotinate, lactate, pyruvate,
     Enomoto and colleagues (63) provided unequivocal                              -hydroxybutyrate, and acetoacetate (102–104), monovalent
genetic proof that URAT1 is crucial for urate homeostasis:                       anions that are also substrates for URAT1 (63). Increased
A handful of patients with “familial renal hypouricemia”                         plasma concentrations of these antiuricosuric anions result in
(OMIM [Online Mendelian Inheritance in Man] accession                            their increased glomerular filtration and greater reabsorption
number 220150; see Glossary) were shown to carry loss-                           by the proximal tubule. The augmented intraepithelial con-
of-function mutations in the human SLC22A12 gene en-                             centrations in turn induce the reabsorption of urate by pro-
coding URAT1, indicating that this exchanger is essential                        moting the URAT1-dependent anion exchange of filtered
for proximal tubular reabsorption. Furthermore, pyrazin-                         urate (trans-stimulation) (Figure 6).
amide, benzbromarone, and probenecid failed to affect                                  Urate reabsorption by the proximal tubule thus exhib-
urate clearance in patients with homozygous loss-of-func-                        its a form of secondary sodium dependency, in that sodium-
tion mutations in SLC22A12, indicating that URAT1 is                             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.                  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-
The anti-uricosuric agent pyrazinoate (PZA), a metabolite of pyrazin-      imal doses of salicylate—75, 150, and 325 mg daily—were
amide, has dual effects on urate transport by the proximal tubule. Urate   shown to increase serum uric acid levels by 16, 12, and 2
uptake by brush-border membrane vesicles isolated from canine kidney         mol/L, respectively (78). However, the effect on the risk
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-           for gout of this salicylate-induced increase in the serum
dent uptake of PZA and a potentiation of urate uptake via urate trans-     uric acid level has not been determined.
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.           Other Renal Urate Transporters
Paradoxical effects of pyrazinoate and nicotinate on urate transport in         At the basolateral membrane of proximal tubular cells,
dog renal microvillus membranes. J Clin Invest. 1985;76:543-7.)            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
brush-border urate exchange; urate itself is not a substrate
for the sodium–anion transporter. The molecular identity                   carboxylates, such as pyrazinoate and lactate (117, 118)
of the relevant sodium-dependent anion cotransporter or                    (Figure 6). Candidate proteins for this basolateral urate
cotransporters remains unclear; however, a leading candi-                  exchange activity include both OAT1 (119) and OAT3
date gene is SLC5A8 (see Glossary), which encodes a sodi-                  (120, 121) (see Glossary), each of which function as an-
um-dependent lactate and butyrate cotransporter (105).                     ion1 – dicarboxylate2 exchangers (121–123) at the baso-
Preliminary data indicate that the SLC5A8 protein can also                 lateral membrane of the proximal tubule. These proteins
transport both pyrazinoate and nicotinate, potentiating                    (or similar transporters) conceivably facilitate the basolat-
urate transport in Xenopus oocytes that co-express URAT1                   eral influx or efflux of urate.
(106).                                                                          As mentioned previously, the quantitative role of hu-
     The antiuricosuric mechanism explains the long-                       man urate secretion remains unclear. Nonetheless, several
standing clinical observation that hyperuricemia is induced                molecular candidates have been proposed for the electro-
by increased -hydroxybutyrate and acetoacetate levels in                   genic urate secretion pathway across the apical membrane
diabetic ketoacidosis (95), increased lactic acid levels in                of proximal tubules, including the urate transporter/chan-
alcohol intoxication (45), or increased nicotinate and                     nel (UAT, also known as galectin-9) (124) and the voltage-
pyrazinoate levels in niacin and pyrazinamide therapy, re-                 driven organic anion transporter-1 (OATV1) (125). The
spectively (96). Urate retention is also known to be pro-                  apical ATP-driven anion transporter multidrug resistance
voked by a reduction in extracellular fluid volume (107)                    protein 4 (MRP4) (see Glossary) has also been shown to
and by excesses of angiotensin II (108, 109), insulin (62,                 mediate urate efflux (126).
508 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                          www.annals.org
                                                                                                                      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                                                ticular properties of the urate crystal to interact directly
     Urate crystals are directly able to initiate, to amplify,                    with lipid membranes and proteins through cell membrane
and to sustain an intense inflammatory attack because of                           perturbation and cross-linking of membrane glycoproteins
their ability to stimulate the synthesis and release of hu-                       in the phagocyte. This interaction leads to the activation of
moral and cellular inflammatory mediators (Figure 8).                              several signal transduction pathways, including G proteins,
                                                                                  phospholipase C and D, Src tyrosine kinases, the mitogen-
Urate Crystal–Induced Cell Activation and Signaling                               activated protein kinases ERK1/ERK2, c-Jun N-terminal
     Urate crystals interact with the phagocyte through 2                         kinase, and p38 mitogen-activated protein kinase (see
broad mechanisms. First, they activate the cells through                          Glossary) (127–130). These steps are critical for crystal-
the conventional route as opsonized and phagocytosed                              induced interleukin (IL)– 8 (see Glossary) expression in
particles, eliciting the stereotypical phagocyte response of                      monocytic cells (130 –132), which plays a key role in the
lysosomal fusion, respiratory burst, and release of inflam-                        neutrophil accumulation that is discussed later in this re-
matory mediators. The other mechanism involves the par-                           view (133).
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Review          Pathogenesis of Gout


Crystal-Induced Cellular Response                                      mately 90% of the neutrophil chemotactic activity of hu-
     Cellular kinetic analyses using experimental animal               man monocytes in response to urate crystals (133). Neu-
models of gout (134, 135) indicate that monocytes and                  tralization of IL-8 or its receptor may substantially reduce
mast cells participate during the early phase of inflamma-              the IL-8 –induced neutrophilic inflammatory process (148)
tion, whereas neutrophil infiltrates occur later during in-             and provide a potential therapeutic target in gout. Several
flammation (Figure 8). Phagocytes from noninflamed                       other neutrophil chemotactic factors, including the calci-
joints may contain urate crystals (136), and most of these             um-binding proteins (calgranulins) S100A8 and S100A9
phagocytes are macrophages (137). The state of differenti-             (see Glossary) (149, 150), have also been shown to be
ation of mononuclear phagocytes determines whether the                 involved in neutrophil migration induced by urate crystals
crystals will trigger an inflammatory response. In less dif-            (Figure 8).
ferentiated cell lines, synthesis of tumor necrosis factor–
(TNF- ) (see Glossary) and endothelial cell activation oc-             SPONTANEOUS RESOLUTION         OF   ACUTE GOUT
curred after urate crystal phagocytosis, whereas well-differ-
                                                                             The self-limited nature of acute gout is thought to
entiated macrophages failed to induce TNF- synthesis or
                                                                       involve several mechanisms (151), as shown in Figure 8.
to activate endothelial cells (137). Similarly, freshly isolated
                                                                       Clearance of urate crystals by differentiated macrophages
human monocytes lead to a vigorous response by induction
                                                                       in vitro has been linked to inhibition of leukocyte and
of TNF- , IL-1 , IL-6, IL-8, and cyclooxygenase-2 secre-
                                                                       endothelial activation (137, 138, 152). Neutrophil apopto-
tion (see Glossary), whereas human macrophages differen-
                                                                       sis (see Glossary) and other apoptotic cell clearance repre-
tiated in vitro for 7 days failed to secrete cytokines (see
                                                                       sent a fundamental mechanism in the resolution of acute
Glossary) or to induce endothelial cell activation (138).
                                                                       inflammation. Furthermore, transforming growth factor–
These findings indicate that monocytes play a central role
                                                                       (see Glossary) becomes abundant in acute gouty synovial
in stimulating an acute attack of gout, whereas differenti-
                                                                       fluid and inhibits IL-1 receptor expression and IL-1–
ated macrophages play an anti-inflammatory role in termi-
                                                                       driven cellular inflammatory responses (153, 154).
nating an acute attack and preserving the asymptomatic
                                                                             Upregulation of IL-10 expression has been shown to
state (Figure 8).
                                                                       limit experimental urate-induced inflammation and may
     Experimental animal models suggest that mast cells are
                                                                       function as a native inhibitor of gouty inflammation (155).
involved in the early phase of crystal-induced inflammation
                                                                       Similarly, urate crystals induce peroxisome proliferator–ac-
(134), and they also release inflammatory mediators, such               tivated receptor- (PPAR- ) (see Glossary) expression in
as histamine (139), in response to C3a, C5a, and IL-1. The             human monocytes and promote neutrophil and macro-
vasodilatation, increased vascular permeability, and pain              phage apoptosis (156). Research has yet to determine if the
are also mediated by kinins, complement cleavage peptides,             PPAR- – based therapy currently available for type 2 dia-
and other vasoactive prostaglandins (see Glossary) (140).              betes would also be useful in gout management.
Neutrophilic Influx and Amplification                                        Inactivation of inflammatory mediators by proteolytic
      Neutrophilic synovitis (see Glossary) is the hallmark            cleavage, cross-desensitization of receptors for chemokines,
of an acute gouty attack (Figure 8). Neutrophilic– endo-               release of lipoxins (see Glossary), IL-1 receptor antagonist,
thelial cell interaction leading to neutrophilic influx ap-             and other anti-inflammatory mediators all facilitate the res-
pears to be an important event in this inflammation and                 olution of acute gout. As shown in Figure 8, increased
represents a major locus for the pharmacologic effect of               vascular permeability allows the entry of large molecules
                                                                       (such as apolipoproteins B and E [see Glossary]) and other
colchicine. Neutrophil influx is believed to be promoted by
                                                                       plasma proteins into the synovial cavity, which also con-
the endothelial–neutrophil adhesion that is triggered by
                                                                       tributes to the spontaneous resolution of acute flares (157,
IL-1, TNF- , and several chemokines (see Glossary), such
                                                                       158).
as IL-8 and neutrophil chemoattractant protein-1 (MCP-
1). Neutrophil migration involves neutrophilic– endothe-
lial interaction mediated by cytokine-induced clustering of            CHRONIC GOUTY ARTHRITIS
E-selectin (see Glossary) on endothelial cells. Colchicine                  Chronic gouty arthritis typically develops in patients
interferes with the interactions by altering the number and            who have had gout for years (Figure 9). Cytokines, che-
distribution of selectins on endothelial cells and neutro-             mokines, proteases, and oxidants involved in acute urate
phils in response to IL-1 or TNF- (141).                               crystal–induced inflammation also contribute to the
      Once in the synovial tissue, the neutrophils follow              chronic inflammation, leading to chronic synovitis, carti-
concentration gradients of chemoattractants such as C5a,               lage loss, and bone erosion. Even during remissions of
leukotriene B4 (see Glossary), platelet-activating factor,             acute flares, low-grade synovitis in involved joints may per-
IL-1, and IL-8 (142). Among these factors, IL-8 and                    sist with ongoing intra-articular phagocytosis of crystals
growth-related gene chemokines play a central role in neu-             by leukocytes (136). Tophi on the cartilage surface, which
trophil invasion in experimental models of acute gout                  can be observed through arthroscopy (159), may contrib-
(143–147). For example, IL-8 alone accounts for approxi-               ute to chondrolysis despite adequate treatment of both
510 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                     www.annals.org
                                                                                                                      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                                  Weight control, limits on red meat consumption, and
chondrocytes phagocytize microcrystals and produce active                         daily exercise are important foundations of lifestyle modi-
metalloproteinases. Furthermore, crystal– chondrocyte cell                        fication recommendations for patients with gout or hyper-
membrane interactions can trigger chondrocyte activation,                         uricemia and parallel recommendations related to preven-
gene expression of IL-1 and inducible nitric oxide synthase,                      tion of coronary heart disease, diabetes, and certain types
nitric oxide release, and the overexpression of matrix metallo-                   of cancer. Patients with gout could consider using plant-
proteinases (see Glossary) that leads to cartilage destruction                    derived -3 fatty acids or supplements of eicosapentaenoic
(161). The crystals can also suppress the 1,25-dihydroxychole-                    acid and docosahexanoic acid instead of consuming fish for
calciferol–induced activity of alkaline phosphatase and osteo-                    cardiovascular benefits. The recent recommendation on
calcin (see Glossary). Thus, crystals can reduce the anabolic                     dairy consumption for the general public would also be
effects of osteoblasts, thereby contributing to damage to the                     applicable for most patients with gout or hyperuricemia
juxta-articular bone (162) (Figure 9).                                            and may offer added benefit to individuals with hyperten-
                                                                                  sion, diabetes, and cardiovascular disorders. Further risk–
SUMMARY                                                                           benefit assessments in each specific clinical context would
     The disease burden of gout remains substantial and                           be helpful. Daily consumption of nuts and legumes as rec-
may be increasing. As more scientific data on modifiable                            ommended by the Harvard Healthy Eating Pyramid (32)
risk factors and comorbidities of gout become available,                          may also provide important health benefits without in-
integration of these data into gout care strategy may be-                         creasing the risk for gout. Similarly, a daily glass of wine
come essential, similar to the current care strategies for                        may benefit health without imposing an elevated risk for
hypertension (163) and type 2 diabetes (164). Recommen-                           gout, especially in contrast to beer or liquor consumption.
dations for lifestyle modification to treat or to prevent gout                     These lifestyle modifications are inexpensive and safe and,
are generally in line with those for the prevention or treat-                     when combined with drug therapy, may result in better
ment of other major chronic disorders (32). Thus, the net                         control of gout.
health benefits from these general healthy lifestyle recom-                             Effective management of gout risk factors (for exam-
mendations (32) are expected to be even larger among                              ple, hypertension) and the strategic choice of certain ther-
many patients with gout, particularly those with coexisting                       apies for comorbid conditions may also aid gout care. For
insulin resistance syndrome, diabetes, obesity, and hyper-                        example, antihypertensive agents with uricosuric properties
tension.                                                                          (for example, losartan [165] or amlodipine [86]) could
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Review          Pathogenesis of Gout


have a better risk– benefit ratio than diuretics for hyperten-            References
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516 4 October 2005 Annals of Internal Medicine Volume 143 • Number 7                                                                                  www.annals.org
Annals of Internal Medicine
Current Author Addresses: Dr. Choi: Division of Rheumatology, De-     Dr. Mount: Brigham and Women’s Hospital, Renal Division, Room
partment of Medicine, University of British Columbia, Arthritis Re-   540, 4 Blackfan Circle, Boston, MA 02115.
search Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z      Dr. Reginato: Massachusetts General Hospital, 55 Fruit Street, Boston,
1L7.                                                                  MA 02114.




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