Gout

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Gout
Synonym	Podagra (when affecting the first MTP joint), gouty arthritis.
Definition	Chronic crystal arthropathy caused by monosodium urate deposition due to hyperuricemia.
Epidemiology	Most common form of inflammatory arthritis, increased prevalence amongst Māori and Pacific peoples.
Causes	Sustained hyperuricemia, due to urate underexcretion, overproduction, or both.
Inheritance	Strong heritable component
Genetics	SLC2A9 and ABCG2
Pathophysiology	Hyperuricemia leading to MSU crystal formation, triggering intense innate immune inflammation via the NLRP3 inflammasome.
Clinical Features	Acute monoarthritis, typically the first MTP joint, and can progress to chronic tophaceous disease.
Tests	Synovial fluid analysis, serum urate, inflammatory markers, renal function, and imaging like US or DECT.
DDX	Septic arthritis and CPPD
Treatment	Long term urate lowering therapy

Gout represents the most common form of inflammatory arthritis in adults, arising from the complex interplay between metabolic dysregulation and innate immune activation. Fundamentally, it is a crystal deposition disease, characterized by the precipitation and accumulation of monosodium urate (MSU) crystals within articular structures, periarticular tissues, and occasionally other organ systems. This crystallization process is a direct consequence of sustained hyperuricemia, defined as the supersaturation of extracellular fluids with urate.

Historically recognized since antiquity and often colloquially termed the "disease of kings" due to perceived associations with dietary excess, the contemporary understanding of gout has evolved significantly. It is now appreciated not merely as an episodic articular ailment but as a chronic, systemic metabolic disorder with potentially profound and far-reaching health consequences.

The global burden of gout is substantial and demonstrably increasing, paralleling worldwide trends in longevity, obesity, and metabolic syndrome. Beyond the debilitating pain and functional limitation associated with acute flares and chronic arthropathy, gout imposes significant socioeconomic costs through healthcare utilization and lost productivity. Furthermore, a robust body of evidence links gout and its precursor, hyperuricemia, to a spectrum of comorbidities, most notably cardiovascular disease, chronic kidney disease, and diabetes mellitus.

Aetiopathophysiology

The development of gout is predicated upon a series of interconnected pathophysiological events, beginning with hyperuricemia and culminating in MSU crystal deposition and a subsequent inflammatory response.

Hyperuricemia: The Prerequisite Condition

Hyperuricemia, an elevation of serum urate (SUA) concentration, is the fundamental prerequisite for gout. Urate, the ionized form of uric acid, is the final breakdown product of purine metabolism in humans, a process primarily catalyzed by the enzyme xanthine oxidase. Purines derive from both endogenous cellular turnover and dietary sources. Defining hyperuricemia lacks universal consensus, with thresholds often cited as SUA > 0.42 mmol/L (7.0 mg/dL) in men and > 0.36 mmol/L (6.0 mg/dL) in women, or a single threshold around 0.40 mmol/L (6.8 mg/dL), which approximates the physicochemical saturation point of MSU in physiological fluids at normal body temperature. In New Zealand when considering targets for treatment, we use cut offs of 0.36 or 0.3 if tophi are present.

Crucially, hyperuricemia itself does not equate to gout. It is a necessary, but not sufficient, condition. Epidemiological data indicate that only a minority of individuals with hyperuricemia will develop clinical gout. For instance, studies have shown that approximately 22% of men with SUA levels exceeding 0.54 mmol/L (9.0 mg/dL) develop gout over a 5-year period, and even among those with levels ≥ 0.60 mmol/L (10.0 mg/dL), fewer than half manifest gout within 15 years. This dissociation highlights that factors beyond the absolute SUA level are critical determinants of both crystal deposition and the subsequent inflammatory response, suggesting individual susceptibility is modulated by local tissue factors and variations in immune regulation.

Hyperuricemia arises from an imbalance between urate production and excretion, predominantly driven by impaired excretion.

• Urate Underexcretion: Accounting for approximately 90% of hyperuricemia cases, reduced excretion via renal and intestinal pathways is the principal mechanism. Urate handling is complex, involving filtration, reabsorption, and secretion, primarily regulated by a suite of transporters in the renal proximal tubules and the gut. Key transporters include URAT1 (encoded by SLC22A12), GLUT9 (SLC2A9), and ABCG2, among others. Genetic polymorphisms in these transporter genes are major determinants of inter-individual variations in SUA levels and are strongly associated with gout risk. This genetic influence on the predominant mechanism of hyperuricemia (underexcretion) explains much of the heritability of gout and contributes significantly to population differences in prevalence, such as the high rates observed in New Zealand Māori and Pacific peoples. Factors impairing renal excretion include chronic kidney disease (CKD), volume depletion, acidosis, certain medications (notably diuretics like thiazides and loop diuretics, low-dose aspirin, cyclosporine), lead exposure, and conditions associated with metabolic syndrome.
• Urate Overproduction: This accounts for a smaller proportion (~10%) of cases. Causes include increased dietary purine intake (e.g., red meat, organ meats, certain seafood, beer rich in guanosine) , accelerated nucleic acid turnover in conditions like myeloproliferative disorders, lymphoma, hemolysis, or tumor lysis syndrome, and rare inherited enzymatic defects affecting purine metabolism, such as deficiencies in hypoxanthine-guanine phosphoribosyltransferase (HPRT) (causing Lesch-Nyhan syndrome or the less severe Kelley-Seegmiller syndrome) or superactivity of phosphoribosyl pyrophosphate (PRPP) synthetase.
• Combined Mechanisms: Certain factors, like excessive alcohol consumption, can contribute through both increased urate production (via accelerated hepatic ATP breakdown) and decreased excretion (via generation of organic acids competing for tubular secretion).

Monosodium Urate (MSU) Crystal Formation and Deposition

At physiological pH (around 7.4) and high extracellular sodium concentrations, soluble urate exists predominantly as MSU. When SUA levels exceed the saturation threshold (approximately 0.40 mmol/L or 6.8 mg/dL), the potential for MSU crystallization arises. However, crystallization is not solely dependent on supersaturation. Local environmental factors play a crucial modulatory role. Lower temperatures favor crystallization, explaining the predilection for gout to affect cooler, peripheral joints like the first metatarsophalangeal (MTP) joint. Changes in pH (acidosis promotes precipitation), dehydration, and the presence of specific components within the connective tissue matrix (e.g., collagen, proteoglycans in cartilage) can also influence nucleation and crystal growth. MSU crystals preferentially deposit extracellularly in relatively avascular or avascular tissues such as articular cartilage, tendons, ligaments, bursal walls, and subcutaneous tissues, particularly around distal joints. Initial deposition forms microscopic crystal aggregates (microtophi), which, with sustained hyperuricemia, can coalesce into macroscopic collections known as tophi.

The Inflammatory Cascade: Role of the Inflammasome and Immune Cells

The clinical manifestations of gout, particularly the acute flare, are driven by an intense inflammatory response triggered by MSU crystals. This process is primarily mediated by the innate immune system. MSU crystals are recognized as danger signals by resident cells in the joint, such as macrophages and monocytes. Upon phagocytosis, these crystals activate intracellular multiprotein complexes known as inflammasomes, with the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome playing a pivotal role.

Activation of the NLRP3 inflammasome leads to the autocatalytic cleavage of pro-caspase-1 into its active form, caspase-1. Active caspase-1 then cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their mature, biologically active forms, IL-1β and IL-18.¹ IL-1β is a master pro-inflammatory cytokine in the context of gout.¹ It binds to its receptor on various cells (endothelial cells, synoviocytes, chondrocytes, incoming neutrophils), initiating a potent downstream signaling cascade. This results in the upregulation and release of numerous secondary inflammatory mediators, including other cytokines (e.g., IL-6, TNF-α), chemokines (e.g., IL-8/CXCL8), and adhesion molecules. This inflammatory milieu orchestrates the massive recruitment of neutrophils from the circulation into the joint space, a hallmark of the acute gout flare.

Neutrophils further amplify the inflammatory response by releasing their own pro-inflammatory mediators, reactive oxygen species, and lysosomal enzymes upon encountering MSU crystals. However, neutrophils also participate in the resolution phase of inflammation. Mechanisms such as the formation of aggregated neutrophil extracellular traps (NETs) can physically trap MSU crystals and inflammatory mediators, while NET-associated proteases can degrade cytokines and chemokines, contributing to the eventual self-limitation characteristic of gout flares. The central pathogenic role of the NLRP3/IL-1β axis provides a compelling rationale for therapeutic strategies targeting IL-1, particularly in cases refractory to conventional anti-inflammatory agents.

Pathogenesis of Tophi and Chronic Inflammation

Chronic, inadequately controlled hyperuricemia leads to the progressive accumulation of MSU crystals, forming clinically apparent tophi. Tophi are not inert deposits but complex, organized structures akin to chronic foreign body granulomas. They consist of a core of MSU crystal aggregates embedded within a matrix containing lipids and proteins, surrounded by layers of inflammatory cells (including macrophages, multinucleated giant cells, lymphocytes, mast cells) and fibrotic tissue.

Persistent low-grade inflammation within and around tophi, driven by ongoing interactions between crystals and immune cells, contributes significantly to the structural damage seen in chronic gouty arthropathy. This includes promoting osteoclast activity leading to bone erosions, degrading articular cartilage, and damaging adjacent tendons and ligaments.

Epidemiology

Gout stands as the most common inflammatory arthritis affecting adults worldwide, with its prevalence and incidence showing a concerning upward trend in recent decades.

Global prevalence estimates vary depending on the populations studied and diagnostic methodologies employed, typically ranging from less than 1% to as high as 6.8% in certain Western populations. The disease burden is increasing globally, a trend observed not only in developed nations where prevalence has historically been higher, but also increasingly in developing countries and regions like Southeast Asia. This rise is closely linked to global increases in life expectancy, obesity, metabolic syndrome, and changes in dietary patterns.

Gout exhibits distinct demographic patterns. It is significantly more common in men than in women, with reported male-to-female ratios ranging from 2:1 to 6:1. The prevalence rises sharply with increasing age in both sexes, peaking in older adulthood.

Aotearoa New Zealand stands out globally for its exceptionally high prevalence of gout. National data indicate that approximately 6% of the adult population (aged 20 years and over) is affected, representing a significant increase from around 4.5% in 2012. This overall figure, however, masks profound ethnic disparities, with Māori and Pacific peoples experiencing a disproportionately high burden of disease.

Overall, Māori and Pacific peoples have a gout prevalence 2 to 3 times higher than non-Māori, non-Pacific New Zealanders. These disparities are particularly stark in younger adults (age 20–44 years), where Māori have three times, and Pacific peoples have seven times, the prevalence of their non-Māori, non-Pacific counterparts. The burden escalates dramatically with age, especially in men. Astonishingly, estimates suggest that among men aged 65 years and over, gout affects approximately 35% of Māori and 50% of Pacific individuals, compared to 18% of non-Māori, non-Pacific men. Specific studies have reported prevalence rates in Māori men ranging from 9.3% to 13.9% and in Pacific men reaching 14.9%. Beyond prevalence, Māori and Pacific peoples also tend to experience an earlier age of onset, more frequent flares, and more severe disease manifestations, including higher rates of tophaceous gout and accelerated joint damage.

The underlying reasons for these striking disparities are multifactorial, but genetic predisposition plays a paramount role. Specific variants in genes encoding crucial renal and gut urate transporters, notably SLC2A9 (GLUT9) and ABCG2, are found at higher frequencies in Polynesian populations and confer a substantially increased risk of hyperuricemia and gout. For example, certain SLC2A9 variants increase gout risk more than five-fold in Pacific peoples, while the Q141K variant in ABCG2 confers a two- to three-fold increased risk in Pacific Island and NZ Caucasian samples, though interestingly, not significantly in NZ Māori samples studied. These genetic findings align with earlier biochemical studies demonstrating reduced renal clearance of urate in Māori and Pacific individuals compared to those of European ethnicity. This strong genetic underpinning means that lifestyle factors, while relevant, likely play a proportionally smaller role in driving hyperuricemia in these high-risk populations compared to genetic factors, a point crucial for patient education and reducing associated stigma. Socioeconomic factors also contribute, with higher gout prevalence noted in more deprived areas.

The following table provides a comparative overview of gout prevalence, illustrating the particularly high burden in New Zealand, especially among Māori and Pacific men.

Risk Factors and Comorbidities

Beyond the specific NZ context, several factors consistently increase the risk of developing hyperuricemia and gout globally:

• Non-modifiable Factors: Increasing age is a strong risk factor. Male sex confers a significantly higher risk, although prevalence increases in women after menopause. Genetic predisposition, evidenced by family history and specific gene variants (primarily affecting urate transport), plays a crucial role. Certain ethnicities, like NZ Māori and Pacific peoples, exhibit higher susceptibility.
• Modifiable Factors: Hyperuricemia itself is the primary modifiable factor, targeted by ULT. Lifestyle factors contribute significantly, including obesity or high body mass index (BMI). Dietary habits associated with increased risk include high consumption of purine-rich foods (red meat, organ meats, shellfish) and beverages high in fructose or alcohol (especially beer and spirits). Certain medications are well-known culprits, particularly thiazide and loop diuretics, low-dose aspirin, cyclosporine, pyrazinamide, and ethambutol.

Gout frequently coexists with a cluster of metabolic and cardiovascular conditions, reinforcing its nature as a systemic disease. Strong associations exist with:

• Chronic Kidney Disease (CKD): A bidirectional relationship exists; CKD impairs urate excretion increasing gout risk, while hyperuricemia and gout may contribute to CKD progression.
• Cardiovascular Diseases (CVD): Including hypertension (very common), coronary artery disease, heart failure, and stroke. Gout is increasingly recognized as an independent risk factor for cardiovascular events and mortality.
• Metabolic Syndrome and its Components: Including obesity, insulin resistance, diabetes mellitus, hypertension, and dyslipidemia.
• Other Associations: Include steatotic liver disease, osteoarthritis , and emerging links with conditions like erectile dysfunction, atrial fibrillation, obstructive sleep apnea, osteoporosis, and venous thromboembolism.

Clinical Features

Asymptomatic Hyperuricaemia

This initial stage is defined by elevated SUA levels in the absence of any clinical signs or symptoms of gout, such as acute flares or tophi. It represents the necessary biochemical precursor to gout. While most individuals with hyperuricemia remain perpetually asymptomatic, this phase is characterized by the potential for subclinical MSU crystal deposition in articular and periarticular tissues. Advanced imaging techniques, particularly ultrasound (US) and dual-energy computed tomography (DECT), are increasingly capable of detecting these silent crystal deposits in individuals with asymptomatic hyperuricemia, highlighting ongoing pathology even before clinical symptoms emerge.

Acute Gout Flare (Acute Gouty Arthritis)

The hallmark clinical event of gout is the acute flare, an episode of intense, localized inflammatory arthritis triggered by the interaction between MSU crystals and the innate immune system.¹

• Onset and Duration: Flares typically develop rapidly, often awakening the patient from sleep (nocturnal onset). The inflammation escalates quickly, reaching peak intensity within a relatively short timeframe, usually 8 to 24 hours.¹ Gout flares are characteristically self-limiting, meaning they typically resolve spontaneously, even without specific treatment, over a period of approximately 7 to 14 days.
• Symptoms: The cardinal symptom is excruciating joint pain, often described as the worst pain ever experienced. This is accompanied by prominent signs of inflammation: marked swelling, palpable warmth, and striking erythema (redness) of the overlying skin, which can sometimes mimic cellulitis. The affected joint is exquisitely tender, often intolerant to even the lightest touch, such as the pressure of a bedsheet. The skin may appear tense, shiny, or even purplish, and desquamation (peeling) can occur as the flare subsides. Systemic symptoms, including fever, chills, malaise, and tachycardia, may accompany the articular inflammation, particularly in polyarticular flares or severe attacks.
• Joint Distribution: Gout typically presents as a monoarthritis, especially in the early stages of the disease. There is a strong predilection for joints of the lower limb. The classic and most frequent presentation is podagra, involving the first MTP joint (base of the big toe). Podagra is the initial manifestation in about half of cases and occurs at some point in most individuals with gout. Other commonly affected sites include the midfoot (instep), ankle, knee, wrist, fingers, and elbow. Involvement of more proximal joints like the hip or shoulder, or the axial skeleton (spine, sacroiliac joints), is uncommon but can occur. While typically monoarticular initially, flares can become polyarticular, involving multiple joints simultaneously or in rapid succession, sometimes affecting several joints within the same limb. Atypical presentations, such as polyarticular involvement of the small joints of the hands, may be more common in elderly individuals or those with long-standing disease.The potential for gout to affect almost any joint and present atypically necessitates a high index of suspicion, as it can mimic conditions like septic arthritis or rheumatoid arthritis (RA).
• Triggers: Acute flares are often precipitated by events that cause abrupt fluctuations (either increases or decreases) in SUA levels, disrupting the equilibrium of MSU crystals in the tissues. Common triggers include excessive alcohol intake (particularly beer), consumption of purine-rich foods, dehydration, acute medical illness, surgery, trauma to a joint, and initiation or cessation of certain medications, including diuretics, aspirin, and paradoxically, the initiation of ULT itself.

Intercritical Gout

This stage refers to the asymptomatic intervals between acute gout flares. During these periods, the patient typically feels well, without overt joint pain or inflammation. However, it is crucial to understand that the underlying pathophysiology is not quiescent. Hyperuricemia usually persists, MSU crystal deposition continues within joints and tissues, and evidence suggests that subclinical, low-grade inflammation may persist in affected joints. Indeed, MSU crystals can often be identified in synovial fluid aspirated from previously affected joints even during these asymptomatic periods. Without effective long-term ULT, the duration of these intercritical periods tends to shorten over time, leading to more frequent flares.

Chronic Tophaceous Gout and Gouty Arthropathy

If gout remains untreated or undertreated for extended periods (often years), it can progress to a chronic, destructive stage characterized by the formation of tophi and the development of chronic gouty arthropathy. This advanced stage reflects a substantial and persistent burden of MSU crystal deposition.

• Tophi: These are macroscopic aggregates of MSU crystals embedded within a granulomatous inflammatory matrix. Clinically, they appear as firm, often irregular, subcutaneous or deeper nodules, typically yellowish or white in color. While often painless themselves, they can become secondarily inflamed, tender, ulcerate through the skin (discharging a chalky, white material consisting of MSU crystals), and become infected. Common sites for tophi include the periarticular tissues of the fingers, hands, toes, feet, elbows, and knees; the helix or antihelix of the ear; bursae (especially olecranon and prepatellar); and tendons (classically the Achilles tendon). Rare locations include the eyes, heart valves, kidneys, and lungs. The presence of tophi signifies a large total body urate burden and long-standing, inadequately controlled disease.
• Chronic Gouty Arthropathy: This refers to the persistent joint damage and functional impairment resulting from chronic inflammation, tophaceous infiltration, and bone and cartilage erosion. Patients experience chronic pain (which may be less intense than acute flares but more persistent), stiffness, joint swelling, reduced range of motion, and eventual joint deformity. Radiographically, characteristic erosions and joint space changes become evident (see Investigations section). Clinically, chronic gouty arthropathy can sometimes mimic other chronic inflammatory joint diseases like RA or erosive osteoarthritis. The broad clinical spectrum, from asymptomatic deposition to destructive arthropathy, emphasizes that management must focus on eliminating the underlying crystal burden through long-term ULT, rather than solely addressing acute symptoms.

Extra-articular Manifestations

While primarily an articular disease, the consequences of MSU crystal deposition can extend beyond the joints:

• Renal Manifestations: Uric acid nephrolithiasis (kidney stones) is common in individuals with gout, particularly those who overproduce uric acid or have persistently acidic urine. Chronic urate nephropathy, characterized by MSU crystal deposition in the renal interstitium leading to inflammation, fibrosis, and progressive renal impairment, can also occur, although its prevalence and clinical significance relative to other causes of CKD in gout patients are debated. Acute uric acid nephropathy, causing acute kidney injury due to precipitation of uric acid crystals in tubules, is typically seen in the context of massive urate overproduction, such as tumor lysis syndrome.
• Ocular Manifestations: Though uncommon, MSU crystals can deposit in various ocular structures, leading to tophi on the conjunctiva or sclera, band keratopathy, blurred vision, or rarely, inflammatory conditions like uveitis or scleritis.
• Neurological Manifestations: Tophi can occasionally cause nerve compression syndromes (e.g., carpal tunnel syndrome if involving the wrist) or, very rarely, spinal cord impingement if deposited in spinal structures.

Other: Pathological fractures may occur through bones weakened by large tophaceous deposits.

Clinical Assessment

History

Key elements to elicit include the characteristics of symptomatic episodes, the pattern of joint involvement, potential triggers, associated risk factors, and evidence of chronic disease or complications.

The description of the symptomatic episodes is often highly informative. Clinicians should inquire about the speed of onset, seeking descriptions of pain developing rapidly, often overnight, and reaching maximal intensity within 24 hours. The severity of pain should be explored; descriptions of excruciating, unbearable pain are typical. Associated inflammatory signs like overt redness, swelling, and warmth should be documented. The duration of untreated episodes (typically resolving within 1-2 weeks) and, crucially, the presence of completely asymptomatic periods between attacks (intercritical periods) are characteristic features of early gout. Asking about previous similar episodes, even if milder or attributed to other causes, is essential. The temporal pattern of abrupt onset, rapid peak intensity, and complete resolution between early episodes provides strong diagnostic clues that can help differentiate gout from conditions with a more insidious onset or persistent symptoms, such as osteoarthritis or rheumatoid arthritis.

The specific location and pattern of joint involvement are also critical. Direct questioning about involvement of the first MTP joint (podagra) is vital, given its high frequency in gout. Inquiry should extend to other common sites like the midfoot, ankle, knee, wrist, elbow, and fingers. Determining whether attacks are typically monoarticular or polyarticular, and whether involvement is symmetrical or asymmetrical, helps refine the differential diagnosis.

Identifying potential triggers for the most recent or previous flares can provide supportive evidence. Patients should be asked about recent changes in alcohol consumption, dietary intake (particularly purine-rich foods), hydration status, recent trauma or surgery, initiation of new medications (especially diuretics or ULT), or intercurrent illness.

A systematic review of risk factors is necessary. This includes inquiring about a family history of gout or hyperuricemia, known personal history of elevated uric acid levels, typical dietary patterns, alcohol use, current medications with potential to affect urate levels, and the presence of relevant comorbidities such as CKD, hypertension, diabetes, obesity, or established cardiovascular disease.

Finally, the history should explore evidence of chronic gout or complications. This includes asking about persistent joint pain or stiffness between flares, the presence of noticeable lumps or nodules under the skin (potential tophi), particularly around joints or on the ears, and any history of kidney stones.

Examination

Physical examination findings in gout vary depending on the stage of the disease, ranging from dramatic acute inflammation to the subtle or overt signs of chronic disease.

Acute Flare Findings

During an acute gout flare, the physical examination is typically dominated by signs of intense, localized inflammation in the affected joint(s). Observation reveals marked erythema, which can be striking and may extend beyond the joint margins, sometimes mimicking cellulitis. Significant swelling due to synovial effusion and periarticular edema is usually present. Palpation confirms localized warmth over the joint and, most characteristically, exquisite tenderness – often the patient cannot tolerate even light pressure on the affected area.

Assessment of range of motion typically demonstrates severe limitation, primarily due to pain and swelling. Examination should include assessment for systemic signs such as fever, although this is non-specific and can also be present in septic arthritis. It is important to examine other joints to ascertain whether the presentation is monoarticular or polyarticular.

Chronic Tophaceous Gout Findings

In patients with chronic or advanced gout, the examination focuses on identifying signs of cumulative crystal deposition and resultant joint damage. The pathognomonic finding is the presence of tophi. These should be sought by careful inspection and palpation in characteristic locations: the helix or antihelix of the ears, extensor surfaces of joints (especially fingers, toes, elbows, knees), olecranon and prepatellar bursae, and along tendons, particularly the Achilles. Tophi typically feel firm or rubbery and are usually non-tender unless acutely inflamed. The overlying skin may be thin, stretched, or show visible yellowish-white deposits beneath the surface. Evidence of draining sinuses, ulceration, or secondary infection should be noted.

Examination of the joints may reveal signs of chronic gouty arthropathy, including persistent swelling (synovitis or effusion), tenderness (often less severe than during an acute flare), joint deformity, reduced range of motion, or crepitus on movement. The pattern of joint involvement should be assessed. The physical findings in acute gout are dramatically inflammatory, whereas the chronic stage is defined by the presence of tophi and structural joint changes. Identifying tophi is not only diagnostic for gout but also signifies a high urate burden and long-standing disease, mandating aggressive ULT with lower SUA targets to facilitate crystal dissolution and prevent further damage. The examination should also include assessment for signs related to common comorbidities, such as peripheral edema (heart failure, CKD) or peripheral neuropathy (diabetes).

Investigations

A range of investigations can aid in the diagnosis and management of gout, from the gold standard synovial fluid analysis to blood tests and various imaging modalities.

Synovial Fluid Analysis

The definitive diagnosis of gout rests upon the identification of MSU crystals in fluid aspirated aseptically from an affected joint or a tophus. Even minute quantities of fluid are often sufficient for analysis. The aspirated fluid should ideally be examined promptly (within 24-48 hours) using compensated polarized light microscopy.

Under compensated polarized light, MSU crystals exhibit characteristic morphology and birefringence. They appear as needle-shaped or rod-shaped crystals, typically ranging from 2 to 20 µm in length. Crucially, they demonstrate strong negative birefringence: they appear bright yellow when their long axis is aligned parallel to the axis of slow vibration of the first-order red compensator plate, and blue when aligned perpendicular to it. During an acute flare, these crystals are often seen within the cytoplasm of neutrophils (intracellular), reflecting active phagocytosis, although extracellular crystals are also typically present. MSU crystals can also be identified in fluid aspirated from asymptomatic joints during the intercritical period, where they are usually extracellular.

Synovial fluid from a gout flare is typically inflammatory in nature. Grossly, it appears cloudy or turbid and yellow, with reduced viscosity. Cell counts are elevated, usually ranging from 10,000 to 70,000 white blood cells (WBCs)/µL, although counts can sometimes exceed 100,000/µL. There is a predominance of neutrophils.

Despite being the gold standard, synovial fluid analysis has limitations. Arthrocentesis is an invasive procedure, may be technically challenging for certain joints (e.g., small joints of the hands/feet, axial joints), and is not always performed, particularly in primary care settings. The sensitivity for detecting crystals, while generally high (reported around 84-90%), is not absolute. False-negative results can occur, especially if the aspiration is performed very early in a flare before significant crystal shedding into the fluid, if the sample volume is inadequate, or due to technical issues with microscopy or observer experience. Accurate interpretation requires expertise to distinguish MSU crystals from other birefringent particles, such as calcium pyrophosphate (CPPD) crystals (which are typically rhomboid-shaped and positively birefringent), cholesterol crystals, lipid droplets, or artifacts like corticosteroid crystals from prior injections or microscopic debris. Observer variability in crystal identification has been documented. Perhaps most critically, the presence of MSU crystals does not exclude concomitant septic arthritis. Therefore, if there is any clinical suspicion of infection, the synovial fluid must also be sent for Gram stain and bacterial culture.

Serum Urate Measurement

Measurement of SUA is essential for assessing the underlying biochemical abnormality, determining gout risk, establishing a baseline before initiating ULT, and monitoring the therapeutic response to ensure target levels are achieved and maintained. However, its utility for diagnosing an acute gout flare is limited and potentially misleading.

A significant proportion of patients experiencing an acute gout flare will have SUA levels within the normal range or even below normal at the time of presentation – a phenomenon termed normouricemic gout. Studies report normouricemia during flares in 12% to as high as 63% of cases. The presumed mechanism involves the systemic inflammatory response during the flare; pro-inflammatory cytokines such as IL-1β and IL-6 may increase renal urate excretion, potentially mediated via adrenocorticotropic hormone (ACTH) and cortisol release, which have uricosuric effects. Consequently, a normal or low SUA level measured during an acute attack does not rule out the diagnosis of gout. It is recommended practice to repeat the SUA measurement 2 to 4 weeks after the flare has completely resolved to establish the patient's true baseline (intercritical) urate level. This paradoxical drop in SUA during flares represents a critical diagnostic pitfall, emphasizing the need to integrate the entire clinical picture and avoid relying solely on a single SUA measurement during an acute episode.

While not diagnostic in isolation during a flare, the presence of hyperuricemia, particularly at higher levels (e.g., >0.48 mmol/L or 8 mg/dL), measured during an intercritical period, provides strong supportive evidence for gout and contributes significantly to the score in classification criteria when crystal confirmation is lacking.

Imaging Findings

Imaging plays an increasingly important role in the diagnosis, assessment of severity, and monitoring of gout.

• Radiography (X-ray): Conventional radiographs are often normal in early gout or during the first few acute flares, potentially showing only non-specific soft tissue swelling. Their primary value lies in detecting the characteristic structural changes associated with chronic tophaceous gout, which typically take several years (often 6-12 years) to become apparent. Radiography helps assess the extent of joint damage and can aid in differentiating gout from other chronic arthropathies. Classic radiographic features of chronic gout include :
  • Well-defined, "punched-out" erosions with sclerotic margins, often located juxta-articularly or para-articularly.
  • Characteristic overhanging edges of bone adjacent to erosions, sometimes described as a "rat bite" appearance.
  • Relative preservation of the joint space until late in the disease process.
  • Absence of significant periarticular osteopenia (a feature distinguishing it from RA).
  • Asymmetric distribution, typically favouring distal joints of the lower extremities.
  • Visible soft tissue masses corresponding to tophi, which may occasionally show calcification, particularly in patients with coexisting CKD.

• Ultrasound (US): Musculoskeletal US has emerged as a valuable tool for gout diagnosis and assessment, offering several advantages including non-invasiveness, lack of ionizing radiation, relatively low cost, wide availability, and the ability to visualize soft tissues and crystal deposition in real-time. US is particularly useful when synovial fluid aspiration is difficult, unsuccessful, or contraindicated, and it can detect characteristic features even in early disease or during intercritical periods. Its utility is recognized by its inclusion as a diagnostic domain in the 2015 ACR/EULAR classification criteria. Specific US findings suggestive of gout, defined by the Outcome Measures in Rheumatology (OMERACT) US working group, include:
  • Double Contour (DC) Sign: This is considered the most specific US sign for gout. It appears as an abnormal hyperechoic (bright), irregular line of MSU crystal deposition on the surface of the hyaline articular cartilage, running parallel to the underlying hyperechoic line of the subchondral bone cortex. It must be distinguished from the normal cartilage interface sign (an artifact seen with perpendicular insonation) and from the intra-cartilaginous deposition seen in CPPD. The DC sign may diminish or disappear with effective ULT. Common sites include the first MTP joint and the femoral condyles.
  • Tophi: Appear as heterogeneous masses of varying echogenicity (hyperechoic or mixed), often described as having a "wet clumps of sugar" appearance. They may be surrounded by a small anechoic (dark) rim. Tophi can be located intra-articularly, within synovial tissue, periarticularly, within bursae, or within tendons.
  • Aggregates / "Snowstorm" Appearance: This refers to the presence of mobile, hyperechoic foci floating within synovial fluid or embedded within hypertrophied synovium, representing aggregates of MSU microcrystals or microtophi.
  • Erosions: US is more sensitive than radiography for detecting early bone erosions. Gouty erosions appear as cortical breaks visualized in two perpendicular planes, often located adjacent to tophaceous deposits.

In addition to these specific signs, US can also detect non-specific signs of inflammation, such as synovial hypertrophy, joint effusion, and increased vascularity on power Doppler imaging. The diagnostic accuracy of US depends on the specific features assessed and the operator's experience. While the DC sign is highly specific, its sensitivity may be lower than that of tophi detection. Combining multiple features improves overall accuracy.

• Dual-Energy Computed Tomography (DECT): DECT is a more advanced imaging technique that utilizes the differential attenuation of X-rays at two distinct energy levels (e.g., 80 kVp and 140/150 kVp) to differentiate materials based on their atomic composition. It can specifically identify and quantify MSU deposits, distinguishing them from calcium-containing structures (bone, calcifications, CPPD crystals) and soft tissues. Post-processing software typically color-codes MSU deposits (often green) for visualization. DECT is highly specific for detecting urate and is particularly valuable in diagnostically challenging situations, such as when arthrocentesis is negative or inconclusive, or in patients with atypical presentations. It provides a non-invasive method to confirm the presence of urate deposition and assess the total body urate burden. Like US, DECT evidence of urate deposition is included in the ACR/EULAR 2015 classification criteria. Studies have reported good diagnostic performance, with sensitivities around 90% and specificities ranging from 83% to 100%. However, sensitivity might be lower in patients with very recent onset or acute disease. Interpretation requires awareness of potential artifacts (e.g., beam hardening, nail bed artifacts, motion) that can mimic urate deposits. There is ongoing discussion regarding the optimal volume threshold for defining a positive scan. DECT can also be used to monitor the reduction of urate deposits in response to ULT.
• Magnetic Resonance Imaging (MRI): MRI is not a primary tool for diagnosing gout. While it can visualize tophi (which typically show intermediate signal intensity on T1- and T2-weighted images with variable post-contrast enhancement), synovitis, bone marrow edema, erosions, and cartilage damage, these findings are often non-specific. MRI may be useful in selected cases to assess the extent of soft tissue involvement, evaluate for complications like tendon rupture or nerve impingement, or help differentiate gout from other conditions (e.g., infection, tumor) when the diagnosis remains uncertain after other investigations.

The evolving diagnostic armamentarium, particularly the integration of US and DECT, signifies a shift towards a more multi-modal approach. While synovial fluid analysis remains the benchmark, the limitations in its practical application have paved the way for these advanced imaging techniques to play a crucial role, especially in challenging cases, allowing for accurate diagnosis even when crystals cannot be directly visualized. Furthermore, the ability of US and DECT to detect subclinical crystal deposition highlights the continuous nature of the underlying pathology, even during asymptomatic periods, potentially informing future strategies for risk stratification and treatment monitoring.

Other Investigations

• Inflammatory Markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are usually elevated during acute gout flares, reflecting systemic inflammation, but these are non-specific markers and can be raised in many other inflammatory or infectious conditions. They may help distinguish inflammatory from non-inflammatory joint pain but do not specifically diagnose gout.
• Blood Counts: A complete blood count (CBC) often shows leukocytosis with a neutrophilic predominance during acute attacks. The CBC is also important for assessing baseline hematologic status and screening for potential comorbidities or alternative diagnoses (e.g., anemia, myeloproliferative disorders).
• Renal Function Tests: Assessment of renal function (e.g., serum creatinine and estimated glomerular filtration rate) is essential at baseline and periodically thereafter. This is crucial for several reasons: CKD is a major risk factor for and comorbidity of gout; renal function dictates the safe use and dosing of many medications used to treat gout (NSAIDs, colchicine, allopurinol); and monitoring is needed to detect potential urate nephropathy.
• Liver Function Tests (LFTs): Baseline LFTs are advisable before starting ULT, particularly febuxostat, which carries a risk of hepatotoxicity. They may also be relevant given the association between gout and non-alcoholic fatty liver disease.
• Metabolic Profile: Measuring fasting blood glucose and lipid levels is recommended to screen for commonly associated comorbidities like diabetes mellitus and dyslipidemia.
• 24-hour Urinary Uric Acid Excretion: This test, historically used to classify patients as "overproducers" (>800 mg or ~4.8 mmol/24h) or "underexcretors" of uric acid, is now rarely performed in routine clinical practice. The advent of highly effective xanthine oxidase inhibitors (XOIs) like allopurinol and febuxostat, which are effective regardless of the underlying mechanism, has diminished its clinical utility for guiding therapy selection. It might still be considered in specific circumstances, such as patients with very early onset gout (e.g., <25 years old), a strong family history suggestive of an inherited disorder, recurrent nephrolithiasis, or when considering the use of uricosuric agents.

Diagnosis

Considerations

The diagnostic process typically follows a stepwise approach:

Clinical Suspicion: The process begins with a clinical suspicion based on the patient's history and physical examination. A history of recurrent, rapid-onset, intensely painful monoarthritis, particularly involving the first MTP joint (podagra), coupled with characteristic inflammatory signs on examination (erythema, swelling, warmth, tenderness), strongly suggests gout. The presence of known risk factors (e.g., male sex, older age, obesity, relevant comorbidities, diuretic use, family history) further increases the likelihood.

Confirmation via Crystal Identification (Gold Standard): Whenever feasible and clinically indicated (especially if septic arthritis is suspected or the diagnosis is uncertain), arthrocentesis of the affected joint (or aspiration of a suspected tophus) should be performed. The definitive diagnosis is established by identifying the characteristic needle-shaped, negatively birefringent MSU crystals in the synovial fluid or tophaceous material using compensated polarized light microscopy. If clinically indicated, the aspirate should also be sent for gram stain to exclude infection.

Alternative / Supportive Evidence: When synovial fluid analysis is not possible, non-diagnostic, or negative despite strong clinical suspicion, the diagnosis relies on a combination of other findings:

• Serum Urate Level: Measurement during an intercritical period (ideally ≥2 weeks post-flare) is crucial. Hyperuricemia provides strong supportive evidence.
• Imaging: Advanced imaging modalities play a key role here. US demonstrating a double contour sign or tophi, or DECT showing urate deposition, provides strong evidence for gout. Characteristic erosions on radiography support chronic gout but are insensitive early on.²⁷
• Clinical Criteria: Applying validated classification criteria, such as the ACR/EULAR 2015 criteria, can formally integrate clinical, laboratory, and imaging findings to classify a patient as having gout.

Therapeutic Response: While a rapid response to colchicine or NSAIDs is suggestive, it is not specific enough for definitive diagnosis.

ACR/EULAR Criteria

The structure of the ACR/EULAR 2015 criteria is as follows:

Entry Criterion: The patient must have experienced at least one episode of peripheral joint or bursal swelling, pain, or tenderness. If this criterion is not met, the criteria cannot be applied.

Sufficient Criterion: The presence of MSU crystals in a symptomatic joint/bursa (identified via synovial fluid analysis) or within a tophus (identified via aspirate analysis) is sufficient on its own to classify the patient as having gout. No further scoring is required if this criterion is met.

Scoring System (Applied if Sufficient Criterion is Not Met): If MSU crystals are not demonstrated, points are assigned based on features across clinical, laboratory, and imaging domains. A total score of ≥ 8 points classifies the patient as having gout.

Clinical Domains:

• Pattern of Joint/Bursa Involvement: Ankle or midfoot involvement during a symptomatic episode = 1 point; First MTP joint involvement = 2 points.
• Characteristics of Symptomatic Episodes: Erythema overlying affected joint = 1 point; Cannot bear touch/pressure on affected joint = 1 point; Difficulty walking or using affected joint = 1 point; Time course (presence of ≥2 of: time to maximal pain <24h, resolution of symptoms in ≤14 days, complete resolution between episodes) = 1 point for one typical episode, 2 points for recurrent typical episodes.
• Clinical Evidence of Tophus: Presence of a draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, typically on joints, ears, olecranon bursa, or tendons = 4 points.

Laboratory Domains:

• Serum Urate Level: Measured ideally during an intercritical period by uricase method. <4 mg/dL (<0.24 mmol/L) = -4 points; 4 to <6 mg/dL (0.24 to <0.36 mmol/L) = 0 points; 6 to <8 mg/dL (0.36 to <0.48 mmol/L) = 2 points; 8 to <10 mg/dL (0.48 to <0.60 mmol/L) = 3 points; ≥10 mg/dL (≥0.60 mmol/L) = 4 points.
• Synovial Fluid Analysis: If performed and MSU crystals are not found = -2 points.

Imaging Domains:

• Ultrasound: Evidence of double contour sign = 4 points.
• DECT: Evidence of urate deposition in the symptomatic joint/bursa = 4 points.
• Radiography: Evidence of gout-related bone erosion (defined as erosion with sclerotic margin and overhanging edge, excluding DIP joints and gull-wing appearance) on plain radiographs of hands or feet = 4 points.

(Note: Only the highest score within the joint involvement pattern is counted. Only one imaging modality demonstrating urate deposition (US or DECT) or damage (radiography) counts towards the score).

Challenges

Several common scenarios pose diagnostic challenges:

Diagnosing Gout with Normal Serum Urate: As previously discussed, SUA levels can be paradoxically normal or low during an acute flare. In such cases, diagnosis cannot rely on the contemporaneous SUA level. The options are:

• Confirm diagnosis via synovial fluid crystal identification.
• Repeat SUA measurement 2-4 weeks after the flare resolves to establish the baseline level.
• Utilize the ACR/EULAR criteria, relying on clinical features, imaging findings (US/DECT), and the intercritical SUA level if available.

Diagnosing Gout with Negative Synovial Fluid Analysis: A negative aspirate does not definitively rule out gout. Potential reasons include sampling too early in the flare, insufficient fluid volume, low crystal concentration, or technical/interpretive error. Management options include:

• Repeating the arthrocentesis at a later time or from a different affected joint.
• Relying on the combination of strong clinical suspicion and supportive evidence from the ACR/EULAR criteria, particularly positive findings on advanced imaging (US or DECT) which can directly visualize urate deposits. DECT, in particular, has shown diagnostic yield in patients with suspected gout but negative microscopy.

Diagnosing Gout with Atypical Presentations: When gout presents polyarticularly, in upper limb joints, or axially, the clinical picture may overlap significantly with other conditions. In these instances, synovial fluid analysis (if feasible) or advanced imaging (US/DECT) becomes particularly crucial for confirming urate deposition and differentiating from mimics like RA, PsA, or infection.

The successful diagnosis of gout, especially in challenging scenarios like normouricemic flares or negative aspirates, requires a nuanced approach that moves beyond reliance on single tests. It involves careful clinical pattern recognition, judicious use of the validated ACR/EULAR classification criteria, and the strategic incorporation of advanced imaging modalities like US and DECT, all underpinned by sound clinical judgment.

Differential Diagnosis

The main differential diagnoses in the setting of an acute monoarthritis are septic arthritis and CPPD.

Septic Arthritis: Clinical presentation can be indistinguishable from an acute gout flare, with a hot, red, swollen, and exquisitely painful joint, often accompanied by fever and systemic malaise. Risk factors include advanced age, pre-existing joint disease (RA, OA), prosthetic joints, diabetes, immunosuppression, IV drug use, and recent skin infection or surgery. Synovial fluid analysis is paramount: while WBC counts are typically very high (>50,000/µL, often >100,000/µL with neutrophil predominance), there is significant overlap with severe gout flares. Positive Gram stain (sensitivity ~50%) or culture (~90% sensitive for non-gonococcal) confirms infection. Importantly, gout and septic arthritis can coexist in the same joint (~1.5% of cases); therefore, finding MSU crystals does not rule out infection, and microbiological studies are mandatory if sepsis is suspected. Calcium Pyrophosphate Deposition (CPPD) Disease (Pseudogout): Caused by the deposition of CPPD crystals, pseudogout can present with acute flares of synovitis that closely mimic gout. It often affects larger joints like the knee and wrist more commonly than gout, but involvement of the first MTP joint can occur. Diagnosis is confirmed by identifying weakly positively birefringent, rhomboid- or rod-shaped CPPD crystals in synovial fluid. Radiographs may show characteristic chondrocalcinosis (calcification of hyaline or fibrocartilage), although this is not always present. US can help differentiate by showing CPPD crystal deposition within the cartilage layer, as opposed to the superficial deposition (DC sign) seen in gout.

Table 2: Differential Diagnosis of Acute Monoarthritis

Feature	Gout	Septic Arthritis	CPPD (Pseudogout)
Typical Joint(s)	1st MTP (Podagra), Midfoot, Ankle, Knee	Knee, Hip, Shoulder, Wrist (Large joints common)	Knee, Wrist, Shoulder, Ankle (Large joints common); can affect 1st MTP
Onset Speed	Rapid (<24 hours)	Rapid (hours to days)	Rapid (similar to gout) or Subacute
Systemic Symptoms (Fever)	Can occur, especially polyarticular	Common, often with chills/malaise	Less common than septic arthritis
Synovial Fluid WBC (/µL)	Inflammatory (10k-70k, can be >100k)	Highly Inflammatory/Purulent (>50k, often >100k)	Inflammatory (often 5k-50k, can overlap with gout/sepsis)
Synovial Fluid Gram Stain	Negative	Positive in ~50% (non-gonococcal)	Negative
Synovial Fluid Culture	Negative	Positive in ~90% (non-gonococcal); lower for gonococcal	Negative
Crystal Analysis	Negatively birefringent	No crystals unless comorbid for gout	Positively birefringent

Management

Urate Lowering Therapy

The cornerstone of gout management lies in the long-term control of serum urate levels through sustained urate-lowering therapy (ULT). Indications for commencing ULT are recurrent flares (generally two or more a year) and include the presence of tophi, chronic gouty arthritis, radiographic joint damage, and early-onset disease with serum urate persistently above 0.60 mmol/L. In contrast, asymptomatic hyperuricemia alone does not warrant pharmacological intervention, given the lack of evidence for benefit in this population.

Targets: The overarching aim is to achieve and maintain a serum urate concentration below the saturation threshold for monosodium urate crystal formation - typically less than 0.36 mmol/L, or less than 0.30 mmol/L in the presence of tophi. Achieving this biochemical target not only prevents future flares but also facilitates gradual dissolution of existing crystal deposits, thereby halting disease progression.

Allopurinol: First-line pharmacological therapy remains allopurinol, a xanthine oxidase inhibitor. Allopurinol can be safely started during an acute flare, provided it is commenced at a low dose and co-prescribed with anti-inflammatory prophylaxis to mitigate flare precipitation. The initial dose and titration schedule should be tailored to renal function: doses as low as 50 mg on alternate days may be appropriate in patients with impaired renal clearance, with gradual escalation until target serum urate is achieved or the maximum tolerated dose is reached.

Monitoring includes regular assessment of serum urate and renal function during the dose escalation phase, alongside periodic full blood count and liver function tests.

Second line options: In cases where allopurinol is not tolerated or fails to achieve target urate levels despite appropriate dosing, alternative therapies include febuxostat or probenecid.

• Febuxostat may be considered in patients with allopurinol hypersensitivity or intolerance, though caution is warranted in those with significant cardiovascular comorbidities.
• Probenecid, a uricosuric agent, is suitable for patients with preserved renal function and no history of nephrolithiasis but requires high fluid intake to mitigate the risk of stone formation.

Prophylaxis: During the initiation of ULT, patients should receive prophylaxis against flares for at least 3 to 6 months. Options include colchicine (0.5 mg daily or twice daily, with caution in renal impairment), low-dose NSAIDs, or prednisone. Education on the narrow therapeutic margin of colchicine is essential, as is vigilance for drug interactions and gastrointestinal intolerance.

Monitoring: A treat-to-target strategy underpins effective gout management. This involves monthly monitoring of serum urate until the target is achieved, followed by maintenance testing every 6 to 12 months. Patients should be advised that flares may persist for over a year despite reaching target urate levels, and resolution of tophi may take several years. Failure to respond despite biochemical control should prompt reassurance and review of adherence. For those with persistent disease activity, referral for specialist input may be warranted.

Acute Flares

Management of acute gout flares should prioritise rapid symptom relief using anti-inflammatory agents tailored to the individual’s comorbidities and renal function. NSAIDs, colchicine, or corticosteroids are the mainstays. If the patient is already on allopurinol or another ULT without interruption, it should be continued during the flare. Poor response to treatment should prompt reconsideration of the diagnosis and, if not previously performed, joint aspiration to confirm the presence of crystals and exclude infection. Persistent or atypical presentations, including flares lasting longer than two weeks or involving unusual joint distributions, should prompt rheumatology referral.

Other Considerations

Attention must also be paid to health inequities, particularly among Māori and Pacific peoples in Aotearoa New Zealand, who are disproportionately affected by gout yet less likely to receive regular ULT.

Lifestyle modification, though often insufficient on its own to achieve biochemical targets, should be encouraged. Patients should be supported to reduce alcohol and purine-rich food intake, optimise hydration, and manage weight. Concurrently, clinicians should screen for and manage associated comorbidities, including hypertension, diabetes, dyslipidaemia, obesity, cardiovascular disease, and renal impairment.

Resources

Imaging of Gout - Szopinska 2020.pdf - 4.67 MB (f)

Gout 2015 ACR EULAR Criteria.pdf - 1.05 MB (f)

ACR/EULAR Criteria Calculator

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,