Gout is a life-long, recurrent metabolic disorder considered to be type of arthritis, with both acute exacerbations and chronic joint damage and pain. Usually, the acute exacerbation of gout is associated with a rapid onset of severe pain and swelling in the joints. Most commonly affecting the big toe, inflammation and arthritic changes may also affect the heel, ankle, hand, wrist, or elbows, among other places in the body. Gout can affect the spine and can be a factor in low back pain.¹
While several studies have assessed the frequency of acute gout flares, many factors will affect how often flares occur including the number of prior gout attacks, treatment compliance, patient’s BMI, diet, and others.²⁻⁴
Prevalence of Gout
In terms of prevalence, gout is the most common form of inflammatory arthritis and appears to be growing globally. Data that show that gout affects 3.9% (9.2 million) of the adult population in the United States.⁵
Worldwide, in 2017, there were approximately 41.2 million prevalent cases of gout, with 7.4 million incident cases per year and almost 1.3 million years lived with disability. Gout was highest in developed regions and countries, with the highest age‐standardized point in New Zealand, Australia, and the US. The US, Canada, and Oman had the highest increases in age‐standardized point prevalence estimates of gout from 1990 to 2017, with increases of 34.7%, 28.5%, and 28.0%, respectively.⁶
Causes of Gout
Gout is caused by the chronic deposition of monosodium urate crystals which form in the presence of increased urate concentrations¹ In its initial stages, the condition is recognized by acute, intermittent episodes of synovitis presenting with joint swelling and pain (also termed acute gouty arthritis, an acute gout attack, or an acute gout flare).⁷ Monosodium urate crystals may directly stimulate the inflammasome in leukocytes, causing an acute inflammatory attack.⁸ Should the cumulative joint damage from repetitive acute exacerbations become significant, permanent remodeling of the joint can lead to chronic pain and dysfunction. The time between flares is referred to as the inter-critical period.
Uric acid is metabolized by the uricase enzyme. Genetic analysis of primates suggests that in apes, uricase function became negligible during the Eocene and early Miocene eras, approximately 17 million years ago. This “pseudogenization” or inactivation of uricase due to parallel nonsense gene mutations theoretically allowed early primates to experience an enhanced conversion of fructose to fat, thus enhancing survivability. Side effects of this potentially include the development of metabolic syndrome and diabetes mellitus type II.⁹
Uric acid is the result of purine metabolism, which mainly occurs in the liver. Uric acid is primarily excreted (about two-thirds) by the kidneys while the remainder is excreted into the intestine.
Risk Factors for Gout
Diet and Obesity
A 2019 study using population data found that “BMI, alcohol intake, adherence to a DASH‐style diet, and diuretic use were all associated with serum urate levels and the presence of hyperuricemia in a dose‐dependent manner.”¹⁰
Another review in 2013, based on the National Health and Nutrition Examination Surveys, found that: In the US, the crude prevalence of gout was 1–2% among participants with a normal BMI (18.5–24.9 kg/²), 3% among overweight participants, 4–5% with class I obesity, and 5–7% with class II or class III obesity. The adjusted prevalence ratio comparing the highest to a normal BMI category was 2.46 (95% CI: 1.44, 4.21) in 1988–1994, and 2.21 (95% CI: 1.50, 3.26) in 2007–2010. Notably, there was a progressively greater prevalence ratio of gout associated with successively higher categories of BMI.¹¹
Purine-rich diets are known to contribute to hyperuricemia and include foods such as meat, especially organ meats, game meats, certain seafood, beer, and fruit.¹² In addition, the increased consumption of fructose, especially high fructose corn syrup has been linked to increased hyperuricemia and associated conditions such as diabetes mellitus type II and coronary artery disease. Fructose consumption is known to trigger uric acid production by increasing the degradation of ATP to AMP, a uric acid precursor, and contributing to a rise in uric acid within minutes. In addition, fructose consumption also increases uric acid concentration through de novo purine synthesis.¹³
Identifying dietary risk factors for gout has been an area of interest in medicine since antiquity. A systematic review of the literature performed in 2014 showed: Alcohol consumption increased the risk of incident gout, especially beer and hard liquor. Several dietary factors increased the risk of incident gout, including meat intake, seafood intake, sugar-sweetened soft drinks, and consumption of foods high in fructose. Diary intake, folate intake, and coffee consumption were each associated with a lower risk of incident gout and in some cases a lower rate of gout flares. Thiazide and loop diuretics were associated with a higher risk of incident gout and a higher rate of gout flares.
Related Risks
Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity, and early menopause were each associated with a higher risk of incident gout and/or gout flares.¹⁴
Associated Conditions of Risk for Developing Gout
There are a few disease states that put patients at higher risk of developing gout, each further described below:
hemochromatosis
hyperparathyroidism
hypomagnesemia secondary to Gitelman syndrome or Bartter syndrome
history of joint trauma
Hemochromatosis arthropathies are seen due to the excess iron storage altering the xanthine oxidase enzyme as well as uric acid production. Urate is created due to the byproduct of purine catabolism and it is a chelator for iron. In some instances, elevated serum uric acid levels have suggested iron elevation. Iron can increase the production of uric acid and cause monosodium urate crystals to form in joints which in turn generates a surplus of reactive oxidative species and puts the body under stress leading to further activation of gout arthropathy in hemochromatosis patients. It is important to realize that this relationship is a “consequence of the association of ferritin with inflammatory states.”¹⁵
Hyperparathyroidism is also associated with gout. A study showed that parathyroid hormone (PTH) was significantly positively associated with hyperuricemia. This study had adjusted for confounders like age, body mass index, ethnicity, vitamin D, BUN, and creatinine levels.¹⁶ In another study, 143 patients with primary hyperthyroidism had decreased uric acid levels status post parathyroidectomy, which provides evidence that elevated PTH may be associated with elevated serum uric acid levels.¹⁷
Hypomagnesemia more likely is associated with pseudogout, especially seen in patients with Bartter syndrome or Gitelman syndrome. These renal tubular defects cause renal loss of magnesium, and calcium crystal deposition is seen with these syndromes. The association was seen in patients who were undergoing kidney and liver transplantation. Synovial fluid and leukocyte count demonstrated calcium pyrophosphate dihydrate (CPPD) crystals mimicking pseudogout. This was seen with patients before transplantation with magnesium depletion.¹⁸
Joint trauma, such as stubbing the toe or repetitive physical activity such as hiking, is associated with gout as well. With mechanical agitation on joints, there can be increased monosodium urate crystals in joint spaces, therefore increasing the likelihood of gout attacks.¹⁹ It has been demonstrated that with trauma, there is intra-articular flaking of the urate crystals.²⁰
How to Diagnose Gout
Differential Diagnosis: Rheumatoid Arthritis and Osteoarthritis
Correctly diagnosing gout and differentiating it from other inflammatory arthritic conditions is critical to successful and timely treatment, as well as subsequent prevention. Gout should be differentiated from other forms of inflammatory arthritides, such as rheumatoid arthritis, septic arthritis, inflammatory episodes of osteoarthritis, and calcium pyrophosphate dihydrate crystal deposition disease (CPPD or pseudogout).
Aspiration and Imaging
While a uric acid serum concentration is often ordered to clinically differentiate an acute arthritic presentation (results above 7 mg/dL increases the likelihood of gout), the reference standard for diagnosing acute gout is joint aspiration with synovial fluid analysis for monosodium urate (MSR). Joint aspiration subjected to polarized light microscopy is especially critical when differentiating gout (uric acid deposition) from CPPD (calcium deposition).
Other diagnostic modalities that have been explored include ultrasound, standard X-ray, and dual-energy computed tomography (CT). However, most patients with gout are initially seen in primary care or emergency medicine settings, where such analysis is rarely performed.²¹
Additional diagnostic approaches include clinical algorithms developed by organizations such as the American College of Rheumatology,²² the American College of Physicians,²³ and the American Academy of Family Physicians.²⁴ Such algorithms incorporate patient history, clinical signs and symptoms, and serum lab testing in addition to ultrasonography, dual-energy computed tomography (DECT), computed tomography, and plain radiography.
Patient Presentation: Signs of Gout
Patients with gout tend to present with an inflammatory monoarthropathy, usually the great toe involving the metatarsophalangeal joint. The midfoot, ankle, knee, wrists, and finger joints can also be involved. Patients usually complain of excruciating pain in the affected joint with swelling, erythema, and tenderness to even slight palpation.
Typical onset is 6 to 24 hours, with pain lasting several days to 2 weeks. Triggers for gout attacks can include trauma, dehydration, acidosis, and rapid weight loss due to acute phase response. An important factor to consider in patients who have gout is their diet, especially alcohol, which can increase risk of gout attacks.²⁵
Treatment Options for Gout
In May 2020, the American College of Rheumatology issued a guideline for the long-term and acute management of gout.²² The guideline recommends:
indications and use of urate-lowering therapy (ULT) and long-term therapy
treatment of acute gout flares
lifestyle and medication recommendations
While management of chronic as well as acute flares of gout is often approached pharmacologically, a wide variety of therapeutic options for managing acute gout attacks, the life-long management of chronic gout/hyperuricemia, and the potential impacts on the patient’s comorbid conditions is available as shown in Table I.
In addition, lifestyle interventions can help to reduce risk of hyperuricemia and resultant development of gout including:
weight loss
decreased purine intake
increased omega-3 fatty acid intake
increased intake of low-fat dairy, coffee, tart cherries or cherry juice, quercetin, bromelain, and botanicals (Hibiscus).²⁹
Gout and Inflammatory Arthritis: A Patient Case and Discussion
A 65-year-old-male presented to the ED with sudden onset pain in his left toe. Patient reports having prior episodes in the past year but not as severe as this episode. On physical examination, he shows signs of tophi on his left foot. The first metatarsophalangeal joint is swollen, tender to palpation, and erythematous in nature. He has tried NSAIDs and acetaminophen without much improvement.³⁰
Laboratory results demonstrated joint synovial fluid with leukocytosis, an elevated CRP, and elevated serum uric acid. Foot X-rays illustrate soft tissue swelling around the 1st metatarsophalangeal joint. Arthrocentesis of his joint showed leukocyte count at 50,000 with > 50% polymorphonuclear cells and negative birefringent crystals. The patient was diagnosed with an acute gout attack and was discharged to home with colchicine and prednisone taper.²²
An arthrocentesis and synovial fluid analysis are important due to differentiation between gout, pseudogout, and septic joint. All three have different management options. An elevated CRP is a nonspecific marker that acknowledges the inflammation. CRP is an acute phase reactant in gout.³¹ Patients’ serum uric acid level must be obtained because it allows for better understanding of which treatment option to choose and how rigorous a treatment plan must be. Target serum uric acid level is < 6 mg/dL because a saturation level of uric acid of > 6.8 mg/dL can cause tophaceous and gouty attacks.³² X-rays are taken to determine the damage of uric acid crystals to surrounding joints.
For this 65-year-old male, colchicine and a prednisone taper are provided for treatment because he has used NSAIDs in the past with no improvement in pain. Usually, NSAIDs area first-line treatment for gout. Since the patient has also had previous gout attacks with no treatment, the prednisone will help decrease the inflammation. Prednisone can also be injected into the joint to further reduce inflammation. Colchicine can help decrease the uric acid levels.
This patient came back for a follow-up after a few weeks with resolved symptoms of gout. He was educated on diet adherence as well as possible allopurinol treatment in the future if his gout attacks resume.
Practical Takeaways
Long-term management for gout is significantly dependent upon the patient’s adherence to diet and compliance with medical treatment.
NSAIDs and colchicine are first-line treatment for gout. Corticosteroids are only used if NSAIDs show no improvement or are contraindicated.
Laboratory results including serum uric acid and synovial fluid analysis are important in differentiating between gout and pseudogout, as treatment options differ.
