uric acid crystals

What Are the Crystals That Cause Gout and Pseudogout?

By Rony Kampalath, MD
Updated on October 21, 2023
Medically reviewed by David Ozeri, MD

Crystal-induced arthropathies are medical conditions where microscopic crystals form within joint spaces, leading to inflammation and, over time, potential joint damage. The two most commonly recognized forms are gout and pseudogout. Gout, a prevalent disease, affects more than 3% of American adults and is specifically caused by the accumulation of monosodium urate (or uric acid) crystals. Pseudogout, also known as calcium pyrophosphate deposition (CPPD) disease, is similarly common, affecting approximately 3% of individuals in their 60s and as many as half of those in their 90s, and is caused by crystals of calcium pyrophosphate dihydrate.1,2 Although their underlying causes differ, the symptoms of gout and pseudogout can significantly overlap, a fact underscored by the descriptive name "pseudogout." Both conditions can manifest in various ways, ranging from being entirely asymptomatic to causing severe, debilitating illness, but importantly, they are treatable with specific, individualized medical approaches.

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Types of Crystals

Monosodium urate crystals, the primary culprits behind gout, derive from uric acid, a substance naturally present in the blood as a byproduct of purine metabolism. Normally, the body efficiently eliminates excess uric acid through the kidneys, which excrete it in urine, and to a lesser extent, via the gut. However, when kidney function becomes less efficient at clearing uric acid, or if metabolic disorders lead to its overproduction, uric acid levels in the blood can rise, creating an environment conducive to crystal formation. Dietary choices, particularly the consumption of purine-rich foods like meat and seafood, and alcohol intake can also influence serum uric acid levels. In contrast, calcium pyrophosphate dihydrate (CPPD) crystals, responsible for pseudogout, originate within the joint cartilage itself. Cartilage cells (chondrocytes) naturally produce pyrophosphate; for reasons not yet fully understood, its levels within the cartilage can abnormally increase, leading to CPPD crystal formation and deposition. Interestingly, clinical observations indicate that approximately 5% of patients diagnosed with gout also have coexisting CPPD crystals in their joints, highlighting a potential overlap between these conditions.

Causes

The formation of monosodium urate crystals in gout fundamentally requires persistently elevated levels of uric acid in the blood, a condition known as hyperuricemia. Uric acid is predominantly synthesized in the liver through the processing of purines, which are derived from both the body's internal metabolic processes and ingested foods. While most uric acid is effectively excreted by the kidneys and gut, the majority of hyperuricemia cases result from a reduced efficiency of uric acid excretion by the kidneys. Common conditions contributing to this renal inefficiency include obesity, chronic kidney disease, dehydration, and hypothyroidism. Less frequently, inherited genetic disorders can lead to either decreased uric acid excretion or increased uric acid production. Although dietary habits and lifestyle factors, historically linking gout to the "disease of kings" and rich foods, undeniably influence uric acid levels, an individual's genetic makeup likely exerts a more significant impact on their blood uric acid concentration.3 The causes of CPPD crystal formation in the joints, leading to pseudogout, are less comprehensively understood. However, contributing factors can include inherited predispositions, such as familial chondrocalcinosis, and joint trauma. Certain metabolic conditions, like hemochromatosis (excessive iron storage) and hyperparathyroidism (overactive parathyroid gland leading to high calcium), are also associated with the development of pseudogout, alongside some rare genetic disorders.

Symptoms and Complications

Gout exhibits diverse manifestations, affecting both joints and potentially the kidneys. It can lead to acute or chronic joint inflammation, accumulation of urate crystals in soft tissues forming tophi, kidney stones, or chronic kidney disease. General symptoms like fever or malaise may accompany acute flares. An acute gout flare-up is characterized by intense pain, redness, and swelling, usually affecting a single joint, most commonly the first metatarsophalangeal joint (at the base of the big toe) or the knee, though multiple joints can be involved. Triggers include trauma, surgery, starvation, dehydration, specific foods, alcohol, or certain drugs. While flares typically resolve within days or weeks, with asymptomatic periods in between, repeated attacks without proper management can become more frequent, last longer, and lead to chronic gout with irreversible long-term joint damage. Tophaceous gout involves solid, usually non-painful, uric acid collections forming in soft tissues around joints, tendons, bursae, or even ears, causing inflammation and tissue damage. Chronically elevated uric acid also significantly impacts kidneys, leading to uric acid kidney stones (causing flank pain or blood in urine) or chronic renal disease (chronic urate nephropathy), underscoring the systemic nature of gout.

Calcium pyrophosphate deposition (CPPD) disease, or pseudogout, similarly presents with variable symptoms, from asymptomatic states to acute or chronic disease. Acute CPPD attacks often affect larger joints, such as the knee, wrists, shoulders, ankles, feet, and elbows, and can be triggered by joint injury, surgery, or severe illness. Patients experience pain, redness, warmth, and decreased joint function, with symptoms typically resolving spontaneously within days or weeks. Chronic CPPD disease can mimic other forms of arthritis, frequently coexisting with or presenting similarly to degenerative osteoarthritis, which causes progressive joint degeneration. It can also imitate rheumatoid arthritis (RA), characterized by symptoms like morning stiffness, fatigue, and restricted joint motion affecting multiple limb joints, with inflammation that may wax and wane over months. Certain populations are at higher risk for pseudogout, including those with hemochromatosis, low magnesium levels, or hyperparathyroidism, which involves an overactive parathyroid gland leading to high blood calcium.4

Diagnosis

When an acute gout attack is suspected, a physician conducts a thorough assessment, combining patient history, physical examination findings, laboratory tests (such as blood uric acid levels), and X-rays. While elevated uric acid levels support suspicion, the definitive diagnosis of gout, especially during a first arthritis episode, relies on identifying monosodium urate crystals directly from the affected joint fluid. This is performed via arthrocentesis, a simple procedure to draw fluid from the joint. The joint fluid is then examined under polarized light microscopy, where gout crystals uniquely appear needle-shaped and yellow, a property known as negative birefringence. If crystal identification is not feasible, a clinical diagnosis of gout may still be made based on the patient's history, X-rays, and physical findings. For gout-related kidney stones, suspected due to flank pain or blood in urine, a CT scan can identify their presence and location. Subsequent analysis of passed stones, along with urine uric acid levels and pH, helps determine stone composition and guides treatment. Similarly, the diagnosis of CPPD disease ultimately hinges on identifying CPPD crystals in joint fluid. Under polarized light, CPPD crystals appear blue, exhibiting positive birefringence, which distinguishes them from gout crystals. Advanced imaging like SPECT CT and musculoskeletal ultrasound also aid in diagnosis. If crystal analysis is unavailable, CPPD disease can be strongly suspected based on clinical history and X-ray findings—particularly acute arthritis of large joints (e.g., knees), especially in patients over 65, and when mimicking osteoarthritis or rheumatoid arthritis.

Treatment

The primary objective in treating an acute gout attack is to rapidly reduce pain and inflammation. This is typically achieved using nonsteroidal anti-inflammatory drugs (NSAIDs), steroid medications, or colchicine, all of which can be given orally. The choice of medication is individualized, considering patient tolerance and any coexisting health conditions. For optimal efficacy, treatment should commence within 24 hours of symptom onset. For long-term management of chronic gout, the focus shifts to preventing future attacks by consistently lowering uric acid levels. This is achieved through medications that either reduce uric acid production, such as allopurinol and febuxostat, or those that increase its excretion via urine, like probenecid. In cases refractory to conventional treatments, pegloticase, a drug that actively breaks down uric acid, may be used.5 The decision to start uric acid-lowering therapy is highly individualized, based on factors like attack frequency, uric acid levels, and the presence of tophi. While crucial for long-term control, these therapies are not initiated during an acute flare, as they can paradoxically trigger or worsen an attack; anti-inflammatory medications are often co-prescribed during the initial phase. This therapy is usually lifelong, emphasizing the importance of adherence, complemented by dietary and lifestyle adjustments.

Treatment for pseudogout primarily aims to relieve symptoms during acute episodes. Similar to gout, acute attacks respond well to anti-inflammatory medications such as NSAIDs, steroids, or colchicine. If only one joint is affected, healthcare providers may drain fluid from the joint (arthrocentesis) and inject steroids directly into the joint space, offering rapid pain and inflammation relief. For patients experiencing frequent CPPD attacks, a low-dose daily regimen of colchicine may be prescribed as a preventative measure to reduce the number and severity of future episodes.

A Word From Verywell

Crystal-induced arthropathies, such as gout and CPPD disease, can cause considerable pain and functional impairment, significantly impacting an individual's quality of life. Fortunately, a comprehensive array of effective treatment options is available to manage these conditions. Successful management hinges on an individualized treatment approach, carefully tailored to the specific severity of the patient's disease, their symptoms, and the presence of any coexisting medical conditions that might influence therapeutic choices. We strongly encourage you to engage in an open and detailed discussion with your healthcare provider to determine the most appropriate and effective treatment plan aligned with your unique health profile and lifestyle needs.

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5 Sources
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  1. Elfishawi MM, Zleik N, Kvrgic Z, et al. The rising incidence of gout and the increasing burden of comorbidities: a population-based study over 20 years. J Rheumatol. 2018;45(4):574-579. doi:10.3899/jrheum.170806
  2. Harvard Health Publishing. Pseudogout (CPPD).
  3. Major TJ, Topless RK, Dalbeth N, Merriman TR. Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts. BMJ. 2018 Oct 10;363:k3951. doi:10.1136/bmj.k3951
  4. American Academy of Family Physicians. Pseudogout.
  5. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720. doi:10.1001/jama.2011.1169

Additional Reading

By Rony Kampalath, MD Dr. Kampalath is a board-certified diagnostic radiologist specializing in abdomen imaging. He previously worked as a primary care physician.
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