31st January 2024

Background

Crystal arthropathy is the deposition of crystals in one or more joints, resulting in joint destruction and soft tissue inflammatory reaction. 

The two most common types of crystal arthropathy are gout and pseudogout. Gout is due to the deposition of monosodium urate crystals, and pseudogout is due to crystal deposition other than monosodium urate. Commonly, these crystals are calcium pyrophosphate dihydrate, but pseudogout can also occur due to deposition of the following:

• Calcium phosphate hydroxyapatite
• Calcium oxalate aluminium phosphate (deposited in end-stage renal failure patients on dialysis)
• Cholesterol deposited in rheumatoid arthritis and osteoarthritis 

Prevalence

Crystal arthritis is more common in men, with a 20:1 male-to-female ratio. It is associated with increasing age, co-morbidities, and certain medical therapies. Importantly, it can be seen in tumour lysis syndrome in cancer patients receiving chemotherapy. 

Tumour lysis syndrome occurs commonly in non-Hodgkin’s lymphoma and acute leukaemia but can also arise in other forms of cancer. It can occur spontaneously but is also commonly due to intracellular components being released during cell death in those receiving chemotherapy. The contents released into the bloodstream results in hyperuricaemia, hyperkalaemia, hypocalcaemia and hyperphosphataemia. The accumulation of urate can precipitate in joint spaces, causing gout. 

Risk factors 

Dietary factors associated with gout

• Meat consumption, specifically beef, pork, and lamb
• Alcohol: beer has a higher association with gout than spirits. There is no specific association between wine consumption and gout
• Sugary drinks- Consuming 2 or more sugar-sweetened soft drinks daily is strongly associated with gout
• There is an association between coffee consumption and gout but not with tea. 

Medications

• Diuretics- thiazide and loop diuretics. Thiazide and loop diuretics lead to urate reabsorption at the proximal convoluted tubule (PCT) via the URAT1 transporter. It is thought to be due to salt and water loss promoting urate reabsorption, but the mechanism is still unclear. 
• Cyclosporin when compared to tacrolimus and azathioprine in transplant recipients. This is due to reduced urate excretion and, therefore, a risk of gout. 

Co-morbidities

• Obesity
• Hypertension
• Diabetes mellitus
• Hypercholesterolaemia and hypertriglyceridemia
• Cancers
• Increased age
• Osteoarthritis
• Previous joint trauma 
• Metabolic disease such as hyperparathyroidism, hemochromatosis and hypomagnesaemia are less common. 

Pathophysiology

In gout and pseudogout, crystal deposition in the joint occurs, which can be asymptomatic despite a trigger for the inflammatory process. An acute gout flare results in a significant degree of pain; however, the specific trigger of this is still unknown. During the inflammatory process, neutrophils cause phagocytosis of the crystals and release pro-inflammatory cytokines. 

Gout is a problem with either purine metabolism or urate excretion. Adenine and guanine, 2 purine nucleic acids are metabolised into uric acid. Approximately two-thirds of uric acid is eliminated by the kidneys, and the remaining third by the gastrointestinal tract. 

Uric acid has low water solubility and is mostly circulated in the plasma bound to albumin. In the renal tract, it is filtered via 4 channels: the urate transporter (UAT), 2 organic anion transporters (OAT1 and OAT3) and URAT1, which is responsible for tubular reabsorption of urate located at the apical membrane of the PCT. The URAT1 channel is thought to be key in the association of gout and diuretic use. With increasing diuresis, there is an increase in urate reabsorption; this, in combination with dehydration, provokes a gout attack. Alterations in these channels increases the risk of gout. 

The normal level of urate is 1.5-6.0mg/dL in women and 2.5- 7.0 mg/dL in men. High urate levels, typically >7mg/dL can result in gout. Please note if the urate level is measured during an acute attack, the level may be below 7mg/dL- this does not exclude gout as a cause. This is thought to be due to the presence of tophi or a uric acid pool related to the acute flare; therefore, urate levels may be normal. If measured during intercritical phase (between acute painful attacks), the urate level will likely be elevated. 

Under excretion can occur at the level of the kidneys due to altered transportation through the renal tubules or under excretion at the level of the gut (extra renal). This triggers an acute inflammatory reaction and the innate immune system. 

There are five recognised stages of gout:

1. Asymptomatic hyperuricaemia
2. Acute gouty arthritis
3. Intercritical gout (between acute painful attacks)
4. Chronic tophaceous gout- tophi are urate crystal deposition in soft tissue. They are often asymptomatic. 
5. Gouty nephropathy 

Although an acute attack of gout is self-limiting, the crystals remain within the joint space and, with time, can cause local erosion and destruction of the joint and surrounding soft tissue. The only way to definitively treat gout is by lowering the serum urate level. While elevated serum urate levels predispose the patient to developing gout, it does not automatically guarantee that gout will arise. 

The following are contributing factors to an acute gout flare:

• Trauma
• Cold temperatures
• Previous disease
• Diet 
• Dehydration

Pseudogout belongs to a group of diseases known as calcium pyrophosphate deposition (CPPD) diseases, to which chondrocalcinosis also belongs. It is also recognised to have different stages:

• CPPD: occurrence of calcium pyrophosphate crystals, with or without symptoms
• asymptomatic CPPD: chondrocalcinosis +/- changes of osteoarthritis, but clinically asymptomatic
• acute CPPD crystal arthritis (formerly pseudogout): self-limiting synovitis in the setting of CPPD
• osteoarthritis with CPPD: typical changes of osteoarthritis in the setting of CPPD
• chronic CPPD crystal inflammatory arthritis

References 

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