Introduction

Gout is the most common inflammatory joint disease in men and the most common inflammatory arthritis in older women. It is caused by deposition of monosodium urate crystals in joints and soft tissues following chronic hyperuricaemia. Chronic hyperuricaemia is associated with disorders of purine metabolism due to under excretion or over production of uric acid, the final metabolite of endogenous and dietary purine metabolism. Gout usually presents as a monoarthritis in the first metatarsophalangeal joint (big toe) of the foot and is often referred to as podagra (from the Greek ‘seizing the foot’). Subsequent attacks may be polyarticular. Other commonly affected joints include the mid-foot, ankle, knee, wrist and finger joints. Although the attack is extremely painful, it is usually self-limiting resolving spontaneously in 1–2 weeks. Acute attacks are managed with rest, ice and one of the following pharmacological agents: NSAIDs, colchicine or corticosteroids. Some patients may only ever experience one attack, but often a second attack occurs within 6–12 months, with increased risk of subsequent attacks. Patients with recurrent attacks require long-term prophylaxis with drugs that lower the serum urate level. The drug of choice is usually allopurinol, however, a small percentage of patients are unable to tolerate allopurinol and require treatment with an alternative urate-lowering agent such as febuxostat or a uricosuric agent such as benzbromarone, sulphinpyrazone or probenecid. It is essential that pharmacological measures are combined with non-pharmacological measures such as dietary and lifestyle modification to prevent recurrent attacks. Inappropriate management of gout can result in chronic tophaceous gout with polyarticular, destructive low-grade joint inflammation, joint deformity and tophi.

Epidemiology

Gout is one of the oldest recognised diseases and was identified by the Egyptians in 2460 BC. Hippocrates described it as ‘arthritis of the rich’ due to the association with certain foods and alcohol. Gout affects 1–2% of adults in developed countries, and in recent decades there has been a significant rise in its prevalence and incidence (Zhang et al., 2006). The USA has seen a doubling in the number of cases with the rate of gout increasing to 4.1% in older males. However, unlike the rest of the world, prevalence in the UK appears not to be rising and from 2000 to 2005 remained at 1.4% (Rider and Jordan, 2010). The increasing numbers in many developed countries have been attributed to trends in lifestyle leading to increased risk of gout, for example, obesity, metabolic syndrome, hypertension, alcohol consumption and increased age of the general population. Although the Maori population have a marked genetic predisposition to gout, prior to 1700 they did not experience this inflammatory joint disease. It was changes in diet and lifestyle following European settlement that led to the appearance and increasing prevalence in the country. New Zealand now has probably the highest prevalence in the World with one in eight men affected (Richette and Bardin, 2010). A similar pattern has also been seen in Eastern China, where gout was considered a very rare disease in the 1980s. Changes in diet and lifestyle due to Western influences have seen its prevalence rise to 1.1% in Eastern China in 2008.

In the UK, the presentation of gout in men before the age of 45 years is unusual, but in those over the age of 75 years prevalence is greater than 7% in men and 4% in women (Doherty, 2009; Jordan et al., 2007; Zhang et al., 2006). Gout is predominantly a disease of men with a male to female ratio of 3.6:1. In women, it tends to develop after menopause when levels of oestrogen, a known uricosuric, fall.

Although environmental factors are clearly implicated in the development of gout, studies have shown that inheritance also plays an important role. In recent years, research into the genetic background of gout has identified several renal urate transporters including URAT-1 and GLUT-9 and the genes that encode them, for example, SLC22A12 and SLC2A9, respectively. Polymorphisms in these genes are associated with increased hyperuricaemia and gout (Dalbeth and Merriman, 2009; Doherty, 2009).

Pathophysiology

Uric acid is mainly a by-product from the breakdown of cellular nucleoproteins and purine nucleotides synthesised de novo with about a third coming from the breakdown of dietary purine intake (Fig. 54.1). Uric acid is a weak acid with a pK_a of 5.75, and at the physiological pH of the extra-cellular compartment 98% of uric acid is in the ionised form of urate. This is mainly present as monosodium urate due to the high concentration of sodium in the extra-cellular compartment. Human beings and higher primates lack the enzyme uricase that degrades uric acid to the highly soluble allantoin resulting in higher concentrations of urate close to the level of solubility. Monosodium urate has a solubility limit of 380 µmol/L; when the concentration exceeds 380 µmol/L, there is a risk of precipitation and the formation of monosodium urate crystals.

Fig. 54.1 Purine pathway.

The production of urate is dependent upon the balance between purine ingestion, de novo synthesis in the cells and the actions of xanthine oxidase at the distal end of the purine pathway. Xanthine oxidase is the enzyme that catalyses the oxidation of hypoxanthine, the breakdown product from the catabolism of cellular nucleoproteins and purine nucleotides, to xanthine and xanthine to uric acid.

Gout can be classified as primary or secondary, depending on the presence or absence of an identified cause of hyperuricaemia.

Primary gout is not a consequence of an acquired disorder, but is associated with rare inborn errors of metabolism and isolated renal tubular defects in the fractional clearance of uric acid. A rare group of enzyme defects result in an increased de novo purine synthesis such as hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome), phosphoribosyl pyrophosphate synthetase super activity, glucose-6 phosphatase deficiency and myogenic hyperuricaemia (Table 54.1).

Table 54.1 Causes of primary and secondary gout

Secondary gout is the consequence of the use of specific drugs or develops as a consequence of other disorders. Certain diseases are associated with enhanced nucleic acid turnover, for example, myeloproliferative and lymphoproliferative disorders, psoriasis and haemolytic anaemia, and can lead to hyperuricaemia. Renal mechanisms are responsible for the majority of hyperuricaemia in individuals with over production representing less than 10% of patients with gout. The kidney excretes about two-thirds of the uric acid produced daily with the remainder being eliminated via the biliary tract with subsequent conversion to soluble allantoin by colonic bacterial uricase. Approximately 90% of the daily load of urate filtered by the kidneys is re-absorbed. This re-absorption process is mediated by specific anion transporters such as URAT-1 which is located on the apical side of the renal proximal tubular cells and is an important determinant of urate re-absorption (Richette and Bardin, 2010). The URAT-1 transporter is targeted by a number of drugs including benzbromarone, probenecid, losartan and sulphinpyrazone.

Risk factors

Hyperuricaemia is one of the main risk factors for gout and occurs in about 15–20% of the population (Doherty, 2009). Fortunately, only a minority of individuals with increased serum uric acid levels develop gout suggesting the importance of other contributing factors (Box 54.1).

Presentation and diagnosis

An acute attack of gout has a rapid onset, with pain being maximal at 6–24 h of onset and spontaneously resolving within several days or weeks. The first attack usually affects a single joint in the lower limbs in 85–90% of cases, most commonly the first metatarsophalangeal joint (big toe). The next most frequent joints to be affected are the mid-tarsi, ankles, knees and arms. The affected joint is hot, red and swollen with shiny overlying skin. Even the touch of a sheet on the affected joint is too painful for the patient to bear. The patient may also have a fever, leucocytosis, raised erythrocyte sedimentation rate (ESR), and the attack may also be preceded by prodromal symptoms such as anorexia, nausea or change in mood. Following resolution of the attack, there may be pruritis and desquamation of the overlying skin on the affected joint.

Monosodium urate crystals preferentially form in cartilage and fibrous tissues where they are protected from contact with inflammatory mediators. The deposition of crystals may continue for months or years without causing symptoms; it is only when the crystals are shed into the joint space or bursa that inflammatory reaction occurs precipitating an acute attack of gout. The shedding of crystals can be triggered by a number of factors including direct trauma, dehydration, acidosis or rapid weight loss. The acute phase response associated with intercurrent illness or surgery may also precipitate an attack; during this phase, there is increased urinary urate excretion with a lowering of serum uric acid which leads to partial dissolution of monosodium urate crystals and subsequent shedding of crystals into the joint space.

The shed crystals are phagocytosed by monocytes and macrophages, activating the NACHT–LRR–PYD-containing protein-3 (NALP3) inflammasome and triggering the release of interleukin-1β (IL-1β) and other cytokines, a subsequent infiltration of neutrophils and the symptoms of an acute attack (Dalbeth and Haskard, 2005). The NALP3 inflammasome (cryopyrin) is a complex of intracellular proteins that is activated on exposure to microbial elements, such as bacterial RNA and toxins. Activation of NALP3 leads to the release of caspase-1, which is required for cleavage of pro-IL-1β to active IL-1β (Richette and Bardin, 2009). IL-1β has been shown to be critically associated with the inflammatory response induced by monosodium urate crystals (Rider and Jordan, 2010).

A third of patients will have normal uric acid concentrations during an acute attack of gout due to increased urinary urate excretion. The most appropriate time to measure serum urate for monitoring purposes is when the attack has completely resolved. The gold standard for the diagnosis of gout is the demonstration of urate crystals in synovial fluid or in a tophus by polarised light microscopy (Zhang et al., 2006). Crystals may be found in fluid aspirated from non-inflamed joints, even in those joints which have not previously experienced an attack. The crystals are large (10–20 μm) and needle shaped with a strong, intense, characteristic light pattern under polarised light. In contrast, the calcium pyrophosphate dehydrate crystals associated with pseudo-gout are small rhomboid crystals of low intensity. Gout and septic arthritis may co-exist and in order to exclude septic arthritis synovial fluid is sent for Gram staining and culture.

Course of disease

The course of gout follows a number of stages; initially, the patient may be asymptomatic with a raised serum uric acid level (Fig. 54.2). Some patients may only ever experience one attack, but often a second attack occurs within 6–12 months. Subsequent attacks tend to be of longer duration, affect more than one joint and may spread to the upper limbs. Untreated disease can result in chronic tophaceous gout, with persistent low-grade inflammation in a number of joints resulting in joint damage and deformity. The disease is characterised by the presence of tophi (Fig. 54.3), monosodium urate crystals surrounded by chronic mononuclear and giant-cell reactions. Tophi deposition can occur anywhere in the body, but they are commonly seen on the helix of the ear, within and around the toe or finger joints, on the elbow, around the knees or on the Achilles tendons. The skin overlying the tophi may ulcerate and extrude white, chalky material composed of monosodium urate crystals.

Fig. 54.2 Schematic representation of the stages of gout.

Fig. 54.3 Chronic tophaceous gout.

Treatment

The management of gout can be split into the rapid resolution of the initial acute attack and long-term measures to prevent future episodes (see Box 54.3).

Gout is often associated with other medical problems including obesity, hypertension, excessive alcohol and the metabolic syndrome of insulin resistance, hyperinsulinaemia, impaired glucose intolerance and hypertriglyceridaemia. This contributes to the increased cardiovascular risk and deterioration of renal function seen in patients with gout. Management is not only directed at alleviating acute attacks and preventing future attacks, but also identifying and treating other co-morbid conditions such as hypertension and hyperlipidaemia. Pharmacological measures should be combined with non-pharmacological measures such as weight loss, changes in diet, increased exercise and reduced alcohol consumption.

Management of an acute attack

Drugs used in the management of an acute attack include NSAIDs, colchicine and corticosteroids. NSAIDs are the recommended first-line agents, but in a number of patients their use is contraindicated and a second-line agent is indicated (Box 54.4). Where the pain is not adequately controlled by treatment, paracetamol and weak opiate analgesics, for example, codeine or dihydrocodeine may be added to the regimen to provide additional relief. Treatment should be continued until the attack is terminated, usually between 1 and 2 weeks. The affected joints should also be rested for 1–2 days and initially treated with ice which has a significant analgesic effect during an acute attack.

Box 54.4 Management of an acute attack of gout

Promptly and safely resolve pain

First line: NSAID (use maximum dose)

Second line: Colchicine

Third line: Corticosteroid (consider first line in mono-articular disease)

(±Simple and opiate analgesia if needed, for example, paracetamol, codeine dihydrocodeine)

Rest the joint 1–2 days and treat with ice

Remove contributing factors

Review medication

Review lifestyle

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