Gout

From Ganfyd

Gout is a disorder of uric acid metabolism. It can lead to recurrent episodes of joint inflammation, tissue deposition of uric acid crystals, and if untreated can cause destruction of the affected joints (tophaceous gout).

In contrast to many other rheumatic diseases, gout can be easily treated. Synovial fluid aspiration and analysis give a definitive diagnosis but serum urate is often used as a proxy marker. However, while most people with gout have hyperuricaemia (high levels of serum urate), not all people with hyperuricaemia have gout.

Aetiology

Uric acid crystals from a tophaceous deposite (H&E staining)

Gout can, and usually does develop when excessive stores of uric acid are present. Indeed most gout can be considered to a due predominantly due to polygenetic disorders of urate exceretion. Uric acid is a byproduct of purine metabolism. Diet with a high content of purine is thus a risk factor for gout. Lacking uricase, humans remove uric acid primarily by renal excretion. In man about 5–10% of the urate filtered by the kidney is excreted, most having been reabsorbed at the tubules, mainly by the proximal convoluted tubule. Earlier studies had suggested that the urate is almost fully reabsorbed and that the urate excreted by the kidney is the result of tubular secretion, but more recent data suggest that secretion plays little part, and that excreted urate largely represents the filtered urate which escapes reabsorption.^[1].

Drugs that aggravate gout Aspirin Diuretics Thiazide Diuretics Loop Diuretics Pyrazinamide Ethambutol Nicotinic acid Fructose Many common (not diet) soft drinks aggravate gout [2] Many chemotherapeutic agents Ciclosporin

It is only recently that the major species differences that complicated our understanding of urate metabolism have been overcome. There are key renal tubular proteins, all of whom seem to have a transporter role^[3][4][5]:

• Responsible for tubular secretion of urate
  • UAT (urate transporter/channel)
  • OAT1 (organic anion transporter 1)
  • OAT3 ((organic anion transporter 3)
• Responsible for tubular reabsorption of urate
  • hURAT1 (human uric acid transporter 1, SLC22A12) an urate-anion exchanger located at the apical membrane of the proximal tubular cells
    • Inhibited by benzbromarone
    • Loss of function mutations reduce risk of gout
• Strong genetic association predictive of risk of gout
  • SLC2A9 (high-capacity urate transporter, Glut9)
  • ABCG2
  • SLC17A3

Higher primates and the Dalmatian dog have lost the Uricase pathway and therefore are prone to gout

Of patients with primary gout, 90% develop excess stores of uric acid because they are unable to excrete sufficient amounts of uric acid in their urine (underexcretion). The remaining patients produce excessive amounts of uric acid (overproduction). Paradoxically, over 90% of treatment is to reduce production, and only 1% is uricosuric drugs.

Cherries Cherries are said to alleviate gout. Strong evidence is not available. Much better evidence exists that: Coffee protects against gout[6].

Acute gout can occur in situations that lead to increased levels of serum uric acid, such as the use of alcohol, overindulgence in certain foods, trauma, haemorrhage, or the use of medications (such as thiazide and loop diuretics) that elevate levels of uric acid. Situations that lead to the rapid depletion of adenosine triphosphate (ATP) can result in the accumulation of adenosine 5'-diphosphate, adenosine monophosphate (AMP), and, subsequently uric acid. Alcohol, for example, accelerates the conversion of ATP to AMP. Alcohol also increases lactate relative to pyruvate and thereby reduces the excretion of uric acid. Beer contains guanosine and thereby increases the purine load. Cabbages contain a compound that inhibits urate excretion.

Flares of gout also can occur in situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid. This is because relatively sudden changes in level disturb the equilibrium situation in the joint where urate not only is in a supersatuated solution but urate crystals are actually present as microcrystals covered by a biological protein film that inhibits further seed crystallization. Exposure of naked urate released to correct urate concentration across the gradient between the synovial fluid and blood creates the potential for the uncontrolled macrocystallisation in the synovial fluid that is characteristic of gout.

In the Middle Ages in the British Isles, gout was a winter disease - a diet high in purines from food sources available at times of low food production triggered it. Modern gout is more a summer condition, and cases follow the begining of periods of hot weather, mediated by dehydration.

Clinical

In 90% of patients. the initial presentation of gout is acute mono-articular arthritis, typically the smaller, lower-extremity joints.

Onset is acute reaching maximal intensity in 8-12 hours. The joint(s) are red, hot, swollen and exquisitely tender. The redness is often a more sullen purple rather than the pillar box colour of infection. The patient will withdraw from your touch.

Untreated, the first attacks resolve spontaneously in less than 2 weeks. Initially the natural history is of intermittent inflammatory arthritis, the joint returning to normal between attacks. 10% of patients gout, especially elderly women, particularly those with renal insufficiency and taking a thiazide diuretic, can initially present as a polyarticular arthritis. These attacks may occur in pre-existing Heberden and Bouchard nodes. Such patients also may develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.

Mistaking an attack of gout for an infection in or around a joint is common among the less experienced. A history of recurrent arthritis or the patient's own diagnosis may put you right. It may not be possible to avoid treating with antibiotics, but remaining aware of the possibility allows, eventual preventive treatment of the condition. Retrospective analysis usually clarifies matters.

Untreated, the clinical characteristics of gout change with time; the attacks become more polyarticular, more joints are involved but inflammation in a given joint may become less intense. Proximal and upper-extremity joint involvement is more likely, attacks become more frequent and last longer Eventually, patients may develop a chronic polyarticular arthritis, that can resemble rheumatoid arthritis. Indeed, if a patient presents with a chronic polyarticular arthritis that began as an intermittent arthritis, a crystalline disorder should be considered in the differential diagnosis. While gout typically causes inflammation in a joint, it also can cause inflammation in other structures such as bursas and tendons.

Losartan appears to have a small uricosuric effect. This might influence the choice of treatment of hypertension or heart failure where gout or hyperuricaemia is present.

Gout and diuretics

Use of loop and thiazide diuretics is associated with gout, as they induce hyperuricaemia by increasing urate reabsorption. However this is not necessarily a direct action of the diuretics. Rather hyperuricaemia occurs when diuretics produce sufficient salt and water loss as to result in volume contraction and it is the volume contraction that causes urate reabsorption at the proximal tubule^[7]. Accordingly it is the patients base line urate status before introduction of any diuretic that appears to be important^[8] with to date the exception of bumetanide. There is good evidence that this drug is actually uricosuric^[9].

Accordingly there is a predictable dose response behaviour both with dose of an individual diuretic and the worsening of hyperuricaemia when combination therapy is used.

Investigations

Radiology

In Acute gout may be normal in the first attack. Recurrent attacks may show joint narrowing and sclerosis with osteophytes. Less commonly, punched out areas of bony tophi may develop. The eMedicine website ^[10] shows pictures of films.

Biochemistry

Serum urate - Hyperuricaemia. In an acute attack the level may fall.

Joint aspiration may reveal birefringent needles of uric acid.

Treatment

Diet

Not the diet

Clinical Evidence reported that "Advice to reduce dietary intake of purines" was of "unknown effectiveness" as there have been no RCTs ^[11]. Bandolier have also examined the link between diet and gout and reported that consumpation of red meat and seafood is associated with an increase in risk of gout. However, purine-rich vegetables and total protein are not. Also low-fat dairy products are associated with a decreased risk. They concluded "It is clearly not simply that high purine content in food is bad for gout."^[12] Coffee but not tea lowers urate^[13].

Rest

Medical

Acute NSAID: e.g Naproxen 500mg stat 250mg tds or Etoricoxib 120mg od.

• The multiple contra-indications to NSAIDs such as heart or renal failure make colchicine often the first choice in hospital practice

Alternatively:

• Colchicine 1mg stat 500mcg 2-3 hourly until pain relief or GI side effect. In the elderly/mild renal failure the use of 500microgram stat and a 6 or even 8 hourly regime is likely to be more appropriate. As acute colchicine toxicity can first become manifest several hours after a dose, and can be distressing in its own right counselling is strongly advised. Chronic colchicine toxicity by prolonged use of high dose can be fatal.
• Steroids intra-articularly or orally for acute attacks in joint aspirate diagnosed gout^[14].

Prophylaxis:

• Allopurinol 100-300mg daily - do not commence during an acute attack - empirically it prolongs or worsens the attack. The starting dose is varied according to renal function and increased to effect.
• Febuxostat 80-120 mg daily

Historical byway

The classical Punch Cartoon of gout is of the colonel of the Raj sitting on an armchair with his exquisitely painful foot swathed in a cocoon of bandages propped gently on a footstool and moustaches abristle. His troops in the barracks would never suffer from anything so officerlike as gout.

The colonel would be eating the best the mess could offer, rich in purines, brandy and port. The troops would often be eating worse than the cavalry horse with a starchy low protein diet inadequately cooked on a large bonfire providing heat for the whole regiment field kitchen. Most of the rations were inadequately prepared.

This all changed during the Crimean war when the celebrity chef of his day Alexis Soyer ^[15] went out to the Crimea to revolutionise the soldier's diet by the invention of a wood burning stove which could be used by an individual unit giving each man better cooked rations. It has been suggested that he did as much for the health of the army as Florence Nightingale.

The reason for telling this tale is that many older patients with gout refuse to believe it at first as "only posh people get that". The genes have long been widely distributed throughout the population. Adequate nutrition has not.

External Links

British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Management of Gout

• PRODIGY guideline on gout.
• Clinical Evidence on Gout.

References