Gout is a disorder of purine metabolism which is characterized by increased urate levels in the blood, recurrent attacks of acute arthritis and deposition of monosodium urate monohydrate in and around the joints.

These vary from 2-7 mg/dl and levels above 7.0 mgldl in men and 6.0 mg/dl in women denotes hyperuricaemia. The incidence of gout varies from 0.2 to 3 per cent of population, involving predominantly males. The peak age of incidence being in 4th and 5th decades.

Pathogenesis

Uric acid levels in the body play important role in the pathogenesis of the disease. There may be increased production of uric acid (hyperuricaemia) or under excretion of it. Its levels are controlled by the balance between its rates of production and elimination. Uric acid comes from two sources—exogenous and endogenous.

Exogenous sources mainly include foods like sweat bread, pulses, cereals, redmeat, peas, meat etc while the endogenous come from the wear and tear of the tissues.

About two third of uric acid in the body is excreted into urine and one third is secreted in bile, gastric and intestinal secretions, where it is destroyed by colonic bacteria.

Increased levels of uric acid in the blood are hall mark of a case of gout. So in a goutry subject this may result from increased absorption of dietary purines, endogenous over production, diminished renal or gastro intestinal, excretion, diminished endogenous destruction of urate or a combination of these.

Over production of uric acid may occur either as a primary or secondary manifestation of an inborn error of metabolism. It may be primary manifestation of partial hypoxanthnine – guanine phosphoribosyltransfrase deficiency (HGPRT) and of PRPP synthetase superactivity while in LeschNyhan syndrome where there is complete deficiency of HGPRT secondary hyperuricaemia occurs.

In patients with secondary hyperuricacmia, there is increased production of uric acid. This is so in cases with glucose-6-phosphatase deficiency where there is not only increased production of uric acid but also an increased rate of purine biosynthesis.

Over production of uric acid may be as a result of increased breakdown of cellular nuclei as in multiple myeloma, myeloproliferative and lympho proliferative disorders, leukaemias, polycythemia, pernicious anemia, thalassemia and some malignancies. All this results and leads to not only hyperuricemia, hyperuricaciduria but also compensatory increase in purine biosynthesis.

Reduced, excretion of uric acid is mainly due to impaired renal excretion which occurs in disease of kidney, starvation, diabetic ketoacidosis, hyperparathyroidism, hypothyroidism, toxaemia of pregnancy etc. Diuretic therapy is another important cause. Diuretic induced volume depletion leads to enhanced tubular re-absorption of uric acid as well as decreased uric acid filtration.

Uric acid is mainly filtered by the glomerulus, reabsorbed in the proximal tubule and is secreted by the distal tubule. This impaired renal excretion shall be an important factor in the pathogenesis of gout.

Gout

Predisposing factors

Gout is much commoner amongst certain races eg English and Germans. It is common in temperate than in tropical climate. People with higher social status, and intellectuals suffer more from it as compared to their poor cousins.

A history of gout in the family suggests of it being hereditary in nature. Its inheritance is consistent with an autosomal dominant mode. It is more common in males as compared to females: Food also plays important part in the causation of the disease.

Foods like sweet breads, liver, kidneys and spirits like beer, strong wines like port and sherry and red wines such as burgundy and claret and champagne etc evoke attack of gout. Other factors include local trauma and infections especially in gums and tonsils.

Clinical features

Gout may manifest in various forms ranging from asymptomatic hyperuricaemia, acute gout and chronic gout.

1. Asymptomatic hyperuricaemia. It is that stage of gout when uric acid levels in the blood are raised but there are no clinical features of the disease. This state may continue throughout life without any recognizable consequences though such patients are likely to have high risk of renal stones or renal failure. Patients with hyperuricaemia should be closely monitored.

2. Acute gouty arthritis. The first attack of acute gout usually occurs at night when patient apparently well. The patient suddenly wakes with pain, more or less intense, generally in the ball of great toe accompanied by slight shivering.

There is a sensation of burning, throbbing, with tension and stiffness. The joint and surrounding tissues are swollen, hot red and extremely painful. There is fever ranging from 1010 to 102° F.

Usually the acute pain lessens in the day time but may come back at night hours. The attack may last many days and may take up to 2 weeks for the patient to improve. In at least 50% of the patients the first attack occurs in the first metatarsal phalangeal joint and ultimately all patients experience the acute attack in great toe.

Other joints in the body like ankles, knees, small joints of the hand and wrists are next to be involved. These are more like migratory attacks affecting these joints over subsequent days (cluster attacks).

During acute attack there is considerable degree of rise in cell count. Uric acid output rises and there is deposition in the cartilage of the joint and tendon sheaths. The acute attack of gout may be precipitated by dietary or alcoholic excess, surgical operation, starvation and drugs like diuretics.

3. Inter-critical gout. The attack of gout subsides and the second attack may not occur for several years. This asymptomatic phase is called inter-critical gout. Here the patient is totally free of symptoms but when second attack occurs, it is polyarticular, more severe and prolonged and associated with constitutional symptoms. Now the patient progressively passes into chronic stage without any remissions.

4. Chronic gout (tophaceous gout). After many attacks of acute gout, joints may not recover completely, deposits of urates occur in ligaments, articular cartilages and bones. Uncontrolled gout ultimately leads to formation of tophi at various sites.

Gout of more than 10 years and excess production of urate levels as opposed to their rate of excretion as well as renal damage leads to the formation of these tophi which are firm, nodular or fusiform swellings commonly appearing on the helix of the ear.

Other sites are ulnar surface of the forearm, great toe, feet and hand joints. When tophi are inflamed, they may ulcerate and white chalky like material may be discharged. This material is rich in monosodium urate crystale which can be documented by polarizing microscopy.

Cases of chronic gout suffer from renal dysfunction in more than 90% of cases. It may be in the form of hyperuricaemic nephrophathy nephrolithiasis and renal failure. There is increased incidence of hypertension and ischemic heart disease.

Investigations

In any patient suspected of gout, serum uric acid levels be measured in fasting state. 24 hour urinary urate excretion (normal 700 mg) with patient on a low purine diet shall indicate the under excretor or over producer state of uric acid.

Aspiration of synorial fluid from inflamed joint be examined under polarized light for urate crystals which are long needle shaped birefringent crystals.

X-rays of joints may be normal in early stages of disease while chronic cases may show punched out erosions with over hanging edges. In less severe cases there may be lipping at the articular margins, narrowing of the joint space and localized atrophy of the bone.

Diagnosis

A typical history with raised level of uric acid in the blood is diagnostic. It will have to be differentiated from acute rheumatid arthritis. Reactive arthritis or osteoarthritis.

Management

It is primarily (i) Treatment of an acute attack (ii) prevention of further attacks.

Acute attack. The main drugs employed are colchicine and non-steroidal anti-inflammatory drugs (NSAIDs).

Colchicine, though neither analgesic or anti- inflammatory yet it is the drug of choice in an acute attack of gout. It does not inhibit the synthesis or promotes the excretion of uric acid. It has no effect on blood uric acid levels since it inhibits the release of the glycoprotein which aggravates the inflammation. Pain is quickly relieved and the redness of the skin and swelling of the joint subsides.

Dose 1 mg orally every hourly till the attack subsides followed by 1 mg three times a day for a week or so. Total dose of drug in an acute attack should not exceed 10 mg.

Chronic therapy with coichicine is not recommended as it causes aplastic anaemia, agranulocytosis, myopathy and loss of hair. Side effects include nausea, vomiting, watery or bloody diarrhoea and myoneuropathy.

Besides calchicine phenylbutazone 200 mg three times a day or indomethacin 50 mg three times a day produce substantial relief. Dose should be reduced as the patients improves. Other NSAIDs which shall benefit include ibuprofen, (800 mg 8 hly) diclofenac sodium (50 mg 6 hrs) and naproxen (500mg 8 hrly).

In a difficult case where response to the above regimen is not satisfactory, interarticular steroids (ACTH) be given in inflamed joint to terminate the acute attack.

Interval therapy

This is targeted for prevention of future attacks of gout. Advice about life style is important. Patient be directed to avoid purine rich foods and alcoholic drinks (Red meat, Fish, sweet bread, peas, pulses and whole grain cereals kidney, sardines, Live;beer, red wines, strong wines like port and sherry, champagne, etc). Rich heavy foods be avoided. If a patient is addicted to alcohol, otily very light whisky or light wines are permitted.

Patient must reduce his/her wcight if obese. For prevention of future attacks, drugs like allopurinol or probenecid are advised.

Allopurinol reduces serum and urine urate concentration by inhibiting xanthine oxidase which is required for the conversion of xanthine and hypoxanthine to uric acid. Dose is 100-200 mg daily initially to be increased upto 600 mg per day to achieve the desired effect of lowering uric acid levels.

Later the dose is reduced to a maintenance level. Allapurinol should not be started for 4 weeks after the last acute attack since it may precipitate acute attack of gout. Side effects of the drug include rashes fever, nausea, muscle pain, gastric irritation and liver damage. Drug interacts with azathioprine, mercaptopurine and potentiate their effect. Probenecid and salicylates enhance urinary excretion of allopurinol.

Urico suric agent like probenecid promates the excretion of uric acid by competitive inhibition of tubular re absorption of urate in kidney. The drug is neither analgesic nor anti-infimmatory.

Dose 0.25 G twice daily initially and is gradually increased to 1 0 twice daily.

Probenecid is indicated in conditions where elimination of uric acid is impaired so it should not be used in patients with renal insufficiency and renal stones.

Side effects include dyspepsia, rashes, convulsions. Toxic doses may cause respiratory failure. Drug interacts with Thiazides, Indomethacin, oral anti diabetics, sulfonamides, acyclovir and heparin.

Anti hyperuricarmic therapy is aimed at lowering serum uric acid levels and prevention of future attacks so it may have to be given indefinitely.