A practical approach to gout

Current management of an 'old' disease

Epidemiologic factors

Although the prevalence of gout is equal in men and women, men are six times more likely to have serum uric acid concentrations above 7 mg per dL (420 µmol per L)

Gout primarily affects men in the fourth to sixth decades of life. It is rare in premenopausal women and children.

For gout, the male-to-female ratio is 9:1.  For pseudo gout, the male-to-female ratio is 1.5:1.

Because of its low prevalence in young people, children who have an attack should undergo evaluation for a malignant or genetic cause.

Affected women are more likely than their male counterparts to have coexistent renal insufficiency, hypertension, polyarticular attacks, and a past history of diuretic use.

Tophaceous deposits form after many years of hyperuricemia. Women who take diuretics are also prone to the development of tophi, especially in and around the interphalangeal joints of the hand.

Compared with the classic manifestations in younger persons, gout in the elderly is more evenly distributed between the sexes, more often affects joints of the upper extremities, presents with fewer acute episodes, and has a more indolent chronic clinical course.

Mechanisms of hyperuricemia

Primary Hyperuricaemia

• Secondary to disordered uric acid metabolism

• Accounts for 95%

• Inherited disorder with over production (20%) or under excretion (80%)

• Classification based on 24 hour urine collection and urate excretion

Secondary Hyperuricaemia

• Gout is a secondary feature of a number of genetic, or acquired processes and accounts for 5% of cases

Hyperuricemia is defined as a serum uric acid concentration above 7 mg per dL (420 µmol per L). This concentration is also the limit of solubility for monosodium urate in plasma.

At levels of 8 mg per dL (480 µmol per L) or greater, monosodium urate is more likely to precipitate in tissues.

At a pH of 7, more than 90 percent of uric acid exists as monosodium urate.

Hyperuricemia is a risk factor for gout, but some patients with normal serum uric acid levels develop acute gouty arthritis.

Uric acid, the end product of purine metabolism, is a waste product that has no physiologic role.

Humans lack uricase, an enzyme that breaks down uric acid into a more water-soluble product (allantoin), thus preventing uric acid accumulation. Increased serum uric acid concentration is a result of either overproduction or underexcretion of uric acid.

In 90 percent of patients, gout is caused by the underexcretion of uric acid.

Although hyperuricemia is a risk factor for the development of gout, the exact relationship between hyperuricemia and acute gout is unclear.

Acute gouty arthritis can occur in the presence of normal serum uric acid concentrations.

Conversely, many persons with hyperuricemia never experience an attack of gouty arthritis.

Hyperuricemia can have many causes. Serum uric acid levels become elevated in any disorder that results in the proliferation of cells or the excessive turnover of nucleoproteins.

Hyperuricemia can also occur with decreased renal function and in genetic disorders that increase the production or limit the excretion of uric acid . Several medications increase the serum uric acid concentration through modification of the filtered load of uric acid or one of the tubular transport processes.

Hyperuricemia has been associated with hypertriglyceridemia and diabetes mellitus, and it may be a risk factor for the development of coronary artery disease.

Gout and rheumatoid arthritis do not appear to be associated

Listed below are congenital and acquired causes of hyperuricemia in patients with gout.

The two main mechanisms of hyperuricemia are

• uric acid overproduction (in 10% to 15% of patients with primary gout) and

• impaired renal clearance of uric acid (in the remainder of patients).

90% of patients with gout have a disorder of uric acid excretion and drugs that alter renal tubular function can contribute to the occurrence of gout (eg diuretics, aspirin, ethanol)

Diuretics are the most common cause of secondary hyperuricaemia due to volume depletion and enhanced tubular resorption of urate

Increased risk of developing the disease with increasing age and serum urate concentration.

Genetic studies suggest multi factorial inheritance

Two X-linked enzyme disorders cause increased rates of uric acid production:

• hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency and

• phosphoribosylpyrophosphate (PRPP) synthetase overactivity.

These disorders may present with neurologic manifestations in infancy or early childhood.

HGPRT deficiency produces Lesch-Nyhan syndrome, which is characterized by sensorineural deafness and self-mutilation. PRPP synthetase overactivity results in impaired neurologic development.

• Increased uric acid production

  • GENETIC CAUSES

    • Enzymatic defects

    • Hypoxanthine-guanine phosphoribosyltransferase deficiency (HGPRT)

    • Phosphoribosylpyrophosphate synthetase overactivity (PRPP)

    • Glucose-6-phosphatase deficiency

  • ACQUIRED CAUSES

    • High purine diet/pancreatic extracts

    • Obesity

    • Hypertriglyceridemia

    • Alcohol consumption

    • Myeloproliferative disorders

    • Lymphoproliferative disorders

    • Chemotherapy

    • Cytotoxic and radiation therapy for malignancy

    • Primary idiopathic hyperuricemia

    • Hemolytic processes

    • Lympho-proliferative disease (thrombocytopenia, myeloid metaplasia, leukaemias, lymphomas, paraprotinaemias, haemolytic anaemias, pernicious anaemia, infectious monomucleosis)

    • Myeloproliferative disease

    • Polycythemia vera

    • Psoriasis (severe)

    • Paget's disease

    • Rhabdomyolysis

    • Exercise

    • Alcohol

    • Obesity

    • Purine-rich diet

• Reduced uric acid clearance

  1. GENETIC CAUSES

     • Polycystic kidney disease

     • Down syndrome

  2. ACQUIRED CAUSES

  • Drugs (eg, low-dose aspirin, diuretics)

  • Endocrinopathies

  • Metabolic abnormalities

  • Low urine volume with normal renal function

  • Postoperative dehydration or starvation

  • Primary idiopathic hyperuricemia

  • Renal insufficiency

  • Polycystic kidney disease

  • Diabetes insipidus

  • Hypertension

  • Acidosis

    • Lactic acidosis

    • Diabetic ketoacidosis

  • Down syndrome

  • Starvation ketosis

  • Berylliosis

  • Sarcoidosis

  • Lead intoxication

  • Hyper and hypoparathyroidism

  • Hypothyroidism

  • Toxemia of pregnancy

  • Bartter's syndrome

  • Myxoedema

  • Drug ingestion

  • Salicylates (less than 2 g per day)

  • Diuretics

  • Alcohol

  • Levodopa-carbidopa (Sinemet)

  • Ethambutol (Myambutol)

  • Pyrazinamide

  • Nicotinic acid (niacin; Nicolar)

  • Cyclosporine (Sandimmune)

• Combined mechanism

  • Glucose-6-phosphate dehydrogenase deficiency

  • Fructose-1-phosphate aldolase deficiency

  • Alcohol

  • Shock

Evaluation

The "gold standard" for diagnosis of gout is joint aspiration and identification of characteristic needle-shaped, negatively birefringent monosodium urate crystals under compensated polarized light microscopy.

Gram's stain and culture of the aspirated fluid are often performed concomitantly to exclude septic arthritis and cellulitis, both of which may mimic gout.

When crystals are not identified and the culture is negative, a presumptive diagnosis of gout is often made on the basis of other factors, including a classic clinical presentation (eg, podagra), positive family history, and rapid resolution of symptoms with anti-inflammatory treatment.

Patients also should undergo evaluation for hypertension and hyperlipidemia, two potentially treatable conditions that often accompany gout.

Overproduction of Uric Acid

Purines, which are later metabolized to uric acid, enter a common metabolic pathway by which either nucleic acid or uric acid is produced.

Normal production of uric acid is considered to be 600 mg per day in men with normal renal function on a purine-free diet.

Overproduction of uric acid may occur because of an abnormality in the enzymes that regulate purine metabolism.

Two such abnormalities have been documented.

• An increase in the activity of phosphoribosylpyrophosphate synthetase results in increased uric acid synthesis.

• A deficiency of hypoxanthine-guanine phosphoribosyltransferase also increases serum uric acid levels.

A practical approach is to obtain a 24-hour uric acid determination without dietary restriction. A patient on a regular diet who excretes more than 800 mg of uric acid per 24 hours is considered an overproducer.

Underexcretion of Uric Acid

About two thirds to three fourths of all uric acid produced daily is excreted by the kidneys.

The gastrointestinal tract eliminates the other one third to one fourth.

Under normal conditions, uric acid is filtered in the glomeruli of the kidney, reabsorbed in the proximal tubule and secreted distally.

Tubular secretion is almost entirely responsible for the excretion of uric acid. Renal management of uric acid is defective in approximately 98 percent of patients with primary hyperuricemia and gout.

Clinical Presentation <.....More>

The above opinionated views and information serves to educated and informed consumer .  The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. .It should not replaced professional advise and consultation.A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions