Chronic Tophaceous Gout: Risk Factors For The Development of Tophi

What is gout?
Gouty arthritis by definition implies to a condition of joint inflammation due to the deposition of monosodium urat (MSU) crystal.1
Acute joint inflammation usually affecting the first metatarso-phalangeal joint referred to a very painful, redness and swollen joint that subsequently subsided within 5 to 10 days with or without medication. This condition recurred several times and between two acute episodes the patient beyond an intercritical phase. In other rare cases or chronic phase, several joints (polyarthritis) could be affected simultaneously.2,3 Recurrent attack and further deposition of MSU crystal will lead to a chronic condition and tophi develop.4,5,6 The deposition of tophi in the joint and bone will cause a serious damage to its structure and leading to deformities. Usually the development of tophi has a correlation with the severity of gout.
Epidemiology
The prevalence of hyperuricemia, gout and chronic tophaceous gout varies between countries.7 The WHO-ILAR-COPCORD stage I phase 3 researches in Bandungan, central Java, Indonesia, showed that the prevalence rate of gout and hyperuricemia in males 15 years of age and over is high compared to Caucasian populations. The prevalence of gout was 0.8% in the 4,683 people 15 years and older. Gout occurred in 1.7% of the men and 0.05% of the women. Acute gouty arthritis and chronic tophaceous gout were both found in the population sample.8 In Great Britain, the annual incidence rate (1971-1975), varying from 0.25 to 0.35 per 1000 and the prevalence of primary gout was estimated to be 2.3 per 1000.9 While in Taiwan the prevalence of gout was 0.60% in the rural area and 0.67% in the urban area.10 Another study from Indonesia, in northern part of Sulawesi indicating that chronic tophaceous gout was commonly seen among the population. Around 80% in the 208 population samples has developed tophi and various deformities.11 While in United State (USA) 35% in the 60 patients with gout also had tophi and deformities.12 A higher percentage compared to USA, 47% of 75 gouty arthritic patients in Thailand also developed tophi.13
Gouty arthritis was common in men rather than women. Previously, this disease was well known as the disease of King and the king of diseases. A bit different in sex differences founded in Polynesian women. Among them the differences to have hyperucicemia and gout was similar with those founded in men. This is to be believed caused by genetic defect in renal urate handling beside the occurrence of high purine intake and obesity.14
Factors affecting the formation of tophi
Hyperuricemia
A very high concentration of serum uric acid (SUA) always in correlation with the development of tophi. Tophus will be developed if the SUA level greater than 10 mg/dl. 4,5
The uric acid pool in patients with chronic tophaceous gout ranging between 18,000 – 31,000 mg. While in non tophaceous gouty arthritic patients the pool of uric acid is much lesser than the patients with tophus that is 2,400 – 3,600 mg. The uric acid pool was more than ten fold compared to normal person (1,200 mg). It is understandable why the patient with tophus will have an acute attack more frequent than those without tophus. This consideration derived from the fact that only a small amount of uric acid from the pool will be dissolved and excreted every day. 15
Genetic
A substantial part of gouty arthritic patients is a defect in purine metabolism, which is characterized by the increasing of purine synthesis, and it was abnormal. The acceleration of biosynthesis pointed to the genetic changes. Cassim B et al of Congella, South Africa founded that there was an increased in frequency of HLA-B14 in patients with primary gout but clinical significance of this is uncertain.16 The genetic defect resulting in disturbances of purine synthesis control mechanism.17 The most common abnormalities as a result in genetic changes were enzyme deficiency. It is Hypoxanthine guanine phosphoribocyl transferase (HPRT) as the main enzyme in regulating the purine synthesis. The HPRT deficiency will cause hyperuricemia.
The duration of having gouty arthritis
The development of tophus depends on the interval from the first attack of acute gout and it is lies between 3 – 42 years after the onset of gout. Becker and Levinson 4,5 found that tophus will be developed after 11.6 years of the onset of gout, while Nakayama et al 12 found the longer period around 18-19 years after. A few severe cases demonstrated that tophus already exist at the first acute attack of gout.18 This condition occur in a condition where the patient having renal problem, older age, on diuretic treatment and frequent use of non-steroidal anti-inflammatory drugs (NSAIDs). 19,20,21,22,23 Organ transplantation and the use of immunosuppressive agent such as cyslosporine-A was another factor for the formation of tophus at the first acute attack of gout.24
Obesity
Obesity was in correlation with the over production of uric acid and decreases of uric acid excretion. A low purine diet and weight loss program will improve the excretion of uric acid.1, 25,26 Dessein et al showed a beneficial effect of weight loss associated with moderate calorie / carbohydrate restriction (40%), and increases proportional intake of protein (30%) and fat (30%).27
Alcohol consumption
An alcoholic more prone to have gouty arthritis. The alcohol and its relationship with the incidence of gout could be arising from two different ways. The first, alcohol will increase the production of uric acid. Several kinds of alcohol beverages have a very high pure content. 28,29 The principle constituent found to be guanosine, which is probably the most readily absorbed dietary purine.30 Secondly, alcohol will decrease the excretion of uric acid.1,30 The second mechanism still on debatable. There is no evidence that beer taken in usual quantities will reduce the renal excretion of uric acid.30
In alcoholic gouty arthritic patients, the acute attack occurs in lower concentration of SUA in comparison to non-alcoholic gout patients.31
Purine intake
An abundant of purine consumption will lead to the overproduction of uric acid and at prolonged time will cause hyperuricemia uncontrollable and increasing the possibilities of deposition of uric acid crystal.1,4,5,32 Low purine diet will bring the SUA level to 15% lesser than normal diet.4
Dyslipidemia
Hypertriglyceridemia frequently found with gouty arthritis.4,33 Kelley and Wortman founded that lipid abnormalities among patients with gout was 75-84%.2 While Becker and Levinson founded hypertriglyceridemia in 50-75% of gouty arthritic patients.5
The mechanism of two differently metabolic abnormalities is not clearly understood. One study conducted by Moriwaki Y et al showed that there is a disturbance in apolipoprotein-e4 (apo-e4) allel.34 The apo-e is important in coating process of MSU crystal. The apo-e-coated MSU crystal will inhibit the inflammatory process in the synovium.
Renal function
Renal function is important in handling uric acid. Almost all of SUA will be filtrated in glomerulus and will be reabsorbed in renal tubule, so only a small amount of SUA will be excreted in the urine. Diminished renal function with the excretion less than 600 mg/dl a day will lead to hyperuricemia. It cannot compensate the production rate of SUA.1,4,32,35 This condition mostly has a genetic basis,36 and in the others there is the influences of drugs such as diuretics, pyrazinamide and ethambuthol. 37,38,39 Another factor should be in our mind that would be a major contributor of hyperuricemia and gout was the primary renal disease. 40,41,42,
Drugs
Many drugs could have its potentiality altering the renal function particularly in long-term therapy. The most common drug associated with the development of tophi was diuretic. A study on gout in Great Britain demonstrated that the elderly women are prone to diuretic-induced tophaceous gout but less likely to present with acute gout than man.43 Scott JT and Higgens CS founded that in diuretic induced gout there was one or more additional factors were present.23
Non-compliance to treatment
The invention of urate lowering drugs such as uricosuric agent or xanthine oxydase inhibitor (i.e allopurinol) is a remarkable inventory and brings the incidence of tophus down from 53% to 17%.5,24 In fact, many studies on gout still reported the high incidence of tophus. Nakayama et al 12 reported 35% of gout patients having tophus, and Louthrenoo reported a higher number, that is 47%.13 This condition is closely related to non-compliance to treatment.4,5,12,13
Other rheumatic disease associated with gout
The coincidence of other rheumatic disease with gout is well documented. In Systemic lupus erythematosus (SLE) the association of hyperuricemia and gout was closely associated with renal involvement particularly proteinuria and diuretic therapy.44 While in Rheumatoid arthritis (RA) the coexistence with gout is a questioned, more over with tophaceous gout. There is hypothesis that rheumatoid factor could inhibit the surface activity of monosodium urate crystals.46

Summary
Gout is a uric acid metabolism abnormality and known as one of the painful rheumatic disease. It has genetic basis. The chronic stage leading to joint and bone deformities known as chronic tophaceous gout. The incidence and prevalence of tophus varies between countries or from population to another within country. Hyperuricemia, renal function, non-compliance to treatment, alcohol consumption, obesity, hypertryglyceridemia, and duration of gout is a well-known risk factor for the development of tophus.

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