Monday, 12 November 2012

How Genetic Under-Excretion Of Urate Can Cause Hyperuricaemia

When the body is in a stable state with a stable serum urate concentration, the amount of urate excreted in any day equals the amount produced during that day.

The ability of the kidneys to clear urate is often referred to as the renal clearance of urate or the urate clearance. This can be measured fairly simply by measuring serum urate and the amount of urate eliminated in the urine in a certain period, typically 24 hours (a timed collection). It can also be related to the amount of urate filtered in the given time period, referred to as the fractional excretion of urate. Many patients with gout show either reduced urate clearance or reduced fractional excretion of urate. This usually coincides with a diet high in the type of foods to avoid with gout as described at (in case you were interested).

Similar values for the urate clearance (or the fractional excretion of urate) tend to run in families so the average value for any particular family may be lower or higher than for other families.
Thus, sometimes, a patient with gout will have a poor ability to eliminate a urate load (urate under-excretion) and a similar deficiency can be shown in his son or his nephew. Identical twins (who have identical genes) have much greater similarity in their renal handling of urate than do non-identical twins (who have slightly different genes). This pattern of renal under-excretion of urate is very common and is probably the most important genetic factor which controls the serum urate concentration.

The range of urate clearance in the population is wide and although the average in a large healthy population is approximately 10 ml per minute, the range is between 5 and 15 ml per minute. Thus, members of a family whose urate clearances were between 5 and 6 ml per minute would have much more difficulty in eliminating a urate load than a family who had inherited a urate clearance of 14 to 15 ml per minute, i.e. who had three times the ability to excrete urate.

Sunday, 11 November 2012

What Causes Hyperuricaemia

 Urate production can be regarded as the load or amount of urate produced by the various metabolic processes in the body.
  • What Causes Over-Production Of Urate?
  •  What Causes Under-Excretion?
  •  What Is The Role Of Kidney Disease?
  •  Do Diet And Alcohol Have Any Influence?
  •  Are Other Health Factors Important?
Excretion can be regarded as reflecting the ability of the kidney to eliminate the urate load presented to it. The serum urate concentration thus reflects the balance between production of urate within the body and excretion of urate from the body.

In every patient with gout, a variety of factors contribute to the hyperuricaemia, and different factors contribute in different degrees in different patients. Thus, excessive production of urate will cause hyperuricaemia unless it is compensated by a corresponding increase in the excretion ofurate. Alternatively, reduced excretion of urate will cause hyperuricaemia unless there is a compensatory reduction in urate production.

An increase in urate production is sometimes referred to as over-production of urate, and a reduced excretory capacity for urate is sometimes referred to as under-excretion of urate. These are the two major mechanisms which result in hyperuricaemia.

While both over-production and under-excretion of urate can result in hyperuricaemia, each may be modified by both genetic and acquired (environmental) factors.

Genetic Over-Production Of Urate

The amount of urate produced each day by the body depends upon the control mechanisms for urate formation (synthesis), and this is controlled by enzymes. Enzymes are produced by the DNA or genetic code, so that small structural abnormalities (mutations) occurring in the genetic code for these enzymes can result in defective enzymes that do not function as well as they should. This may mean control of the body's production of purines and hence of urate is defective, and this can result in excessive production (over-production) of urate.

The major enzyme which, when defective, causes gross over-production of urate is called HPRT (hypoxanthine phosphoribosyi transferase). The gene or code for this enzyme is located on the X chromosome, and because of this, any defect in this HPRT gene shows up only in males and is transmitted by a female carrier who is herself normal or only very mildly affected. (Females have two X chromosomes, one from each parent, and both copies would have to be faulty for the defect to show up. Males have one X chromosome, from the mother, and a Y chromosome, from the father.
This means that there is nothing to correct any errors on their X chromosome. Most defects transmitted on the X chromosome therefore only show up in males.) Thus a man with HPRT deficiency would show urate over-production and might pass on the gene to his daughter. She would not usually develop symptoms, but could, transmit the deficiency to her sons.

Although the enzyme deficiency itself is relatively rare, these enzyme mutations can sometimes arise spontaneously and there may be no other members of the family affected. There are about twelve families in Australia known to have this HPRT mutation leading to over-production of urate, but these families include many hundreds of people. There are other rare mutations affecting urate production but they are even less common than the HPRT mutation.