Practical Therapeutics Drugs 9: 141-152 (1975)
Hyperuricaemia - To Treat or Not? B. T. Emmerson Department of Medicine, University of Queensland, Brisbane
1. Introduction In assessing the significance of hyperuricaemia, it is vital to decide whether or not it is producing symptoms. Joint symptoms in association with hyperuricaemia may be due to many causes other than gout. In the great majority of cases of gouty arthritis, the symptoms of joint pain will be typical, that is, there will be episodes of sudden monarticular arthritis of considerable severity, of limited duration and with complete remission. If such a history is not obtained. it is wise to require that urate crystals be demonstrated in synovial fluid before a diagnosis of gout is accepted. The present article therefore will be confined to hyperuricaemia in the absence of gouty arthritis. In this regard it is important to emphasise that hyperuricaemia is a finding rather than a disease. One might almost look upon it as a warning of potential disease and, in patients keen to prevent the future development of disease, it may be worth considering whether therapy to lower an abnormally elevated serum urate concentration to normal will be of any benefit.
2. Is the Hyperuricaemia Persistent? Before investigating the aetiology of hyperuricaemia, it is wise to ensure that the hyperuricaemia persists over 3 consecutive serum urate estimations. Transient hyperuricaemia can occur in many physiological situations and does not necessarily have serious implications.
Hyperuricaemia - To Treat or Not?
142
3. Why Consider Treating Hyperuricaemia?
This question involves consideration of the potential harm which might result from sustained hyperuricaemia. Possible complications to be considered include the risk of gouty arthritis, non-articular complications of gout, and degenerative vascular disease. 3.1 The Risk of Gouty Arthritis The risk of gouty arthritis is proportionate to the degree and duration of the hyperuricaemia. This risk is negligible at serum urate concentrations below 7 mg/lOO mI, is at least 7 % per annum at serum urate concentrations between 7 and 8 mg/l 00 ml, and rises to 3 times this value at urate concentrations greater than 8 mg/IOO ml. Indications for treating hyperuricaemia associated with gouty arthritis are much clearer than those for treating asymptomatic hyperuricaemia and there is little to be lost by the failure to prevent an initial attack of acute gouty arthritis. 3.2 Non-articular Complications of Gout Particular aspects of concern include the possibility that the patient might develop renal disease, hypertension or renal calculi if the hyperuricaemia is left untreated. Advice is controversial because, even in patients with gouty arthritis, evidence concerning the causation of these complications is not soundly based and no uniform consensus of opinion exists. The ability to predict which patients may be at risk of renal calculi by the use of measurements of uric acid concentrations in urine and total uric acid excretions, is so indefinite that prophylactic therapy with drugs to prevent a possible initial attack of renal colic is hardly justified. Simple prophylaxis by the maintenance of a high urine flow rate is worthwhile in those persons noted to have high urinary uric acid excretions or concentrations, but while such advice is simple, many patients seem to experience difficulty in adherence to such a regimen. The greater worry, however, is that a patient with hyperuricaemia might develop irreversible renal disease or hypertension (presumably related to urate crystal deposition within the kidney) without his having had any symptoms whatsoever. Documented cases of such an occurrence are very rare, however, and, in my opinion, the development of asymptomatic renal disease becomes a risk chiefly when the serum urate is persistently of the order of 10 mg/lOO ml, or if the patient is an over-excretor of urate.
Hyperuricaemia - To Treat or Not?
143
The author has observed a family with severe over-production and overexcretion of urate due to a life-long enzyme deficiency in which some members at the age of 70 years still had only mildly elevated serum urate concentrations and no more evidence of renal disease or hypertension than one would have expected for their age. Because overproducers of urate who develop gout are in the group of gouty patients who usually demonstrate the most florid complications, one would have expected members of this particular family to have shown considerably more in the way of renal complications than was actually found. Such a study also suggests that, as long as renal excretory capacity for urate enables a balance to be maintained between urate production and excretion, excessive production of urate may not be damaging to the kidneys and prolonged hyperuricaemia of moderate degree may not lead to a significant degree of renal disease. Although hypertension is common in patients with gouty arthritis, the mechanism of its production is ill-understood. Sometimes, both the hypertension and hyperuricaemia are secondary to obesity; sometimes the hyperuricaemia is secondary to reduced renal excretion of urate caused by the hypertension and, although evidence is lacking, it is possible that another mechanism might involve the formation of microtophi within the kidney. The most common situation, particularly with asymptomatic hyperuricaemia, would be for hypertension to be the primary factor and hyperuricaemia to be secondary to it, rather than the reverse. In such a situation, drug therapy aimed at the hyperuricaemia would not be beneficial.
3.3 Degenerative Vascular Disease Although the mechanism of the association is not well understood, there is good epidemiological evidence that hyperuricaemia is frequently associated with coronary artery disease in some populations. There is no evidence, however, that deposition of urate crystals is involved in the development of degenerative vascular disease and, in view of the high incidence of hypertriglyceridaemia in patients with gout and the frequent finding of hyperuricaemia in patients with type IV hyperlipoproteinaemia, it seems more likely that the association of hyperuricaemia with vascular disease occurs because both are secondary to the one primary phenomenon, possibly the hypertriglyceridaemia. In such patients, or in patients in whom the aim was the prevention of degenerative vascular disease, efforts would be better directed towards control' of the hypertriglyceridaernia than the hyperuricaemia. There is no evidence that the control of hyperuricaemia retards the development or progression of degenerative vascular disease.
Hyperuricaemia - To Treat or Not?
144
4. Why Hesitate to Treat Hyperuricaemia? The side-effects of drugs which reduce serum urate are generally not serious and one's first reaction might be to sympathise with the approach that the taking of a few tablets each day would probably do no harm and might possibly do some good. It would at least result in the patient feeling that something was being done and the doctor feeling that he was achieving a normalisation of an abnormal, but measurable, biochemical criterion. However, it must be remembered that: a) All drugs have side-effects in some patients. b) The lowering of an elevated serum urate to normal by drug therapy may actually precipitate acute gouty arthritis for the first time. c) Drug therapy, if needed to normalise the serum urate, must be life-long. Any possible harm from hyperuricaemia occurs only on a time basis of many years and any benefit from therapy can only be detected over a similar period. If hyperuricaemia is worth treating with drugs, it must be persistent and the cause is likely to be such as will continue to operate throughout life. d) An asymptomatic patient taking drugs to prevent the development of something which might never happen needs to be strongly motivated to continue life-long therapy. Such a patient would need to be absolutely convinced that the evidence was such that he was at appreciable risk of developing a disease which would significantly shorten life. Such an attitude requires a particular and peculiar philosophy of life which is held by a relatively small proportion of patients. There is no evidence to show either that isolated hyperuricaemia significantly shortens life span, or that normalisation of hyperuricaemia improves life expectancy. Those who believe that one should eat, drink and be merry, are not going to be interested in taking drugs to prevent something that might never occur. e) If the hyperuricaemia is a manifestation of a more serious underlying disorder, normalisation of a serum urate may merely mask the recognition that the serious underlying disorder exists. 5. When Should Asymptomatic Hyperuricaemia be Treated? Drug treatment for asymptomatic hyperuricaemia would therefore seem justified if all three of the following criteria are met: • When it appears to be primary, persistent and not reversible by simple measures. • When it seems likely to induce serious complications. These are unlikely
145
Hyperuricaemia - To Treat or Not?
•
to occur unless hyperuricaemia is persistently in the range of 10 mg/ 100 m\. When the patient is well motivated to continue prolonged therapy and understands the benefits and risks involved.
6. What Factors Cause Hyperuricaemia? Reference has already been made to conditions associated with hyperuricaemia in which the hyperuricaemia is secondary to some more fundamental disorder. In such a situation, it is more important to direct attention to the underlying condition than to the secondary manifestation. It should also be borne in mind that certain races, particularly the Polynesian and Filipino, tend to be hyperuricaemic when they adopt a Western life style. The following causes of hyperuricaemia need to be considered, although, because the prevalence of each factor is not known, they are not listed in order of importance. Producrion Endogenous
purine synthesis
Exogenous (dietary)
purines
r---::leoprotem
~
Urate
Serum urate concentration
pool
Renal
I
AI imentary
I
I
Excretion
Fig. 1a. The urate pool is a balance between urate production and urate excretion.
146
Hyperuricaemia - To Treat or Not? Production
Endogenous
purine synthesis
Exogenous
~
(dietary)
purines
Nucleoprotein
~
Urate
pool
Renal
~ Alimentary
Serum urate
concentration
I
I
Excretion ProductIOn
Endogenous
purine synthesis
Exogenous (dietary)
purines
Nucleoprotein
Urate
pool
Renal
Excretion
Fig. I h. Hyperuricaemia due to excessive dietary purines. Fig. Ie. Hyperuricaemia due to excessive purine synthesis, e.g. enzyme mutations.
147
Hyperuricaemia - To Treat or Not? Production Endogenous purine synthesis
Exogenous
(dietary) purines
Urate
pool
Renal
Excretion Production
Endogenous
purine synthesis
Exogenous (dietary)
purines
r-----::leOPfotoin
~
Urate
pool
Renal
~ Alimantary
Serum urate concentration
J
I
Excretion
vera.
Fig. Jd. Hyperuricaemia due to excessive nucleoprotein turnover, e.g. polycythaemia
Fig. Je. Hyperuricaemia due to reduced renal excretion of urate, either selectively for urate or as part of a generalised reduction in excretory capacity.
Hyperuricaemia - To Treat or Not?
148
6.1 Obesity There is much evidence from population studies that adiposity is associated with hyperuricaemia. There are also occasional case reports of patients who are hyperuricaemic when obese, but in whom urate metabolism becomes normal with weight loss. 6.2 Type IV Hyperlipoproteinaemia As already mentioned, hyperuricaemia is a common feature of this condition. In addition, studies of our gouty patients have shown a very high incidence of hypertriglyceridaemia, which does not always seem explicable by the frequently associated increase in body weight or alcohol consumption. In view of the clear association between hypertriglyceridaemia and degenerative vascular disease, it would seem that therapy should be directed towards normalising the abnormal plasma lipid profile before attention is paid to the hyperuricaemia. 6.3 Hypertension Hyperuricaemia is a frequent association of hypertension and, in view of the acceleration of degenerative vascular disease by hypertension, it would seem that the first priority in hypertensive patients should be adequate control of their blood pressure. In patients already known to be hyperuricaemic, the avoidance of drugs known to promote hyperuricaemia would be advisable. 6.4 Diet Both excessive purine consumption (such as occurs in people who eat large amounts of meat or other foods of high purine content daily) and the ketosis associated with starvation are frequently accompanied by hyperuricaemia. In the former case, the hyperuricaemia can be moderated by a reduction in the excessive purine intake and, in the latter case, both the ketosis and the hyperuricaemia can be resolved by less severe calorie restriction or by carbohydrate administration. 6.5 Alcohol The regular consumption of moderate amounts of alcohol (exceeding 20 g of ethanol/24 hours) is a very frequent finding among gouty patients. Heavy
Hyperuricaemia - To Treat or Not?
149
alcohol consumption results in an increase in the serum lactate concentration which reduces the renal excretion of urate, the degree of elevation of the serum lactate being proportional to the amount of alcohol consumed and the time interval. Thus, extremely heavy alcoholic bouts may lead to extreme hyperuricaemia, whereas more moderate alcohol consumption results in a more moderate hyperuricaemia. As well as alcohol, beer contains purines which probably contribute also to the hyperuricaemia. While few patients are prepared to alter their pattern of alcohol consumption in order to normalise their serum urate concentration, it is nonetheless important for the clinician to recognise the importance of alcohol and its possible role in the maintenance of hyperuricaemia. 6.6 Endocrine Disorders Both reduced function and increased function of both the thyroid and parathyroid glands can result in hyperuricaemia. 6.7 Over-production of Urate Over-production of urate is frequently genetic in origin, some of it being detectable by assays of those enzymes involved in the control of purine synthesis and reutilisation, viz. PRPP synthetase and hypoxanthine-guanine phosphoribosyltransferase. In other patients, urate over-production is acquired, most commonly due to myeloproliferative or lymphoproliferative disorders, such as polycythemia vera or leukaemia. On the other hand, infectious mononucleosis is often associated with urate over-production, as may active psoriasis, disseminated carcinoma, cytotoxic drug therapy and the rare condition of glucose6-phosphatase deficiency or type I glycogen storage disease. In the early stages, metabolic over-production of urate is associated with a high urinary urate excretion which falls only when renal excretory capacity for urate becomes impaired. Such patients are at risk from renal colic during the period of high urinary urate excretion, particularly if their urine volume becomes poor at any stage. 6.8 Under-excretion of Urate Reduced renal excretion of urate. may also be due either to genetic or acquired factors. Genetic determinants of the urate clearance are probably common, but are ill understood. Acquired factors include renal disease of any
Hyperuricaemia - To Treat or Not?
150
Table I. Principles in the management of asymptomatic hyperuricaemia 1. 2.
Ensure that it is persistent and not transient Seek cause Clinical a) Drug ingestion, esp. diuretics, salicylates b) Obesity - > 120 % desirable weight for height c) Hypertension d) Regular alcohol intake e) High purine diet (e.g. three meat meals a day, yeast, liver, sardines, whitebait) f) Inadequate urine volume g) Psoriasis h) Renal colic ii) Biochemical a) Type IV hyperlipoproteinaemia b) Myeloproliferative or Iymphoproliferative disease c) Renal disease d) Thyroid or parathyroid disease
i)
3.
If no cause apparent, assess effect of purine restriction on serum urate over a 7 day period and measure the mean 24 hour urinary urate on the last 2 days. a) If > 600 : overproduction (allopurinol if repeated study shows deterioration in renal function) b) If < 350 : underexcretion (probenecid or sulphinpyrazone if severe hyperuricaemia develops, i.e. of the order of 10 mg/IOO m)) Also gives information concerning urine volume and creatinine clearance.
cause with renal glomerular insufficiency e.g., pyelonephritis or glomerulonephritis. Chronic lead nephropathy is associated with a particularly poor renal excretion of urate. Under-excretion of urate may also be transient, such as is seen with reversible renal insufficiency, or with those metabolic states associated with high serum lactate concentrations - (probably an important aetiological factor in the hyperuricaemia of pregnancy toxaemia). A less well-documented cause of renal under-excretion of urate is a poor urine volume - one of less than 1,400 ml/24 h. Urate clearance appears to be unrelated to the urine flow rate provided this exceeds 1 ml/min. but many people consistently have 24 hour urine volumes of less than 1 litre/24 h. in which situation urine flow rate would be less than 1 ml for a significant portion of the day. The most common cause of under-excretion of urate is that induced by drugs, particularly the administration of diuretics or salicylates. Low dosage
Hyperuricaemia - To Treat or Not?
151
uricosurics or low dosage phenylbutazone can also reduce renal excretion of urate, as may any condition which causes ketonaemia.
7. Conclusion If a careful review of recognised aetiological factors does not explain a finding of hyperuricaemia and if this is of significant degree and sufficiently persistent to justify further investigation, it is wise to assess the effect of purine restriction on the serum and urine urate excretion. While the serum urate concentration usually falls by about 1 mgt 100 ml with purine restriction, hyperuricaemia of dietary origin and hyperuricaemia due to renal under-excretion are particularly responsive to purine restriction; thus a major fall in the serum urate concentration following the administration of a purine-free diet for a week should raise the possibility that one of these two factors is important aetiologically. In my practice, we undertake this regularly on an outpatient basis in conjunction with measurement of urinary urate excretion. Each subject takes a purine-free diet for a week and, on the last 2 of the 7 days, carries out two consecutive 24 hour collections of urine. This not only gives information about the response of the serum urate to purine restriction as well as the usual 24 hour udr:.e volume, but it enables one to calculate both the 24 hour creatinine clearance and the basal urate excretion. If the mean 24 hour urinary urate excretion consistently exceeds 600 mg/day on this purine-free diet, one can consider the patient to have urate over-production. As this is potentially the more serious variety of urate abnormality, .such a finding should alert the clinician to take the hyperuricaemia more seriously in that particular case. This would justify progress observations of the patient over a number of years to determine the pattern of his serum and urine urate in his normal life situation without purine restriction, together with repeated observation of renal function to determine if any deterioration can be detected. If such were to occur, therapy with a drug which would reduce urate production (such as allopurinol) would be justified. If, on the other hand, the mean 24 hour urine urate was less than 350 mg/24 hours, under-excretion of urate due to renal factors can be inferred and a search could be undertaken for correctible aetiologies. The development of severe hyperuricaemia in such a case would be an indication for drug treatment, in which case the administration of uricosuric drugs (such as probenecid or sulphinpyrazone) would be a rational approach. Most subjects will be found to be within the normal range of 350 to 600 mg/24 hours in which case an intrinsic abnormality of urate metabolism is unlikely and exogenous causes of hyperuricaemia may be invoked.
Hyperuricaemia - To Treat or Not?
152
In summary, the discovery of asymptomatic hyperuricaemia should lead to a careful search for the underlying aetiological factors causing the hyper· uricaemia. The only justification for drug treatment would be persistent hyper· uricaemia exceeding 10 mg/ I 00 ml and such a finding would justify careful observation and full assessment of basal urate metabolism before any urate· altering drugs are administered. References Hall. A.P: Bom·. P.L: Dowber. T.R. alld /IIcNall/ara. P.M.. Epidemioiog} of gout and hyperuricaemia. American Journal uf Medicine 42: c7-37 (1%7).
Rostegor. A. alld Tltier.
s.o.:
The phySIOlogic approach to h}peruril';Jemia Nl!w England Journal of Medicine :!86.470-47b(197c).
Author's address: Prof. B. T. Emmerson. University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Qld 4102 (Australia).
Hyperuricaemia - To Treat or Not? B. T. Emmerson Department of Medicine, University of Queensland, Brisbane
1. Introduction In assessing the significance of hyperuricaemia, it is vital to decide whether or not it is producing symptoms. Joint symptoms in association with hyperuricaemia may be due to many causes other than gout. In the great majority of cases of gouty arthritis, the symptoms of joint pain will be typical, that is, there will be episodes of sudden monarticular arthritis of considerable severity, of limited duration and with complete remission. If such a history is not obtained. it is wise to require that urate crystals be demonstrated in synovial fluid before a diagnosis of gout is accepted. The present article therefore will be confined to hyperuricaemia in the absence of gouty arthritis. In this regard it is important to emphasise that hyperuricaemia is a finding rather than a disease. One might almost look upon it as a warning of potential disease and, in patients keen to prevent the future development of disease, it may be worth considering whether therapy to lower an abnormally elevated serum urate concentration to normal will be of any benefit.
2. Is the Hyperuricaemia Persistent? Before investigating the aetiology of hyperuricaemia, it is wise to ensure that the hyperuricaemia persists over 3 consecutive serum urate estimations. Transient hyperuricaemia can occur in many physiological situations and does not necessarily have serious implications.
Hyperuricaemia - To Treat or Not?
142
3. Why Consider Treating Hyperuricaemia?
This question involves consideration of the potential harm which might result from sustained hyperuricaemia. Possible complications to be considered include the risk of gouty arthritis, non-articular complications of gout, and degenerative vascular disease. 3.1 The Risk of Gouty Arthritis The risk of gouty arthritis is proportionate to the degree and duration of the hyperuricaemia. This risk is negligible at serum urate concentrations below 7 mg/lOO mI, is at least 7 % per annum at serum urate concentrations between 7 and 8 mg/l 00 ml, and rises to 3 times this value at urate concentrations greater than 8 mg/IOO ml. Indications for treating hyperuricaemia associated with gouty arthritis are much clearer than those for treating asymptomatic hyperuricaemia and there is little to be lost by the failure to prevent an initial attack of acute gouty arthritis. 3.2 Non-articular Complications of Gout Particular aspects of concern include the possibility that the patient might develop renal disease, hypertension or renal calculi if the hyperuricaemia is left untreated. Advice is controversial because, even in patients with gouty arthritis, evidence concerning the causation of these complications is not soundly based and no uniform consensus of opinion exists. The ability to predict which patients may be at risk of renal calculi by the use of measurements of uric acid concentrations in urine and total uric acid excretions, is so indefinite that prophylactic therapy with drugs to prevent a possible initial attack of renal colic is hardly justified. Simple prophylaxis by the maintenance of a high urine flow rate is worthwhile in those persons noted to have high urinary uric acid excretions or concentrations, but while such advice is simple, many patients seem to experience difficulty in adherence to such a regimen. The greater worry, however, is that a patient with hyperuricaemia might develop irreversible renal disease or hypertension (presumably related to urate crystal deposition within the kidney) without his having had any symptoms whatsoever. Documented cases of such an occurrence are very rare, however, and, in my opinion, the development of asymptomatic renal disease becomes a risk chiefly when the serum urate is persistently of the order of 10 mg/lOO ml, or if the patient is an over-excretor of urate.
Hyperuricaemia - To Treat or Not?
143
The author has observed a family with severe over-production and overexcretion of urate due to a life-long enzyme deficiency in which some members at the age of 70 years still had only mildly elevated serum urate concentrations and no more evidence of renal disease or hypertension than one would have expected for their age. Because overproducers of urate who develop gout are in the group of gouty patients who usually demonstrate the most florid complications, one would have expected members of this particular family to have shown considerably more in the way of renal complications than was actually found. Such a study also suggests that, as long as renal excretory capacity for urate enables a balance to be maintained between urate production and excretion, excessive production of urate may not be damaging to the kidneys and prolonged hyperuricaemia of moderate degree may not lead to a significant degree of renal disease. Although hypertension is common in patients with gouty arthritis, the mechanism of its production is ill-understood. Sometimes, both the hypertension and hyperuricaemia are secondary to obesity; sometimes the hyperuricaemia is secondary to reduced renal excretion of urate caused by the hypertension and, although evidence is lacking, it is possible that another mechanism might involve the formation of microtophi within the kidney. The most common situation, particularly with asymptomatic hyperuricaemia, would be for hypertension to be the primary factor and hyperuricaemia to be secondary to it, rather than the reverse. In such a situation, drug therapy aimed at the hyperuricaemia would not be beneficial.
3.3 Degenerative Vascular Disease Although the mechanism of the association is not well understood, there is good epidemiological evidence that hyperuricaemia is frequently associated with coronary artery disease in some populations. There is no evidence, however, that deposition of urate crystals is involved in the development of degenerative vascular disease and, in view of the high incidence of hypertriglyceridaemia in patients with gout and the frequent finding of hyperuricaemia in patients with type IV hyperlipoproteinaemia, it seems more likely that the association of hyperuricaemia with vascular disease occurs because both are secondary to the one primary phenomenon, possibly the hypertriglyceridaemia. In such patients, or in patients in whom the aim was the prevention of degenerative vascular disease, efforts would be better directed towards control' of the hypertriglyceridaernia than the hyperuricaemia. There is no evidence that the control of hyperuricaemia retards the development or progression of degenerative vascular disease.
Hyperuricaemia - To Treat or Not?
144
4. Why Hesitate to Treat Hyperuricaemia? The side-effects of drugs which reduce serum urate are generally not serious and one's first reaction might be to sympathise with the approach that the taking of a few tablets each day would probably do no harm and might possibly do some good. It would at least result in the patient feeling that something was being done and the doctor feeling that he was achieving a normalisation of an abnormal, but measurable, biochemical criterion. However, it must be remembered that: a) All drugs have side-effects in some patients. b) The lowering of an elevated serum urate to normal by drug therapy may actually precipitate acute gouty arthritis for the first time. c) Drug therapy, if needed to normalise the serum urate, must be life-long. Any possible harm from hyperuricaemia occurs only on a time basis of many years and any benefit from therapy can only be detected over a similar period. If hyperuricaemia is worth treating with drugs, it must be persistent and the cause is likely to be such as will continue to operate throughout life. d) An asymptomatic patient taking drugs to prevent the development of something which might never happen needs to be strongly motivated to continue life-long therapy. Such a patient would need to be absolutely convinced that the evidence was such that he was at appreciable risk of developing a disease which would significantly shorten life. Such an attitude requires a particular and peculiar philosophy of life which is held by a relatively small proportion of patients. There is no evidence to show either that isolated hyperuricaemia significantly shortens life span, or that normalisation of hyperuricaemia improves life expectancy. Those who believe that one should eat, drink and be merry, are not going to be interested in taking drugs to prevent something that might never occur. e) If the hyperuricaemia is a manifestation of a more serious underlying disorder, normalisation of a serum urate may merely mask the recognition that the serious underlying disorder exists. 5. When Should Asymptomatic Hyperuricaemia be Treated? Drug treatment for asymptomatic hyperuricaemia would therefore seem justified if all three of the following criteria are met: • When it appears to be primary, persistent and not reversible by simple measures. • When it seems likely to induce serious complications. These are unlikely
145
Hyperuricaemia - To Treat or Not?
•
to occur unless hyperuricaemia is persistently in the range of 10 mg/ 100 m\. When the patient is well motivated to continue prolonged therapy and understands the benefits and risks involved.
6. What Factors Cause Hyperuricaemia? Reference has already been made to conditions associated with hyperuricaemia in which the hyperuricaemia is secondary to some more fundamental disorder. In such a situation, it is more important to direct attention to the underlying condition than to the secondary manifestation. It should also be borne in mind that certain races, particularly the Polynesian and Filipino, tend to be hyperuricaemic when they adopt a Western life style. The following causes of hyperuricaemia need to be considered, although, because the prevalence of each factor is not known, they are not listed in order of importance. Producrion Endogenous
purine synthesis
Exogenous (dietary)
purines
r---::leoprotem
~
Urate
Serum urate concentration
pool
Renal
I
AI imentary
I
I
Excretion
Fig. 1a. The urate pool is a balance between urate production and urate excretion.
146
Hyperuricaemia - To Treat or Not? Production
Endogenous
purine synthesis
Exogenous
~
(dietary)
purines
Nucleoprotein
~
Urate
pool
Renal
~ Alimentary
Serum urate
concentration
I
I
Excretion ProductIOn
Endogenous
purine synthesis
Exogenous (dietary)
purines
Nucleoprotein
Urate
pool
Renal
Excretion
Fig. I h. Hyperuricaemia due to excessive dietary purines. Fig. Ie. Hyperuricaemia due to excessive purine synthesis, e.g. enzyme mutations.
147
Hyperuricaemia - To Treat or Not? Production Endogenous purine synthesis
Exogenous
(dietary) purines
Urate
pool
Renal
Excretion Production
Endogenous
purine synthesis
Exogenous (dietary)
purines
r-----::leOPfotoin
~
Urate
pool
Renal
~ Alimantary
Serum urate concentration
J
I
Excretion
vera.
Fig. Jd. Hyperuricaemia due to excessive nucleoprotein turnover, e.g. polycythaemia
Fig. Je. Hyperuricaemia due to reduced renal excretion of urate, either selectively for urate or as part of a generalised reduction in excretory capacity.
Hyperuricaemia - To Treat or Not?
148
6.1 Obesity There is much evidence from population studies that adiposity is associated with hyperuricaemia. There are also occasional case reports of patients who are hyperuricaemic when obese, but in whom urate metabolism becomes normal with weight loss. 6.2 Type IV Hyperlipoproteinaemia As already mentioned, hyperuricaemia is a common feature of this condition. In addition, studies of our gouty patients have shown a very high incidence of hypertriglyceridaemia, which does not always seem explicable by the frequently associated increase in body weight or alcohol consumption. In view of the clear association between hypertriglyceridaemia and degenerative vascular disease, it would seem that therapy should be directed towards normalising the abnormal plasma lipid profile before attention is paid to the hyperuricaemia. 6.3 Hypertension Hyperuricaemia is a frequent association of hypertension and, in view of the acceleration of degenerative vascular disease by hypertension, it would seem that the first priority in hypertensive patients should be adequate control of their blood pressure. In patients already known to be hyperuricaemic, the avoidance of drugs known to promote hyperuricaemia would be advisable. 6.4 Diet Both excessive purine consumption (such as occurs in people who eat large amounts of meat or other foods of high purine content daily) and the ketosis associated with starvation are frequently accompanied by hyperuricaemia. In the former case, the hyperuricaemia can be moderated by a reduction in the excessive purine intake and, in the latter case, both the ketosis and the hyperuricaemia can be resolved by less severe calorie restriction or by carbohydrate administration. 6.5 Alcohol The regular consumption of moderate amounts of alcohol (exceeding 20 g of ethanol/24 hours) is a very frequent finding among gouty patients. Heavy
Hyperuricaemia - To Treat or Not?
149
alcohol consumption results in an increase in the serum lactate concentration which reduces the renal excretion of urate, the degree of elevation of the serum lactate being proportional to the amount of alcohol consumed and the time interval. Thus, extremely heavy alcoholic bouts may lead to extreme hyperuricaemia, whereas more moderate alcohol consumption results in a more moderate hyperuricaemia. As well as alcohol, beer contains purines which probably contribute also to the hyperuricaemia. While few patients are prepared to alter their pattern of alcohol consumption in order to normalise their serum urate concentration, it is nonetheless important for the clinician to recognise the importance of alcohol and its possible role in the maintenance of hyperuricaemia. 6.6 Endocrine Disorders Both reduced function and increased function of both the thyroid and parathyroid glands can result in hyperuricaemia. 6.7 Over-production of Urate Over-production of urate is frequently genetic in origin, some of it being detectable by assays of those enzymes involved in the control of purine synthesis and reutilisation, viz. PRPP synthetase and hypoxanthine-guanine phosphoribosyltransferase. In other patients, urate over-production is acquired, most commonly due to myeloproliferative or lymphoproliferative disorders, such as polycythemia vera or leukaemia. On the other hand, infectious mononucleosis is often associated with urate over-production, as may active psoriasis, disseminated carcinoma, cytotoxic drug therapy and the rare condition of glucose6-phosphatase deficiency or type I glycogen storage disease. In the early stages, metabolic over-production of urate is associated with a high urinary urate excretion which falls only when renal excretory capacity for urate becomes impaired. Such patients are at risk from renal colic during the period of high urinary urate excretion, particularly if their urine volume becomes poor at any stage. 6.8 Under-excretion of Urate Reduced renal excretion of urate. may also be due either to genetic or acquired factors. Genetic determinants of the urate clearance are probably common, but are ill understood. Acquired factors include renal disease of any
Hyperuricaemia - To Treat or Not?
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Table I. Principles in the management of asymptomatic hyperuricaemia 1. 2.
Ensure that it is persistent and not transient Seek cause Clinical a) Drug ingestion, esp. diuretics, salicylates b) Obesity - > 120 % desirable weight for height c) Hypertension d) Regular alcohol intake e) High purine diet (e.g. three meat meals a day, yeast, liver, sardines, whitebait) f) Inadequate urine volume g) Psoriasis h) Renal colic ii) Biochemical a) Type IV hyperlipoproteinaemia b) Myeloproliferative or Iymphoproliferative disease c) Renal disease d) Thyroid or parathyroid disease
i)
3.
If no cause apparent, assess effect of purine restriction on serum urate over a 7 day period and measure the mean 24 hour urinary urate on the last 2 days. a) If > 600 : overproduction (allopurinol if repeated study shows deterioration in renal function) b) If < 350 : underexcretion (probenecid or sulphinpyrazone if severe hyperuricaemia develops, i.e. of the order of 10 mg/IOO m)) Also gives information concerning urine volume and creatinine clearance.
cause with renal glomerular insufficiency e.g., pyelonephritis or glomerulonephritis. Chronic lead nephropathy is associated with a particularly poor renal excretion of urate. Under-excretion of urate may also be transient, such as is seen with reversible renal insufficiency, or with those metabolic states associated with high serum lactate concentrations - (probably an important aetiological factor in the hyperuricaemia of pregnancy toxaemia). A less well-documented cause of renal under-excretion of urate is a poor urine volume - one of less than 1,400 ml/24 h. Urate clearance appears to be unrelated to the urine flow rate provided this exceeds 1 ml/min. but many people consistently have 24 hour urine volumes of less than 1 litre/24 h. in which situation urine flow rate would be less than 1 ml for a significant portion of the day. The most common cause of under-excretion of urate is that induced by drugs, particularly the administration of diuretics or salicylates. Low dosage
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uricosurics or low dosage phenylbutazone can also reduce renal excretion of urate, as may any condition which causes ketonaemia.
7. Conclusion If a careful review of recognised aetiological factors does not explain a finding of hyperuricaemia and if this is of significant degree and sufficiently persistent to justify further investigation, it is wise to assess the effect of purine restriction on the serum and urine urate excretion. While the serum urate concentration usually falls by about 1 mgt 100 ml with purine restriction, hyperuricaemia of dietary origin and hyperuricaemia due to renal under-excretion are particularly responsive to purine restriction; thus a major fall in the serum urate concentration following the administration of a purine-free diet for a week should raise the possibility that one of these two factors is important aetiologically. In my practice, we undertake this regularly on an outpatient basis in conjunction with measurement of urinary urate excretion. Each subject takes a purine-free diet for a week and, on the last 2 of the 7 days, carries out two consecutive 24 hour collections of urine. This not only gives information about the response of the serum urate to purine restriction as well as the usual 24 hour udr:.e volume, but it enables one to calculate both the 24 hour creatinine clearance and the basal urate excretion. If the mean 24 hour urinary urate excretion consistently exceeds 600 mg/day on this purine-free diet, one can consider the patient to have urate over-production. As this is potentially the more serious variety of urate abnormality, .such a finding should alert the clinician to take the hyperuricaemia more seriously in that particular case. This would justify progress observations of the patient over a number of years to determine the pattern of his serum and urine urate in his normal life situation without purine restriction, together with repeated observation of renal function to determine if any deterioration can be detected. If such were to occur, therapy with a drug which would reduce urate production (such as allopurinol) would be justified. If, on the other hand, the mean 24 hour urine urate was less than 350 mg/24 hours, under-excretion of urate due to renal factors can be inferred and a search could be undertaken for correctible aetiologies. The development of severe hyperuricaemia in such a case would be an indication for drug treatment, in which case the administration of uricosuric drugs (such as probenecid or sulphinpyrazone) would be a rational approach. Most subjects will be found to be within the normal range of 350 to 600 mg/24 hours in which case an intrinsic abnormality of urate metabolism is unlikely and exogenous causes of hyperuricaemia may be invoked.
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In summary, the discovery of asymptomatic hyperuricaemia should lead to a careful search for the underlying aetiological factors causing the hyper· uricaemia. The only justification for drug treatment would be persistent hyper· uricaemia exceeding 10 mg/ I 00 ml and such a finding would justify careful observation and full assessment of basal urate metabolism before any urate· altering drugs are administered. References Hall. A.P: Bom·. P.L: Dowber. T.R. alld /IIcNall/ara. P.M.. Epidemioiog} of gout and hyperuricaemia. American Journal uf Medicine 42: c7-37 (1%7).
Rostegor. A. alld Tltier.
s.o.:
The phySIOlogic approach to h}peruril';Jemia Nl!w England Journal of Medicine :!86.470-47b(197c).
Author's address: Prof. B. T. Emmerson. University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Qld 4102 (Australia).
