Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7517.623 (Published 15 September 2005) Cite this as: BMJ 2005;331:623
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In his response to our article Dr. Pijak discusses the role of
hyperuricaemia in
cardiovascular and renal disease. Evidence from epidemiological studies
provides contradictory results. Some studies cited by Pijak have found
that
serum uric acid is an independent risk factor for cardiovascular disease;
however, other studies, including the Framingham study (the most
impressive
epidemiological study ever conducted) do not support the role of
hyperuricaemia in the development of coronary heart disease, death from
cardiovascular disease, or death from all causes (1). A very recent
systematic
review of literature published within the last six years concludes that
the
excess risk associated with hyperuricaemia in healthy patients, if any, is
likely
to be small. However, in patients with high cardiovascular risk there is
an
independent, but moderate, relationship between high serum uric acid
levels
and cardiovascular disease (2).
These results prove a relationship but, as
the
authors state, there is no direct evidence to suggest causality. The
translation
into clinical practice of the potential role of uric acid lowering therapy
has
prompted the conduction of a double-blind randomized, clinical trial of
oxypurinol in chronic heart failure (OPT-CHF) (3). The study, measured the
clinical impact of Oxypurinol in NYHA classes 3 and 4 CHF patients, with
ejection fractions less than or equal to 40%, receiving standard therapy.
Oxypurinol failed to demonstrate a statistically significant benefit over
placebo in the primary composite endpoint (3). The role of hyperuricaemia
and uric acid lowering therapy in cardiovascular risk is very far away of
being
clarified, and more clinical investigation is needed. However, the most
important learning points of our report is that asymptomatic
hyperuricaemia
should not be treated in most patients, and that, when indicated,
allopurinol
dose must be adjusted in patients with renal failure.
1. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and
risk for
cardiovascular disease and death: the Framingham Heart Study. Ann Intern
Med 1999; 131: 7-13.
2. Baker JF, Krishnan E, Chen L, Schumacher HT. Serum uric acid and
cardiovascular disease: recent developments, and where do they leave us?
Am
J Med. 2005; 118: 816-26.
3. Cardiome Pharma Corp. Press Release. Cardiome reports clinical
results
from OPT-CHF Study. Available from: http://www.cardiome.com/wordpress/
index.php?cat=2
Competing interests:
None declared
Competing interests: No competing interests
Gutierrez-Macias et al(BMJ 2005:331;623-4) report a case of fatal
allopurinol toxicity.The commencing dose was high.All patiets should start
100mg daily for one month increasing to 200mg daily for one month followed
by 300mg daily thereafter.This much reduces the risk of toxicity and is
much less likely to trigger acute gout attacks.Best practice also demands
that a potent NSAID such as etoricoxib 90mg dialy is coprescribed to
prevent breakthrough attacks during the first six months of allopurinol
treatment.
Dr Adrian Crisp
Consultant Rheumatologist
Addenbrooke's Hospital,
Cambridge
CB2 2QQ,
UK
Competing interests:
None declared
Competing interests: No competing interests
Sir, it seems that Lessons of the week need to be repeated for each
generation. Gutierrez-Macias and colleagues report on the dangers of
treating asymptomatic hyperuricaemia with allopurinol. 20 years ago almost
to the week the BMJ published an almost identical case in lesson of the
week (1) to which I added a further fatal case (2). The current case again
highlights the need to interpret blanket biochemical screens with caution.
Perhaps it can be summed up more simply: "treat the patient not the test
result". It is a pity ,and does the medical profession no credit, that
simple messages such as these have to be repeated in the same section of
the BMJ. The fact that the 2 cases from 1985 have not been cited in an
article from the same journal suggests that as a profession we have a
short and selective memory.
1.Aubock J, Fritsch P. Asymptomatic hyperuricaemia and allopurinol
induced toxic epidermal necrolysis. BMJ 1985;290:1969-70.
2. Renwick I. Asymptomatic hyperuricaemia and allopurinol induced
toxic epidermal necrolysis. BMJ 1985;291:485.
Competing interests:
None declared
Competing interests: No competing interests
In their Clinical review article(1) Gutiérrez-Macías et al. state
that ”....high urate concentrations do not seem to cause cardiovascular
disease, as was previously thought.” However, recent evidence support
the contrary conclusion—that hyperuricemia directly contributes to
cardiovascular or renal disease.
Although hyperuricemia is associated with a number of cardiovascular
or renal risk factors, a substantial body of epidemiological evidence
suggests that serum uric acid is an important, independent risk factor for
cardiovascular and renal disease. (2-4) This is consistent with findings
that endogenous uric acid concentrations correlate with endothelial
dysfunction(5) and that exogenous uric acid causes endothelial dysfunction
when infused into the human brachial artery.(6) In addition,
hyperuricemia is also associated with deleterious effects on oxidative
metabolism, platelet adhesiveness, hemorheology, and aggregation.
Most importantly, rats with mild experimentally-induced
hyperuricemia develop intrarenal vascular disease with increased renin
expression, systemic and glomerular hypertension, and renal injury in the
absence of intrarenal crystal deposition. (7,8) Although these effects
could be blocked by enalapril and losartan, losartan's effect could be
mediated in part by its known uricosuric action, because uric acid levels
tended to be lower in the losartan-treated rats.
Interestingly, recent study showed that one third of
cardiovascular benefit of losartan- versus atenolol-based therapy on the
primary composite endpoint (death, myocardial infarction, or stroke) may
be related to differences in achieved serum uric acid levels.(9) These
study findings contribute to mounting evidence that lowering uric acid can
improve renal function in patients with either minimal or moderate renal
disease.(10,11) Of importance, early treatment with allopurinol may slow
or prevent the progression of kidney disease also in patients with
hyperuricemia and renal impairment but without gout.(12,13)
Allopurinol has also been reported to reduce cardiovascular
complications after coronary artery bypass (14) and in patients with
dilated cardiomyopathy.(15) Moreover, long term high dose allopurinol
was associated with a better mortality than long term low dose in
patients with congestive heart failure(CHF).(16) Consistent with these
findings, allopurinol improves peripheral vasodilator capacity and blood
flow both locally and systemically in hyperuricemic CHF patients.(17)
Taken together, the data mentioned above obviously raise the
possibility that treatment-induced decrease in serum uric acid may indeed
attenuate the risk of cardiovascular and renal complications. These
assumption has prompted initiation of a randomized, double-blind, placebo
-controlled clinical trial (OxyPurinol Therapy for CHF) initiated in
2003.(18) It should be noted, however, that some of the beneficial
effects of allopurinol may also be related to inhibition of xanthine
oxidase, which is one of the main producers of superoxide anions, which
are well known to inactivate endogenous nitric oxide.
1. Gutierrez-Macias A, Lizarralde-Palacios E, Martinez-Odriozola P,
Miguel-De la Villa F. Fatal allopurinol hypersensitivity syndrome after
treatment of asymptomatic hyperuricaemia. BMJ 2005;331:623-624.
2. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S,
et al. Is there a pathogenetic role for uric acid in hypertension and
cardiovascular and renal disease? Hypertension 2003;41:1183-1190.
3. Wang JG, Staessen JA, Fagard RH, Birkenhager WH, Gong L, Liu L.
Prognostic significance of serum creatinine and uric acid in older Chinese
patients with isolated systolic hypertension. Hypertension
2001;37:1069–1074.
4. Gerhardt U, Grobe Huttman M, Hohage H. Influence of hyperglycemia
and hyperuricemia on long-term transplant survival in kidney transplant
patients. Clin Transplantation1999;13:375–379.
5. Britten MB, Elsner M, Walter DH, Schachinger V. Elevated uric
acid levels in hypercholesterolaemia are associated with coronary
endothelial dysfunction [abstract]. Circulation 1999;100(Suppl):I–6.
6. Waring WS, Webb DJ, Maxwell SRJ. Effect of local hyperuricaemia on
endothelial function in the human forearm vascular bed. Br J Clin
Pharmacol 2000;49:511P.
7. Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C Jr, Jones P,
Bradley A, Caskey CT: Hyperuricemia and urate nephropathy in urate oxidase
-deficient mice.
Proc Natl Acad Sci U S A 1994;91:742-746.
8. Mazzali, M, Hughes J, Kim YG, Jefferson J, Kang DH, Gordon KL, et
al. Elevated uric acid increases blood pressure in the rat by a novel
crystal-independent mechanism. Hypertension 2001;38:1101-1106.
9. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De
Faire U, et al. LIFE Study Group. The impact of serum uric acid on
cardiovascular outcomes in the LIFE study. Kidney Int 2004;65:1041-1049.
10. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, Garcia
-Erauskin G, Ruiz-Lucca E. Efficacy of allopurinol and benzbromarone for
the control of hyperuricemia: a pathogenic approach to the treatment of
primary chronic gout. Ann Rheum Dis 1998;57:545–549.
11. Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-Beites A,
Ruiz-Lucea E, Garcia-Erasukin G, et al. Treatment of chronic gout in
patients with renal function impairment: an open, randomized actively
controlled study. J Clin Rheumatol 1999;5:49–55.
12. Neal DA, Tom BD, Gimson AE, Gibbs P, Alexander GJ. Hyperuricemia,
gout, and renal function after liver transplantation. Transplantation
2001;72:1689-1691.
13. Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L,
Van'T Hoff W, et al. Early treatment with allopurinol in familial
juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term
progression of renal disease. QJM 2002;95:597-607
14. Johnson WD, Kayser KL, Brenowitz JB, Saedi SF. A randomized
controlled trial of allopurinol in coronary bypass surgery. Am Heart J
1991;121:20–24.
15. Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA,
et al. Allopurinol improves myocardial efficiency in patients with
idiopathic dilated cardiomyopathy. Circulation 2001;104: 2407–2411.
16. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J,
MacDonald TM. Effect of allopurinol on mortality and hospitalisations in
chronic heart failure: a retrospective cohort study. Heart 2002;87:229-
234.
17. Doehner W, Anker SD. Xanthine oxidase inhibition for chronic
heart failure: is allopurinol the next therapeutic advance in heart
failure? Heart 2005;91:707-709.
18. Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in
heart failure: insights regarding the role of xanthine oxidase and uric
acid in disease pathophysiology. Circulation 2003;107:1951-1953
Competing interests:
None declared
Competing interests: No competing interests
Re: Re: A role for asymptomatic hyperuricemia in the progression of cardiovascular and renal disease
Dr. Gutiérrez-Macías is correct in pointing out that not all
population epidemiology studies, including the reanalysis of Framingham
study(1) and recent systematic review (2) support serum uric acid(SUA)
as an independent risk factor for cardiovascular disease(CVD).
Nevertheless, during the last five years a number of new studies have
found an elevated SUA level to be an powerful independent risk factor for
cardiovascular (3-7) and renal disease (8,9). SUA concentration was
found to be independently correlated with hypertension, insulin resistance
and the risk factors of metabolic syndrome.(10,11) Moreover, even those
with a SUA concentration in the normal range showed an increased risk of
metabolic syndrome as SUA concentration increased (10)
The link of SUA to cardiovascular events in apparently healthy
general population is supplemented by a considerable body of literature
specifically addressing the association of SUA to blood pressure(BP). (12-
16) In particular, at follow-up 4 years from baseline, 458 persons
(13.8%) of 3329 Framingham study participants (mean age 48.7 years; 55.6%
women) free of hypertension, myocardial infarction, heart failure, renal
failure, or gout had developed hypertension, and 1201 persons (36.1%) had
experienced progression to a higher BP stage. (12) Moreover, there is
evidence that not only does hyperuricemia persist after successful BP
control, but that its association with CVD events endures. (17)
Conflicting epidemiological data on the independent prognostic role
of SUA might be accounted for by the complex interrelations between SUA
and a variety of risk markers for CVD, including male gender, BP, and
previous cardiovascular events.(18,19) Furthermore, the effect of
diuretics on glucose and lipids, in addition to that on SUA, might lead to
subtle interactions of potential prognostic value that could be difficult
to control in a multivariate survival analysis.
The results of reanalysis of the Framingham study are an example of
the difficulties that may arise when the conclusions of general population
studies are applied to particular clinical conditions. While the
Framingham study was well designed, it must be borne in mind that the
population studied was small and not representative of the US population.
In that study, only one third of men and 30% of women were hypertensive,
5% of men and 10% of women were taking diuretics at the time of SUA
determination, and renal function was not included among the potential
confounders.(1) Furthermore, the mortality rate in the Framingham study
was approximately half that observed in other studies, e.g. NHANES I. (3)
Another reason why SUA may not always be an independent risk factor
for cardiovascular events could be that the beneficial antioxidant actions
of uric acid may partially counter its potential detrimental effects.(20)
In other words, low SUA levels may increase mortality as a result of
inadequate antioxidant levels and high levels of SUA may function more as
a pro-oxidant to increase the predisposition for the development of
hypertension and vascular disease. This assumption is based on the fact
that there is often a ‘J-shaped’ curve, with the nadir of risk in the
second quartile when one compares SUA levels with cardiovascular events
and all-cause mortality.(3, 21) A similar ‘J-shaped’ relationship was
found in patients with hypertension (17,22) , in patients with type II DM
(23), in hemodialysis patients (24) and in general population.(25) In
the Framingham study, the relation of SUA to coronary heart disease,
cardiovascular mortality and all-cause mortality appeared to be ‘J-shaped’
in men but not in women. (26)
Lastly, I would like to reduplicate that it is now well established
that SUA is an important, independent risk factor for cardiovascular
and renal disease. However, the key question whether a reduction of
SUA would prevent these diseases can only be answered definitively
through randomized clinical trials. The LIFE study seems to be the first
study to demonstrate that lowering SUA level is associated with a
beneficial effect on cardiovascular outcomes.(27) With regard to
negative results from OPT-CHF Study(28) it should be remembered that
there are a number of important limitations associated with allopurinol as
a mean of SUA lowering. For example, in people it causes only a modest
reduction in SUA concentration, up to around 30%. (29) In addition, the
potential CV effects of allopurinol could arise through a number of
mechanisms, and therefore its SUA-lowering effects require cautious
interpretation.
1. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and
risk for cardiovascular disease and death: The Framingham Heart Study. Ann
Intern Med 1999;131:7–13.
2. Baker JF, Krishnan E, Chen L, Schumacher HT. Serum uric acid and
cardiovascular disease: recent developments, and where do they leave us?
Am J Med 2005;118: 816-826.
3. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the
NHANES I epidemiologic follow-up study, 1971-1992. National Health and
Nutrition Examination Survey. JAMA. 2000;283:2404-2410.
4. Hakoda M, Masunari N, Yamada M, Fujiwara S, Suzuki G, Kodama K, et al.
Serum uric acid concentration as a risk factor for cardiovascular
mortality: a long-term cohort study of atomic bomb survivors. J Rheumatol
2005;32:906-912.
5. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, et al. Serum
uric acid, diuretic treatment and risk of cardiovascular events in the
Systolic Hypertension in the Elderly Program (SHEP). J Hypertens
2000;18:1149-1154.
6. Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA,
et al. Uric acid level as a risk factor for cardiovascular and all-cause
mortality in middle-aged men: a prospective cohort study. Arch Intern Med
2004;164:1546-1551.
7. Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y, et al.
Does hyperuricemia affect mortality? A prospective cohort study of
Japanese male workers. J Epidemiol 2000;10:403-409.
8. Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S.
Significance of hyperuricemia as a risk factor for developing ESRD in a
screened cohort. Am J Kidney Dis 2004;44:642-650.
9. Short RA, Johnson RJ, Tuttle KR. Uric acid, microalbuminuria and
cardiovascular events in high-risk patients. Am J Nephrol 2005;25:36-44.
10. Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH, et al.
Relationship between serum uric acid concentration and insulin resistance
and metabolic syndrome. Circ J 2005;69:928-933.
11. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M. Association
between serum uric acid, metabolic syndrome, and carotid atherosclerosis
in Japanese individuals.
Arterioscler Thromb Vasc Biol 2005;25:1038-1044.
12. Sundstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS.
Relations of serum uric acid to longitudinal blood pressure tracking and
hypertension incidence. Hypertension 2005;45:28-33.
13. Alper AB Jr, Chen W, Yau L, Srinivasan SR, Berenson GS, Hamm LL.
Childhood uric acid predicts adult blood pressure: the Bogalusa Heart
Study. Hypertension 2005;45:34-38.
14. Nagahama K, Inoue T, Iseki K, Touma T, Kinjo K, Ohya Y, et al.
Hyperuricemia as a predictor of hypertension in a screened cohort in
Okinawa, Japan. Hypertens Res 2004;27:835-841.
15. Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K. Serum
uric acid and risk for development of hypertension and impaired fasting
glucose or Type II diabetes in Japanese male office workers. Eur J
Epidemiol 2003;18:523-530.
16. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid
and plasma norepinephrine concentrations predict subsequent weight gain
and blood pressure elevation. Hypertension 2003;42:474-480.
17. Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and
cardiovascular events in successfully treated hypertensive patients.
Hypertension 1999;34:144-150.
18. Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG.
Serum uric acid in essential hypertension: an indicator of renal vascular
involvement. Ann Intern Med 1980;93:817–821.
19. Frohlich ED. Uric acid: a risk factor for coronary heart disease. JAMA
1993;270:378–379.
20. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et
al. Is there a pathogenetic role for uric acid in hypertension and
cardiovascular and renal disease? Hypertension 2003;41:1183-1190.
21. Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric
acid to mortality and ischemic heart disease. Am J Epidemiol
1995;141:637–644.
22. Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C,
Brunetti P. Relation between serum uric acid and risk of cardiovascular
disease in essential hypertension: the PIUMA study. Hypertension
2000;36:1072–1078.
23. Lehto S, Niskanen L, Ronnemaa T, Laakso M. Serum uric acid is a strong
predictor of stroke in patients with non-insulin-dependent diabetes
mellitus. Stroke 1998;29:635–639.
24. Hsu SP, Pai MF, Peng YS, Chiang CK, Ho TI, Hung KY. Serum uric acid
levels show a 'J-shaped' association with all-cause mortality in
haemodialysis patients. Nephrol Dial Transplant 2004;19:457-462.
25. Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J. Hyperuricaemia and
risk of cardiovascular disease and overall death. A 12-year follow-up of
participants in the population study of women in Gothenburg, Sweden. Acta
Med Scand 1988;224:549-555.
26. Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart
disease: the Framingham Study. J Clin Epidemiol 1988;41:237-242.
27. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De Faire
U, et al. LIFE Study Group. The impact of serum uric acid on
cardiovascular outcomes in the LIFE study. Kidney Int 2004;65:1041-1049.
28. Cardiome Pharma Corp. Press Release. Cardiome reports clinical results
from OPT-CHF Study. August 15, 2005. Available from:
http://www.cardiome.com/wordpress/?p=252.
29. Turnheim K, Krivanek P, Oberbauer R. Pharmacokinetics and
pharmacodynamics of allopurinol in elderly and young subjects. Br J Clin
Pharmacol 1999;48:501-509.
Competing interests:
None declared
Competing interests: No competing interests