Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to gout and uric acid?
Gout is a relatively common arthritic disease that affects about 4% (I in 25) of the population. It results from the deposition of uric acid in joints due to elevated blood levels and a resulting inflammation ensues which is very painful.
While it can affect any joint or soft tissue, patients typically present with an acute arthritis (an acute painful swelling) of the big toe or indeed the ankles or knees. Some patients experience frequent acute flares while others can develop a progressive chronic form of gout called tophaceous gout due to uric acid build up in the soft tissues.
The prevalence of this condition is increasing in Western Countries. Emerging evidence suggest that gout and hyperuricaemia are risk factors for cardiovascular disease and death. Defining the impact of gout and elevated uric acid on the health of the population is an important research initiative.
What are the key contributing factors towards increased uric acid levels?
It is widely known that elevated levels of serum uric acid (hyperuricaemia) play an important role in the development of gout. However not all people with elevated uric acid levels will develop gout.
Levels of uric acid may increase in the blood if a patient has kidney damage leading to poor excretion of uric acid, or if there is an over production of uric acid in the blood due to ingestion of excessive purine-rich foods.
Certain groups of individuals are predisposed to gout including; men, older subjects, specific race and ethnic groups, obese individuals; diets rich in meat and seafood content; alcohol; fruit juices high in fructose content; subjects with hypertension; patients on thiazide or loop diuretics; post-menopausal and organ transplant recipients; and the use of certain medications.
The avoidance of these risk factors is advocated for patients who are prone to recurrent attacks of gout.
Why did you choose to research the combined impact of gout and uric acid concentrations on the risk of death and why do you think most studies to date have not looked at this?
While there has been some work already published on the clinical outcomes of uric acid and gout in large populations, there remain significant gaps in our knowledge base.
Up to now it was unclear whether the mortality risks associated with gout were magnified for those with higher uric acid levels. Furthermore, it was also unclear whether the risks associated with elevated uric acid were similar across age, sex, and race groups and by disease status.
Our study has contributed to the currently body of knowledge and has improved our understanding of gout uric acid and its consequences.
What did your research involve?
In our study, we examined the relationships of gout and serum uric acid with mortality over a 10 year period in 15,773 individuals from the Third National Health and Nutrition Examination Survey (NHANES III).
The cross-sectional component provided detailed data on the prevalence of gout, hyperuricaemia, cardiovascular conditions and risk factors, and medication use.The longitudinal component provided detailed information vital status right through to 2006.
We were therefore able to determine the death rates (the crude and adjusted) that were associated with a diagnosis of gout and elevated uric acid levels. Furthermore, we were for the first time able to describe the relationships of gout and hyperuricaemia with mortality in several age, sex and race categories as well as in subjects with and without major comorbid conditions.
The entire analysis was conducted by our team at the Graduate Entry School of Medicine at the University of Limerick in Ireland.
What did your research find and were you surprised by these results?
There were some very striking observations which have shed new insights into the importance of gout and hyperuricaemia and in part have confirmed findings from other published studies.
Compared to individuals without gout, we found that individuals with gout died earlier and experienced a 42% higher risk of death. Similarly, individuals with gout experienced a higher risk of dying from cardiovascular disease with a 58% higher risk of cardiovascular death.
We did find that individuals with gout had a greater abundance of many known cardiovascular conditions and risk factors compared to those without gout as others have demonstrated previously. Nevertheless, even when we took these factors into account, individuals with gout and elevated uric acid had higher death rates.
Across most, age, sex and race subgroups, we demonstrated that individuals with the highest uric acid levels (>375 µmol/L), had a 77 % higher risk of death from all causes and a 209% higher risk of cardiovascular death than those who had the lowest levels of uric acid (0 to < 256 µmol/L).
Even more striking we found that, the risk of rising uric acid levels were detrimental to those who might be considered to have healthy lifestyles, (people who never smoked, 11% higher death risk per 60 µmol/L increase); people who never drank, (15% higher risk per 60 µmol/L increase) and, people who were physically active (9% higher risk per 60 µmol/L increase).
Did your research reveal the reasons why individuals with gout died earlier than those without – even after adjusting for risk factors such as diabetes, hypertension and so forth?
Our research suggested that gout, an index of cumulative urate burden, and hyperuricaemia were associated with increased death risk regardless of other well-known cardiovascular riskfactors. In other words, the independence of this relationship would suggest that perhaps gout and hyperuricaemia may be considered in the causal pathway and therefore contribute directly to elevated mortality.
There is good evidence to suggest that hyperuricaemia itself may elevate cardiovascular risk either directly or indirectly with through progressive kidney damage, initiation and worsening of hypertension, or indeed systemic inflammation and the development of the metabolic syndrome.
What are the key determining factors in the relationship between gout and the increased risk of cardiovascular disease?
There is no doubt that a proportion of relationship between gout and cardiovascular risk may be explained by the co-presence of other known cardiovascular risk factors. Subjects with gout had higher levels of several cardiovascular conditions: obesity, hypertension, diabetes, myocardial infarction, heart failure, stroke, and so forth; factors that are strongly associated with increased death risk and cardiovascular risk.
Indeed, the unadjusted analysis confirmed that subjects with gout had a 4-fold risk of death and over a 5-fold risk of cardiovascular death. These findings just cannot be ignored.
However, with adjustment, the risk was decreased somewhat but persisted. This analysis tells us that gout itself may directly contribute to death risk independent of the conventional risk factors that we are all familiar with.
How important a role do you think alcohol plays in causing gout and these associated risks?
There is a strong body of evidence now that consumption of alcohol-containing beverages (especially beer and distilled spirits) is associated with the development of hyperuricaemia and gout. Individuals who drink alcohol in excess have greater risk of a first attack of gout.
Beer appears to confer a higher risk than spirits and the greater the consumption, the greater the risk of a first gouty attack.
While it is possible that alcohol may contribute to death in individuals with gout and hyperuricaemia, the bulk of the evidence would suggest that gout and hyperuricaemia independently predict death. In our study, subjects with gout, but who never drank alcohol, experienced a 72% higher risk of death.
What recent developments have there been in the treatment of gout and its underlying causes?
There are several well established treatments for the management of gout and hyperuricaemia.
The prevention of gout and its debilitating consequences is based on reducing serum uric acid concentrations below 300 µmol/L. Treatment is indicated when recurrent gout attacks (>2/year) or tophi are presented by the patients.
Standard therapy generally consists of using a uric acid lowering agent like allopurinol and for those with preserved kidney function, a diuretic may be employed.
For those who are resistant to allopurinol, treatments have been limited until recently. Novel treatments include the use of febuxostat, a new Xanthine Oxidase Inhibitor, which offers similar efficacy to allopurinol.It produces a dose-dependent decrease in serum urate levels and a daily dose of 40 mg produces a reduction in uric acid levels that is roughly equivalent to allopurinol at a dose of 300 mg per day.
Another new agent is Pegloticase, a porcine uricase that is an alternative therapy for patients with severe gout in whom treatment with other urate-lowering agents has failed to be effective. This is generally reserved for patients in whom rapid clinical response is required.
Several professional organizations have developed guidelines for the management of gout, including the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).These should be consulted for more details information on the management of gout and hyperuricaemia.
Would you have any recommendations in terms of redefining how sufferers are treated now by the healthcare profession?
One of the most important findings that this study highlights is the high rate of cardiovascular death among individuals with gout and/or hyperuricaemia. We would suggest that these patients be considered at high-risk for cardiovascular disease and death and that these undergo appropriate cardiovascular risk assessment and screening.
Aggressive screening for underlying cardiovascular disease and treatment of existing conventional cardiovascular risk factors is necessary. Randomised controlled clinical trials are ultimately required to evaluate whether effective treatment of hyperuricaemia and gout results in fewer cardiovascular events and ultimately lower death risk.
What are your further research plans?
Our team is leading on a number of initiatives to improve our understanding of cardiovascular disease and kidney disease in the general population. Using existing and newly established cohorts, we are examining potential risk factors for cardiovascular disease in specific populations.
With regard to gout and uric acid, we are exploring the relative importance of gout and hyperuricaemia in specific populations and the degree to which patients are investigated and treated. What should be the target threshold for treatment of hyperuricaemia? Should patients with asymptomatic hyperuricaemia be treated?
We are also exploring the hypotheses that 1) elevated levels of uric acid contribute to adverse patient’s outcomes in the general population and in those with specific comorbid diseases, and that 2) deficiencies currently exist in clinical care delivery of patients with gout, deficiencies that can in general be rectified with simple interventions.
Where can readers find more information?
There are several easy-to-read excellent online resources for patients or their relatives who may have gout. These are available at:-
About Prof Stack
Professor Austin Stack is the Foundation Chair of Medicine at the Graduate Entry Medical School at the University of Limerick in Ireland since March 2012; and a Consultant Nephrologist at University Hospital Limerick.
He received his medical degree from the National University of Ireland in 1991. After internship, medical residency and early nephrology training in Ireland, he pursued fellowship training (1996-1999) in Nephrology & Transplantation in the United States at the University of Michigan.
With an interest in healthcare outcomes, Professor Stack studied Clinical Research Design and Statistical Analysis (MSc) at the Racham School of Public Health and was appointed to the research teams at the Kidney Epidemiology and Cost Centre (KECC), and US Renal Data System (USRDS).
He joined the Renal Division at the University of Texas as Assistant Professor of Medicine in 2001 and led a successful epidemiological research and mentorship program until his move to Ireland in 2005. He was awarded his MD in Medicine (Epidemiology) in 2005.
Professor Stack's research themes include: treatment strategies for end-stage renal disease; cardiovascular disease and cardiovascular risk assessment; risk prediction models; and the application of IT communications systems in clinical and epidemiological research.
To date, he has authored more than 120 original and review articles, research abstracts, and book chapters.
He is a funded researcher with grants from the Irish Health Research Board (HRB),US National Institutes of Health (NIH), American Heart Association (AHA), National Kidney Foundation, and industry.
Professor Stack is the Clinical Director of the National Renal IT Project which aims to establish a state-wide renal information network for patients with kidney disease in Ireland and support a Renal Registry.
He sits on the Steering Committee for the US Kidney Disease Surveillance Programme and is the principal investigator for the National Kidney Disease Surveillance System in Ireland that has been recently funded by the Irish Health research Board.