In this article by Dr. Mangesh Tiwaskar, a noted physician highlights the correlation between hyperuricaemia and hypertension.

 

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Hypertension is a rapidly growing global health problem. It is also a major health hazard in India with an estimated prevalence of every 3 in 10 adults. This is predicted to rise to 22.9% in men and 23.6% in women by 2025.

Hyperuricaemia is emerging as an important ‘independent risk factor’ which has attracted academic attention recently. The possible association of Uric Acid (UA) and hypertension has been considered for more than a century. Frederick Mahomed, in the 1870s, proposed UA as an important mediator for hypertension and published the first sphygmograph tracings showing an association of gout with increased systemic blood pressure (BP).

Hyperuricaemia is a frequent companion of metabolic syndrome, diabetes, dyslipidemia, chronic renal disease, and obesity apart from hypertension. It is uncertain, however, if hyperuricaemia is an independent risk factor for adverse outcomes in these situations. There are many confounding factors which impact the SUA levels and hence interventions focusing only on SUA are rare. With the advent of newer anti-hyperuricaemic drugs such as Febuxostat, UA studies are attracting more attention.

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A quick look at the uric acid physiology

UA is an end metabolite of purine metabolism in humans. In few mammals, UA is degraded by enzyme Uricase to Allantoin which can be easily excreted, but during processes of evolution; humans lost Uricase and hence UA tends to accumulate in the human body. The Purines are the skeleton components of Nucleic acids (DNA, RNA). Purines enter the human body after consumption of Purine-rich food like Organ meat or they are biosynthesised in our body. A major portion of endogenous UA is generated by the metabolism of Adenosine Triphosphate (ATP) – human energy source, which is converted into Hypoxanthine, Xanthine, and eventually to UA. UA is then excreted in blood from the cells.

The most interesting fact in entire ATP metabolism is during the process of conversion of Hypoxanthine to Xanthine by Xanthine Oxygenase (XO), there is a release of Reactive Oxygen Species (ROS) which is probably one of the factors blamed for causing atherosclerosis and arteriosclerosis.

Hyperuricaemia is most possibly caused by the Westernised Lifestyle and Food intake rich in Purines. The uric acid (UA) stays soluble physiologically up to 6.4 mg%. Sometimes due to special UA binding proteins, the solubility levels can be 7.0 mg% before reaching the saturation point beyond which UA starts crystallising in the tissues.

So, to define the state of Hyperuricaemia, the cut off for SUA level is 7.0 mg%. In women, this level is lower than in males and requires attention at a lower threshold. The SUA level is known to vary significantly depending on meals, lifestyle, gender, and previous use of diuretics.

During the metabolism of fructose-rich or corn starch syrup rich foods, soft drinks, and alcohol, a large amount of ATP is consumed resulting in the increased amount of UA production. That’s how western food (Fast Food) is linked with the causation of Hyperuricaemia. In fact, all excessive ATP producing and/or consuming situations produce hyperuricaemia. Also, conditions triggering or harvesting anaerobic metabolism leading to excessive lactic acid production results in hyperuricaemia as lactic acid augments renal reabsorption of UA. Renal reabsorption mainly occurs in Proximal tubules with Urate Transporter 1 (URAT1).

So, URAT1 inhibitors like Probenecid or Benzbromarone are effective options for treating Hyperuricaemia due to underexcretion. ARBs and Fibrates are also known to inhibit URAT1. In contrast, diuretics like Thiazide or Frusemide increase UA levels.

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Effect on Hypertension and related events

Several studies have reported the relationship between SUA level and hypertension and some recent cross-sectional, cohort, and interventional studies have identified hyperuricaemia as an independent risk factor for hypertension. Though their close association has made this correlation of high SUA and hypertension very difficult to interpret, recent double-blind intervention trials have attempted to minimise the effect of confounding conditions and quantify the contribution of hyperuricaemia to hypertension.

There is a 1.2 to 1.7 fold increase in incidence of hypertension with every rise of SUA by 1 mg% and also few cohorts elucidated the reduction in blood pressure with URAT1 inhibitors like Probenecid and XO inhibitors Allopurinol.

Based on the above research, it appears that hyperuricaemia worsens the blood pressure control and CV (cardiovascular)outcomes in hypertension by triggering arteriosclerosis due to the effects of increased oxidative stress during UA production, urate transporter disorders, and vascular disorders.

Clinical research also revealed the association of raised SUA with endothelial dysfunction, excessive coronary calcification and reduced flow-responsive dilatation and high pulse wave velocity leading to accelerated target organ damage and poorer CV outcomes.

UA and ‘J’ Curve Phenomenon

Overzealous reduction in UA may have the detrimental effect and UA level <3.2 mg% might end up in overproduction of ROS as UA along with Bilirubin and Ascorbic Acid (Vitamin C) exerts a strong antioxidant effect and plays a pivotal role in neutralising the ROS.

Some studies report increased CV events or deaths; especially in elderly hypertensives; due to excessive UA reduction. Hence, one needs to maintain a fine balance during management of the hyperuricaemia with regular monitoring and treatment modifications.

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Conclusion

Hyperuricaemia is rapidly being recognised as an independent risk factor for lifestyle and metabolic diseases, but its coexistence with hypertension has attracted the highest attention and research. Appropriate estimation, monitoring, and management are necessary for the adequate multi-pronged approach for management of hypertension.

Although it is yet to become a part of consensus guidelines, estimation of SUA levels at the time of diagnosis and at the regular intervals during the follow-up may be cardinal. Although several small-scale interventional studies that focused on UA and hypertension have been recently reported, but future large-scale, placebo-controlled, double-blind, interventional studies are needed to strengthen the correlation between hypertension and hyperuricaemia.

Dr. Tiwaskar has recently published an editorial in the current issue of JAPI. To read it, click here. 

Disclaimer-The information and views set out in this article are those of the author(s) and do not necessarily reflect the official opinion of M3 India. Neither M3 India nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein. 

This article was originally published on 9.01.18.

Currently functioning as the general secretary of Association of Physicians of India, Dr. Mangesh Tiwaskar, a gold medalist, trained in premier Indian institute as well as in International organisations, has been practising for more than two decades as a physician. He holds a special interest in Diabetology and Cardiology. He has authored chapters in medical textbooks, and published and presented many papers on Diabetes and related subjects.