JOURNAL OF EVIDENCE BASED MEDICINE AND HEALTHCARE

Table of Contents

2020 Month : March Volume : 7 Issue : 9 Page : 442-445

Study of Serum Uric Acid Level as an Independent Risk Factor in Acute Ischemic Stroke

Chandrashekhar K.1, Mohammed Anwar Hussain2, Ishwar S. Hasabi3, Suryakanth4, Chethan K. Ganteppanavar5

1. Associate Professor, Department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, Karnataka.
2. Senior Resident, Department of General Medicine, Adichunchanagiri Institute of Medical Sciences, Bellur, Mandya, Karnataka.
3. Professor and Head, Department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, Karnataka.
4. Postgraduate Student, Department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, Karnataka.
5. Postgraduate Student, Department of General Medicine, Karnataka Institute of Medical Sciences, Hubballi, Karnataka.

Corresponding Author:
Dr. Chandrashekhar K,
Associate Professor,
Department of General Medicine,
Adichunchanagiri Institute of Medical Sciences, Bellur, Mandya, Karnataka,
E-mail: chandrashekarkachapur@gmail.com

ABSTRACT
BACKGROUND
Stroke entails a high socioeconomic burden due to increased mortality and morbidity. The role of serum uric acid (SUA) level as an independent risk factor for stroke has been questioned for many years. Evidence from epidemiological studies suggest that elevated SUA levels may be associated with an increased risk of stroke and cardiovascular events.

METHODS
113 patients of first ever lifetime acute ischemic stroke admitted in Karnataka Institute of Medical Sciences, Hubli Hospital, were included. Blood samples were taken and CT scans were done within 24 hrs. of onset of stroke. Serum uric acid levels were analysed in patients and were compared with risk factors like hypertension, diabetes, adverse lipid profile, smoking and alcoholism.

RESULTS
The age of subjects ranged from 25 years to 90 years. Mean age was 59.2 ± 14.5 yrs. Most of the patients were aged ≥ 65 yrs. (46%). 76 were males (67.3%) and 37 females (32.7%). Male to female ratio in this study was 2.05:1. 37.2% patients were diabetic. 56.6% patients were hypertensive. 46.9% patients had elevated SUA levels. Mean SUA levels in 113 acute ischemic stroke patients was 6.5 ± 1.4. Mean SUA levels among males 6.4 ± 1.5 and among females it was 6.6 ± 1.5. (difference not statistically significant). Mean SUA level was higher (6.83 ± 1.5 mg/dl) among hypertensives (6.83 ± 1.5) compared to non-hypertensive patients (6.21 ± 1.4) and the difference was statistically significant. Mean SUA was higher among diabetics (6.9 ± 1.5) as compared to non-diabetics (6.2 ± 1.4) and the difference was statistically significant.

CONCLUSIONS
SUA levels were significantly elevated in ischemic stroke patients within 24 hours after symptom onset. SUA levels were significantly higher among hypertensive patients as compared to normotensive patients. SUA levels were significantly higher among diabetic patients as compared to non-diabetic patients. Due to the high prevalence of high SUA in patients with acute stroke, and its accompanying increase in hypertension and diabetes mellitus, it can be considered as a risk factor for acute stroke.

KEYWORDS
Acute Ischemic Stroke, Uric acid, GCS, Hyperuricemia, Diabetes, Hypertension, Smoking

How to cite this article

Chandrashekhar K, Hussain MA, Hasabi IS, et al. Study of serum uric acid level as an independent risk factor in acute ischemic stroke. J. Evid. Based Med. Healthc. 2020; 7(9), 442-445. DOI: 10.18410/jebmh/2020/95

BACKGROUND

A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurological deficit that is attributable to a focal vascular cause.1 The incidence of cerebrovascular diseases increases with age, and the number of strokes is projected to increase as the elderly population grows, with a doubling in stroke deaths in the United States by 2030. For India, community surveys have shown a crude prevalence rate for ‘hemiplegia’ in the range of 200 per 100,000 persons, nearly 1.5% of all urban hospital admissions, 4.5% of all medical and around 20% of neurological cases.2 Serum Uric Acid is an inert product of ingested and endogen nucleoproteins catabolism. It is the breakdown product of purines from DNA, RNA, ATP and cAMP. In this process hypoxanthine is converted by the enzyme xanthine oxidase to xanthine and further to uric acid. UA is the most abundant aqueous antioxidant in humans. In recent years, much attention has been paid to the role of uric acid in disease modification. In a variety of organs and vascular beds, local uric acid concentrations increase during acute oxidative stress and ischemia, and the increased concentrations might be a compensatory mechanism that confers protection against increased free radical activity.3

Overwhelming evidence suggests that hyperuricemia is linked to obesity, hypertension, reduced HDL cholesterol, hypertriglyceridemia, hyperinsulinemia and reduced insulin sensitivity, components of the metabolic syndrome. Thus, the role of uric acid in patients with stroke or other vascular disease is contentious and there is conflicting data on this subject. Some authors have suggested that elevated uric acid levels are closely associated with stroke risk factors and therefore hyperuricemia is a marker in patients at high risk for stroke. These observations have prompted interest in the potential impact of raised uric acid concentrations in the setting of acute ischemic stroke.4

            The present study was done to estimate serum uric acid levels in patients of acute ischemic stroke and to assess its risk factor potential and also study the association between SUA and other risk factors of stroke namely hypertension, Diabetes mellitus, and adverse lipid profile.

 

METHODS

113 patients of first ever lifetime acute ischemic stroke admitted in Karnataka Institute of Medical Sciences, Hubli hospital were included. The blood samples were taken, and CT scans were done within 24 hours of onset of stroke. Blood samples were sent for biochemical analysis for serum uric acid and other relevant investigations and 2D ECHO was done. The patients were further evaluated for presence of additional risk factors like hypertension, diabetes, adverse lipid profile, smoking and alcoholism. Serum uric acid levels were analysed in patients and were compared with risk factors like hypertension, diabetes, adverse lipid profile, smoking and alcoholism.

RESULTS

 

A total of 113 cases of acute ischemic stroke patients were included and were analysed regarding correlation of serum uric acid with acute ischemic stroke patients and risk factors for acute ischemic stroke like diabetes mellitus, hypertension, dyslipidaemia, smoking, alcohol consumption. Among 113 patients mean age group was 59.2 ± 14.5 years with Male to female ratio of 2.05:1. Among 113 patients, 56.6% were hypertensive and 37.2% were diabetics. One patient had ischemic heart disease.

 

Features

Frequency

Percentage

Diabetes mellitus

42

37.2

Hypertension

64

56.6

Ischemic heart disease

1

0.9

Table 1

 

Among 113, 50.4% were smokers. 30.1% were alcoholics. All smokers and alcoholics were males. Among 113, 55 patients had right hemiparesis constituting 48.3% whereas 48 patients had left hemiparesis, 6 patients had quadriparesis, secondary to brainstem infarct, and 4 had ataxia.

 

Features

Frequency

Percentage

Ataxia

4

3.5

Right hemiparesis

55

48.7

Left hemiparesis

48

42.5

Quadriparesis

6

5.3

Table 2

 

Among 113 patients, 29.2% had right MCA infarct, 29.2% had left MCA infarct, 14.2% had right basal ganglia infarct, 15.1% had left basal ganglia infarct, 3.5% had cerebellar infarct, and 5.3% had pontine infarct, normal CT scan in 3.5%.

 

Features

Frequency

Percentage

Left BG infarct

17

15.1

Left MCA infarct

33

29.2

Right BG infarct

16

14.2

Right MCA infarct

33

29.2

Right cerebellar infarct

4

3.5

Pontine infarct

6

5.3

Normal CT

4

3.5

Table 3

 

There is no universally accepted definition for hyperuricemia based only on serum UA levels. We defined participants as having hyperuricemia if their serum uric acid concentration was > 7.0 mg/dL in men or >6.0 mg/ dL in women. Among 113 acute ischemic stroke patients studied, 46.9% had elevated serum uric acid. Mean serum uric acid in male ischemic stroke patients was 6.4 ± 1.5. Mean serum uric in female ischemic stroke patients is 6.6 ± 1.5. Difference was not statistically significant. Mean serum uric acid level was 6.5 ± 1.4. The difference between mean SUA levels among patients with normal lipid profile and those with dyslipidaemia was not significant. Mean SUA was higher among patients with severe brain injury as compared to those with mild to moderate brain injury. However, the difference was not statistically significant. Mean SUA levels among smokers was 6.4 ± 1.4 and 6.6 ± 1.5. However, this difference was not statistically significant.

DISCUSSION

A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic deficit that is attributable to a focal vascular cause. (1) Stroke accounted for about one third of cardiovascular deaths (5·7 million deaths) and 46·6 million Disability Adjusted Life Years (DALYs) 5 The incidence of stroke increases dramatically with advancing age, and increasing age is the most powerful risk factor for stroke. The incidence of stroke doubles each decade past 55 years of age. Half of all strokes occur in people older than 75 years. Women have higher stroke case-fatality rates as compared with men. Men age 45–75 develop ischaemic strokes at higher rates than women; thereafter, stroke rates are higher in women.6

In India, where ischaemic stroke accounts for 80% of all strokes, 10% to 15% of strokes occur in people younger than 40 years and are mostly related to intracranial atherosclerosis.7 An increased risk is seen with a family history of stroke among first-degree relatives. Genetic factors have been linked with ischemic stroke, but specific genetic variants remain largely unknown.8 Hypertension is the most significant of the risk factors increasing the relative risk for stroke an estimated three- to fourf old.9 Diabetes mellitus obesity, hypertension, and dyslipidaemia often co-exist in patients with DM that add on to stroke risk.10 In addition, DM increases morbidity and mortality after stroke.

Dyslipidaemia, Obstructive sleep apnea (OSA),Aortic-arch atheromatosis, Elevated haematocrit, haemoglobin concentration, increased blood viscosity, Elevation of plasma fibrinogen, Antiphospholipid (APL) antibodies, Elevated von Willebrand factor, Elevated levels of fasting total homocysteine, high-dose oestrogen oral contraceptives are all associated with increased risk for stroke.

 

Figure 1. Molecular structure of Uric Acid

Uric acid is the final breakdown product of purine degradation in humans. It is weak diprotic acid with pKa values of 5.75 and 10.3. Urates, the ionized forms of uric acid, predominate in plasma, extracellular        fluid, and synovial fluid, with ~98% existing as monosodium urate at pH 7.4.11 Although purine nucleotides are synthesized and degraded in all tissues, urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine. The kidneys clear urate from the plasma and maintain physiologic balance by utilizing specific organic anion transporters (OATs). In adulthood, concentrations rise steadily over time and vary with height, body weight, blood pressure, renal function, and alcohol intake.11

SUA also possesses oxidative properties by mediating the production of radicals that have pro-oxidant effect on low density lipoprotein cholesterol.12 SUA also reduces the bioavailability of NO by increasing arginase activity, reduces endothelial NO synthase phosphorylation, and increases intracellular superoxide formation.13 In addition, uric acid caused a decrease in adiponectin production, an insulin sensitizer and anti-inflammatory agent. The oxidative stress and inflammation in adipocytes has been recognized as the mechanism underlying insulin resistance and atherosclerosis Kim et al. revealed in a systematic review involving of 16 cohort studies involving over 238,000 subjects that hyperuricaemia was significantly associated with a higher risk for stroke incidence (adjusted RR = 1.47, P <0.05) and stroke mortality (adjusted RR = 1.26, P < 0.05) compared with normouricaemia.14

In the Apo Lipoprotein Mortality Risk (AMORIS) study, elevated SUA was shown to be associated with a higher risk for haemorrhagic and ischemic stroke.15 in a study on American population by Kanellis J et al with acute stroke, those with higher serum levels of uric acid were observed to be more debilitated with more recurrences and cardiovascular accidents.15 A 3- month follow-up of stroke patients by Weir C J et al in England indicated greater mortality for those who had higher uric acid levels.16

A study in Greece on 163 patients by Millinois et al suffering from non-embolic ischemic stroke indicated more complications and greater risk of recurrence for those with higher uric acid levels. Findings of this study showed that elevated uric acid is associated with an increased risk for acute ischemic/non-embolic stroke in a strictly defined population of elderly individuals independently of concurrent metabolic derangements.17 Another study in USA, ARIC study, showed that hyperuricemia increased the risk for both cerebral and cardiac vascular accidents. A 12.5-year follow-up of hyperuricaemic people in the United States observed higher risks of ischemic stroke and myocardial infarction for these people.18 In this study, we observe greater incidence of acute stroke in patients with high SUA, and increased risk when associated systemic comorbidities like hypertension and Diabetes Mellitus.

CONCLUSIONS

Serum uric acid levels were significantly elevated in patients with acute ischemic stroke. Serum uric acid levels were significantly higher among hypertensive patients as compared to normotensive patients. Serum uric acid levels were significantly higher among diabetic patients as compared to non-diabetic patients. Due to the high prevalence of hyperuricemia in patients with acute stroke, and its accompanying increase in hypertension and diabetes mellitus, it can be considered as a risk factor for acute stroke. So, screening for hyperuricemia in patients with DM and Hypertension and treating and lowering of serum uric acid level can be considered as one of the preventing modalities for stroke while treating high risk population.

 

REFERENCES

 

 

  1. The global burden of disease: 2004 update. Geneva: WHO 2008.
  2. Munjal YP.et al. API textbook of medicine. 9th Jaypee Brothers Medical Publishers 2012: p. 1401.
  3. Kanemitsu H, Tamura A, Kirino T, et al. Xanthine and uric acid levels in rat brain following focal ischemia. J Neurochem 1988; 51(6):1882-1885.
  4. Chamorro A, Obach V, Cervera A, et al. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke 2002; 33(4):1048-1052.
  5. Smith WS, Johnston SC, Hemphill JC. Cerebrovascular diseases. In: Kasper D, Fauci A, Hauser S, et al, eds. Harrison's Principles of internal medicine. 19th McGraw-Hill Education 2015.
  6. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics- 2014 update. A report from the American Heart Association. Circulation 2014; 129(3):e28-e292.
  7. Biller J, Ruland S, Schnek MJ. Ischemic cerebrovascular disease. In: Daroff RB, Jankovic J, Mazziotta JC, et al, eds. Bradley's neurology in clinical practice. 7th Elsevier 2016:920-967.
  8. Adams HP, Bendixen BH, Kapelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of ORG 10172 in Acute Stroke Treatment. Stroke 1993; 24(1):35-41.
  9. MacMahon S, Rodgers A. Primary and secondary prevention of stroke. Clin Exp Hypertens 1996; 18(3-4):537-546.
  10. Amarenco P, Labreuche J, Lavallee P, et al. Statins in stroke prevention and carotid atherosclerosis: systemic review and up-to-date meta-analysis. Stroke 2004; 35(12):2902-2909.
  11. Burns CM, Wortmann RL. Disorders of purine and pyrimidine metabolism. In: Kasper D, Fauci A, Hauser S, et al, eds. Harrison's principles of internal medicine. 19th McGraw-Hill Education 2015: p. 2533.
  12. Patterson RA, Horsley ETM, Leake DS. Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDL: important role of uric acid. J Lipid Res 2003;44(3):512-521.
  13. Zharikov S, Krotova K, Hu H, et al. Uric acid decreases no production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008; 295(5):C1183-C1190.
  14. Kim SY, Guevara P, Kim KM, et al. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 2009; 61(7):885-892.
  15. Kanellis J, Johnson RJ. Elevated uric acid and ischemic stroke: accumulating evidence that it is injurious and not neuroprotective. Stroke 2003; 34(8):1956-1957.
  16. Weir CJ, Muir SW, Walters MR, et al. Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003; 34(8):1951-1956.
  17. Milionis HJ, Kalantzi KJ, Goudevenos JA, et al. Serum uric acid levels and risk for acute ischaemic non-embolic stroke in elderly subjects. J Intern Med 2005; 258(5):435-441.
  18. Hozawa A, Folsom AR, Ibrahim H, et al. Serum uric acid and risk of ischemic stroke: the ARIC Study. Atherosclerosis 2006; 187(2):401-407.