original article Hypertension as Determinant of Hyperuricemia: A Case Control Study from the Sub-Himalayan Region in North India

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1 14 original article Hypertension as Determinant of Hyperuricemia: A Case Control Study from the Sub-Himalayan Region in North India Sujeet Raina 1*, Vishnu Kumar Agarwal 2, Dhiraj Kapoor 3, Kailash Nath Sharma 4, RS Yadav 5 Abstract Background: Association between hyperuricemia and hypertension has been recognized for many years. Whether hyperuricemia is the cause or the effect is debatable. Materials and methods: This case control study was conducted to assess serum uric acid (SUA) levels in fifty newly diagnosed essential hypertensive patients and fifty normotensive controls which were matched for age and sex. Detailed anthropometric characteristics including height, weight, body mass index and waist hip ratio were measured. Hypertension was classified according to Joint National Committee (JNC) 7 criteria. Hyperuricemia was defined as SUA level of 6.8mg/dl or more in both men and women. SUA was measured by uricase method. Before collecting the blood samples, patients were advised to proceed on overnight fast of minimum eight hrs. Student s t test for mean of continuous variables and Chi square test for proportions were used for statistical significance. Results: Present study included 50 newly diagnosed cases of essential hypertension and 50 age and sex matched normotensive healthy volunteer. Prevalence of hyperuricemia was 24% among the cases and 6% among the controls (P<0.05). Odds ratio was 4.9 (CI=1.3 to 18.8). The mean SUA was significantly higher in the cases (5.5±1.7 mg/dl) than in the controls (4.9±1.1 mg/dl; P<0.05). Odds ratio in male hyperuricemic hypertensive versus hyperuricemic normotensive was 6(CI=1.0 to 33.2) and 4.46(CI=0.4 to 42.5) among female hyperuricemic hypertensive versus hyperuricemic normotensives. Conclusion: Strong positive association was observed between hypertension and hyperuricemia in both male and female patients in this study. Introduction Hyperuricemia has been reported in 26 % of untreated hypertensive patients having normal blood urea nitrogen levels. 1 Different studies advocate the association between serum uric acid (SUA) level and hypertension. In a large meta-analysis of 18 prospective cohort studies representing data from 55,607 subjects, incident hypertension increased by 13 % per 1 mg/dl increase of SUA. 2 The various mechanism of this Editorial Viewpoint Hyperuricemia as a cause or an effect of hypertension is debatable. Present study finds hyperuricemia in 24% of hypertensives compared to 6% among controls. association between hypertension and hyperuricemia includes: (a) uric acid induced activation of renin-angiotensin system and action on glomerular apparatus (b) increased insulin resistance and hyperinsulinemia, causing decreased excretion of uric acid, sodium, potassium from renal tubules; and (c) uric acid action in proliferation of vascular smooth muscle, endothelial dysfunction with decreased nitric acid production. 3-8 However, there are numerous confounding factors including metabolic syndrome, diabetes mellitus, obesity, alcohol consumption, salt intake, fluid volume status etc. in the association of hyperuricemia and hypertension. Hyperuricemia is common among adults with pre-hypertension. The observation that hyperuricemia precedes the development of hypertension indicates that it is not simply a result of hypertension per se. Hyperuricemia resulting from 1 Assistant Professor, 2 Postgraduate Student, 3 Professor, 4 Associate Professor, 5 Professor, Dr. Rajendra Prasad Govt. Medical College, Tanda, Kangra, Himachal Pradesh; * Corresponding Author Received: ; Revised: ; Accepted:

2 15 euglycemic hyperinsulinemia may precede the onset of type 2 diabetes, hypertension, coronary artery disease, and gout in individuals with metabolic syndrome. 9 Though ample amount of literature and studies supporting the causal role of hyperuricemia in hypertension is available in western countries, studies in this regard are scanty in the Indian scenario. In spite of the observational studies to investigate the association between uric acid and hypertension, controversy still remains. The present study was undertaken to generate information and evidence concerning this topic. Material and Methods It was an observational case control study conducted in the department of Medicine, Dr. Rajendra Prasad Government Medical College, Kangra at Tanda after getting approval of institutional ethics committee. Fifty newly diagnosed patients with hypertension based on JNC VII and above the age of 18 years were included in this study. Patients with secondary hypertension, diabetes, gout, alcohol abuse, hypothyroidism, hyperparathyroidism, ischemic heart disease, congestive cardiac failure,chronic kidney disease, any acute illness, pregnancy, steroidal medications or any medication likely to increase SUA and patients not willing to participate in the study were excluded. Fifty controls were normotensive healthy volunteer individuals not on any medication among the attendants of the patients or hospital employees fulfilling the exclusion and inclusion criteria. The sample size was The sample size was calculated using STATCALC from epiinfo software with two sided confidence level of 95%, power of 80%, ratio of case to controls of 1:1, odds ratio of 6.3 and proportion of exposed among cases at 25%. The age and sex between the newly diagnosed hypertension cases and normotensive healthy controls were matched. Detailed anthropometric characteristics including height, weight, body mass index and waist hip ratio were measured. Blood pressure was measured and classified as per the Joint National Committee (JNC) 7 guidelines. 10 Hyperuricemia was defined as SUA level of 6.8mg/dl or more in both men and women. 11,12 SUA was measured by uricase method. 13 Fasting blood glucose was done by glucose oxidase-peroxidase method. Total Cholesterol (TC) was measured by CHOD- PAP method, Triglycerides (TG) by GPO- Trinder, high Density Lipoprotein (HDL-C) by Immuno-inhibition and low Density Lipoprotein (LDL-C) by Immuno-inhibition method. Before collecting the blood samples, patients were advised to proceed on overnight fast of minimum eight hrs. The software used for data analysis was Epi Info -7 a free software for statistics developed by CDC - Centers for Disease Control and Prevention. Student s t test was used to compare the mean of the continuous variables. Chi square test was used to compare proportions. No pooled analysis was carried out as pooled analysis in case-control studies is more popular when genetic markers are involved, while pooled analysis in cross-sectional studies is preferred when markers of exposure are explored. Results Fifty newly diagnosed hypertension cases and 50 normotensive controls matched for age and sex were included. The clinical and laboratory characteristics of the study population are shown in Table 1. Prevalence of hyperuricemia was significantly higher among the cases (24%) than controls (6%) (P<0.05). Hyperuricemia was found in 40% male cases and in 13.3% female cases. Hyperuricemia was significantly more in male cases than female cases (p<0.05). Mean serum UA level in male patients was 6.5±1.5mg/dl. In female patients mean SUA levels was 4.9±1.6 mg/dl and the difference is statistically significant (p<0.05). In our study the mean SUA levels were higher in cases (5.5±1.7) than in controls 4.9±1.1 and the difference is statistically significant. (p<0.05). The mean SUA levels were significantly higher in male hypertensive patients (p<0.05). Mean SUA was significantly higher in the male cases (6.5±1.5 mg/dl) than in the male controls (5.4±1.0 mg/dl; P<0.05), and the prevalence of hyperuricemia was 40% among the cases and 10% among the controls (P<0.05). In our study mean SUA was not significantly different in the female cases (4.9±1.6 mg/dl) than in the female controls (4.6±1.0 mg/dl; P=0.46). But prevalence of hyperuricemia was significantly higher in female cases (13.3%) than among the controls (p<0.05). The odds ratio for the hyperuricemia among cases and controls is shown in Table 2. The anthropometric, clinical and laboratory characteristics of hypertensive patients with and without hyperuricemia are compared with controls in Table 3. We found that hyperuricemia was present in 6% normal healthy controls and was more frequent in males (10%) than females (3.3%). Discussion The prevalence of hypertension, a major risk factor for noncommunicable diseases is increasing in developing countries. 14 By the year 2020, deaths due to non-communicable diseases will overtake communicable diseases by almost four times in developing countries. The identification of individual risk factors of hypertension and taking effective preventive measures will control the rising burden. 15 Elevated uric acid levels are often associated with established traditional cardiovascular risk factors; it is not quite sure whether uric acid is the cause or consequence of

3 16 Table 1: Clinical, anthropometry and laboratory characteristics of the study patients and controls and comparison between male and female subjects Variables p-value Male Female (n=20) (n=20) (n=30) (n=30) Smoker 12 (24%) 8 (16%) (50%) 8 (40%) (6.7%) Family history 12 (24%) 14 (28%) (15%) 8 (40%) (30%) 6 (20%) 0.30 of hypertension BMI(Kg/m²) 24.9± ± ± ± ± ± WHR 0.94± ±0.04 < ± ±0.02 < ± ±0.05 <0.05 FBS(mg/dl) 96.4± ±18.9 < ± ± ± ±15.6 <0.05 SUA(mg/dl) 5.5± ±1.1 < ± ± ± ± Hyperuricemia 12 (24%) 3 (6%) < (40%) 2 (10%) (13.3%) 1 (3.3%) <0.05 Lipid profile TC(mg/dl) 205.5± ± ± ± ± ± TG(mg/dl) 192.6± ± ± ± ± ± HDL(mg/dl) 53.5± ± ± ± ± ± LDL(mg/dl) 114.9± ± ± ± ± ± n=number; BMI= body mass index; WHR= waist hip ratio; FBS= fasting blood sugar; SUA= serum uric acid; TC= total cholesterol; TG= triglycerides; HDL= high density lipoprotein; LDL= low density lipoprotein Table 2: Odds ratio for hyperuricemia and hypertension among study subjects Hyperuricemia Odds ratio (95% confidence interval) Total 12 (24%) 3 (6%) 4.9 (CI=1.3 to 18.8) Males 8 (40%) 2 (10%) 6 (CI=1.0 to 33.2) Females 4 (13.3%) 1 (3.3%) 4.46 (CI=0.4to 42.5) n=number; CI=confidence interval hypertension Hyperuricemia is fairly common with the prevalence between 2.6% and 47.2% in various populations. 19 A significant association between SUA and blood pressure has been observed in age group less than 59 years. 20 A study from another northern part of India found hyperuricemia in 37% of hypertensive cases and 17% of controls. 21 Other studies have reported prevalence of hyperuricemia in newly diagnosed hypertensive from 25.4% to 31.8% which are closer to our study In present study odds ratio in hyperuricemic hypertensive versus hyperuricemic normotensive was 4.9(CI=1.3 to 18.8) and it is suggestive of a strong positive association between hypertension and hyperuricemia. Hyperuricemia was significantly more in male Table 3: Distribution of study subjects according to hyperuricemia and association with clinical, anthropometry and laboratory characteristics Variable Elevated SUA (n=12) Normal SUA (n=38) Elevated SUA (n=3) Normal SUA (n=47) Smokers 4 (33.3%) 8 (21.1%) (66%) 6 (12.8%) 0.01 Family 3 (25%) 9 (23.6%) (66.6%) 12 (25.5%) 0.12 history of hypertension BMI (Kg/m²) 25.7±4 24.6± ± ± WHR 0.95± ± ± ± SBP (mmhg) 163.6± ± ± ± DBP (mmhg) 102.6± ± ±4 71.9± FBS (mg/dl) 92.7± ± ±22 88± TC (mg/dl) 214± ± ± ± TG (mg/dl) 204.3± ± ± ± HDL (mg/dl) 54.4± ± ± ± LDL (mg/dl) 118.6± ± ± ± n=number; BMI= body mass index; WHR= waist hip ratio; SBP= systolic blood pressure; DBP= diastolic blood pressure; FBS= fasting blood sugar; SUA= serum uric acid; TC= total cholesterol; TG= triglycerides; HDL= high density lipoprotein; LDL= low density lipoprotein cases than female cases in present study. The statement is an outcome of difference in proportion of hyperuricemia in male and female and although may lack generalisation because of sample chosen, points to an important issue which can be taken up on a larger sample. Other studies found that hyperuricemia was almost equal in both males and females. 22,24 Bibek et al observed higher prevalence of hyperuricemia in female hypertensives (29.2%) than male hypertensives (28.4%). 22 The mean SUA in hypertensives observed in this study was 5.5±1.7 and is close to mean SUA levels found in study conducted by Neki et al, 21 Perlstein et al 25 and Strasak et al. 26 They found mean uric acid level 5.8 ± 1.3 mg/dl, 5.8 ± 0.9 mg/ dl and 5.7 ± 1.2 mg/dl respectively. Similar results observed in a study conducted in Bangladesh by Kashem et al in which mean SUA was 5.8±1.5 mg/dl. 23 However, higher mean SUA levels were observed by Feig et al, where they found mean uric acid was 6.9 mg/ dl in their study patients. 27 Mean SUA levels is lower in our study

4 17 in comparison to 6.0 ± 1.2 mg/ dl found in a study conducted at a higher altitude of 4300 m and 6.1 ± 1.6 mg/dl as found in other study conducted at an altitude of more than 3500 m. 28,29 However, it is higher in comparison to 4.7±1.0 mg/dl found in a study conducted at a tertiary care hospital in the Northern hilly state of Himachal Pradesh, India. 30 Mean SUA level is also higher in comparison to 4.8±1.4 mg/dl found in the study conducted by Bibek et al. 22 Kashem et al in found that mean SUA in males was 6.0 ± 1.4 mg/dl and in female patients mean SUA 5.5 ± 1.3mg/ dl. 23 In another study conducted by Bibek et al in Nepal also observed higher mean SUA level in males 5.23±1.48mg/dl in comparison to females 4.4±1.3mg/dl. 22 It has been observed that mean SUA level was significantly higher in male cases (5.2±1.4 mg/dl) than male normotensives (4.4±1.7 mg/dl) in the study conducted by Bibek et al. Prevalence of hyperuricemia was also higher in hypertensives (28.4%) than normotensives (14.3%) in this study. 22 Kashem et al also observed that mean serum acid levels in male hypertensives (6.0±1.4 mg/ dl) was significantly higher than normotensives (4.8±1.4 mg/dl) and prevalence of hyperuricemia was also significantly higher in male cases (25.9%) than male controls (11.5%). 23 in present study, mean SUA was significantly higher in the male cases than in the male controls and the prevalence of hyperuricemia was also statistically significant among the cases in comparison to controls. A strong association between hyperuricemia and hypertension among males was observed in present study [odds ratio 6 (CI=1.0 to 33.2)]. Though we picked high prevalence of hyperuricemia in female cases but there was no significant difference in mean value probably because we have maximum female of reproductive age group and uricosuric action of estrogen may be the reason behind these results. Bibek et al observed different results in their study. They found that mean SUA level was significantly higher in their female hypertensives (4.4±1.3 mg/ dl) than normotensives (3.7±1.4 mg/ dl). Prevalence of hyperuricemia was also significantly high in female cases (29.2%) than female controls (12.9%). 22 Kashem et al also observed that mean serum acid levels in female hypertensives (5.5±1.3 mg/dl) was significantly higher than normotensives (4.2±1.2 mg/dl) and prevalence of hyperuricemia was also significantly higher in male cases (25%) than male controls (8%). 23 Odds ratio in female hyperuricemic hypertensive versus hyperuricemic normotensive was 4.46 (CI=0.4 to 42.5) and it shows a strong association between hyperuricemia and hypertension in females. In this study we found that hyperuricemia was present in 6% normal healthy controls and was more frequent in male (10%) than females (3.3%). While studying the select nomad tribal population of Rajasthan, India the prevalence of hyperuricemia was found to be 13.5%. 31 Hyperuricemia was more frequent in men (14.4%) than women (12.8%). 31 In the study conducted by Kashem et al hyperuricemia was found in 9.8% controls and prevalence of hyperuricemia was higher in normotensive males (11.5%) than normotensive females (8%). 23 Bibek et al found high prevalence of hyperuricemia (13.7%) in normal healthy controls and prevalence was higher in males (14.3%) than females (12.9%). 22 In our study statistically significant difference was observed when SUA, fasting blood sugar, waist hip ratio of the hypertensives was compared with the normotensive healthy controls. And these are the components of metabolic syndrome, so indirectly hypertensive patients with hyperuricemia also have other components of metabolic syndrome. There was no statistically significant difference in body mass index and fasting lipid profile of hypertensives and normotensives. In a meta-analysis of 17 studies while studying the prognostic values of hyperuricemia on the development of complications in hypertensive patients, it was observed that hyperuricemia could slightly increase the risk of cardiovascular diseases and diabetes in patients with hypertension. 32 In different studies on effects of xanthine oxidase inhibitors on renal function and blood pressure in hypertensive patients with hyperuricemia it was observed that these drugs may delay the progression of renal dysfunction and decrease blood pressure. 33,34 It can be concluded that hyperuricemia is significantly associated with hypertension and hyperuricemia-hypertension risk relationship is present in patients irrespective of metabolic syndrome. 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