Mehwish Gilani  ( Armed Forces Institute of Pathology )
Naveed Asif  ( Armed Forces Institute of Pathology )
Ammad Akram  ( Military Hospital, Rawalpindi )
Mehreen Gilani  ( National University of Medical Sciences, Rawalpindi )
Aamir Ijaz  ( Armed Forces Institute of Pathology )
Saima Shakil Malik  ( Armed Forces Institute of Pathology )

Objective: To analyse the spectrum of renin angiotensin aldosterone system disorders in young hypertensive patients in hospital settings.
Methods: This cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to December, 2016. It comprised hypertensive subjects aged 17-40 years of either gender presenting in the outpatient department. All subjects were having blood pressure more than 140/90mmHg and were not on any anti-hypertensive medicine. Blood sample was taken from each patient to analyse arterial blood gases, plasma renin, serum aldosterone and electrolytes. Association of qualitative variables like age, systolic and diastolic blood pressure with essential hypertension and primary hyperaldosteronism was explored.
Result: Of the 80 patients, 72(90%) were diagnosed with essential hypertension and 8(10%) with primary hyperaldosteronism. None of the patients had Liddle syndrome, apparent mineralocorticoid excess or Gordon syndrome. Mean age of patients having essential hypertension was 30.97±7.1 years, whereas, for those with primary hyperaldosteronism it was 29.25±7.1 years. Systolic blood pressure was significantly higher (p = 0.000) among all patients. No statistically significant association was found between age, systolic and diastolic blood pressure (p<0.05).
Conclusion: Primary hyperaldosteronism as compared to other renin angiotensin aldosterone system disorders was found to be the leading cause of hypertension in young population.
Keywords: Renin angiotensin aldosterone disorders, Primary hyperaldosteronism, Essential hypertension. (JPMA 68: 1179; 2018)

Introduction

Hypertension is one of the most prevalent non-communicable diseases in developed countries accounting for 7.1 million deaths per year and 92 million disability adjusted life years (DALY) worldwide.^1,2 Among young adults between 18 to 39 years of age, 20% of men and 15% women are hypertensive.³ Hypertension reflects a system of pathophysiological disturbances in our body, presenting itself in the form of high blood pressure. Documented mechanisms include increased sympathetic activity, renin angiotensin aldosterone system (RAAS) disorders, increased sodium conserving hormones, deficiency of vasodilators(nitric oxide, prostacyclin, natriuretic peptides), increased vasoconstrictors, abnormalities of the kallikrein-kinin system and renal micro vasculature.⁴ Even though extensive research work and data has been collected on this subject, etiology of hypertension is still not well understood.⁵ However, hypertension is one of the modifiable risk factors for cardiovascular and cerebrovascular morbidity and mortality.⁶
RAAS plays an important role in pathogenesis of hypertension. It regulates systemic vascular resistance and circulatory volume by water and electrolyte balance.⁷ Renin is synthesised from precursor prorenin by the juxtaglomerular apparatus cells. It converts angiotensinogen to angiotensin I in the liver. Angiotensin converting enzyme (ACE), present in lung converts Angiotensin I into Angiotensin II.⁸ This angiotensin II via G protein coupled receptor in the glomerulosa cells causes membrane depolarisation, activation and opening of calcium gated channels. Increased intracellular calcium, signals the production of aldosterone from the adrenal glomerulosa. Aldosterone in turn causes kidneys to reabsorb sodium ions and secrete potassium ions.⁹
Common disorders affecting the RAAS system and causing hypertension include primary hyperaldosteronism, apparent mineralocorticoid excess, Liddle syndrome and Gordon\\\'s syndrome.^10-14 Primary hyperaldosteronism is the leading hormonal cause of hypertension with a prevalence varying from 4.6% to 16.6% among Greeks.¹⁰ Majority of hypertensive patients with primary hyperaldosteronism reporting in primary and tertiary care settings have adrenal tumours or adrenal hyperplasia. Apparent mineralocorticoid excess is an autosomal recessive disorder, being the third most common cause of monogenic hypertension it is characterised by 11 b-hydroxysteroid dehydrogenase type 2(11b-HSD2) enzymes deficiency, responsible for the conversion of cortisol to cortisone.¹¹ Liddle syndrome, the second most common cause of monogenic hypertension, is an autosomal dominant disorder characterised by mutations in the b and - subunits of ENaC (epithelial sodium channels). It presents with hypokalaemia, metabolic alkalosis, salt-sensitive hypertension, suppression of plasma renin activity(PRA) and aldosterone secretion.¹² Gordon syndrome also known as pseudohypoaldosteronism type II is caused by mutations in any of the four genes; WNK1, WNK4, CUL3 and KLHL3 which are the regulators of the thiazide sensitive Na+- Cl- co transporter. It is characterised by hyperkalaemic metabolic acidosis and salt dependent hypertension.¹³
The current study was planned to analyse the spectrum of RAAS disorders in young hypertensive patients, as hypertension is one of the preventable risk factors for death and a predictor of future cardiovascular incidents.³

Patients and Methods

This cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan, from January to December, 2016. After approval from the institutional review board, hypertensive subjects with a blood pressure of more than 140/90mmHg who were not on any anti-hypertensive medicine, aged 17-40 years of either gender were enrolled from among those presenting at the outpatient department. Sample size was calculated after thorough literature review and calculated from given prevalence rate of the most common RAAS disorders (5%) in Asian population15 from given formula of World Health Organisation (WHO) sample size estimation (n= z2p(1-p)/d2).¹⁶ Besides, 165 hypertensive subjects, presenting in the outpatient department (OPD) of tertiary care hospital were recruited in the study. Patients with renal dysfunction, heart failure, pregnancy and secondary hypertension were excluded. Blood samples were collected from subjects by non-probability consecutive sampling technique after taking informed consent. To analyse plasma renin and serum aldosterone levels, 3.0 ml venous blood was collected in each ethylenediaminetetraacetic acid (EDTA) and gel tube. Furthermore, 3.0 ml arterial blood was collected in lithium heparin tube to measure pH, electrolytes-sodium and potassium and blood gases. Plasma rennin was analysed on DIASORIN LIASON® by sandwich chemiluminescence immunoassay and analysis of serum aldosterone was done by BIORAD PhD™ SYSTEM-enzyme-linked immunosorbent assay (ELISA). Arterial blood gases, pH, partial pressure of carbon dioxide (pCO2) and electrolytes-sodium, potassium were measured on COBAS b221 by potentiometry along with calculated bicarbonate. SPSS 24 was used to analyse the data. Mean and standard deviation was calculated for all the parametric quantitative variables while median and interquartile range (IQR) were calculated for non-parametric data (Systolic Blood Pressure in OPD with primary hyperaldosteronism). Chi-square was used to compute the association of age, systolic and diastolic blood in OPD and Endocrine Clinic AFIP (Laboratory), with primary hyperaldosteronism and essential hypertension. P<0.05 was considered significant.

Results

Out of 165 patients examined, 80(48.48%) fulfilled the inclusion criteria. Of them, 12(15%) were females and 68(85%) were males. In terms of age, 21(26.25%) subjects were aged 17-25 years, 22(27.5%) were aged 26-33 years, and group-37(46.25%) were aged 34-41years. Mean systolic blood pressure of all patients was 172.7±19.2 mmHg, whereas, diastolic blood pressure was 100.0±8.3mmHg. Similarly, mean systolic blood pressure in the Endocrine Clinic was 142.7±10.5mmHg and diastolic blood pressure was 90.3±6.5mmHg. Plasma renin and aldosterone levels were measured and aldosterone-to-renin ratio (ARR) was computed. Those having an ARR >130 pmol/mIU were diagnosed as having primary hyperaldosteronism, while patients having ARR <100pmol/mIU were having essential hypertension. Overall, 72(90%) patients were reported with essential hypertension, out of whom 60(83.3%) were males and 12(16.6%) were females, whereas 8(10%) patients were diagnosed with primary hyperaldosteronism and all were males. None of the patients had Liddle syndrome, apparent mineral ocorticoid excess and Gordon syndrome.
Mean age of all the patients was 30.8±7.1 years, while for patients having essential hypertension it was 30.97±7.1 years, whereas, for those with primary hyperaldosteronism it was 29.25±7.1 years (Table-1).



Frequency of cases with essential hypertension in different age groups was: in 17-25years, 5(25%), in 26-33 years, 6(27.7%), in 34-41 years 17(47.2%); while with primary hyperaldosteronism, it was 17-21years 8(37.5%), 26-33 years 6(25%), 34-41 years 14(37.5%). Association of all of these age groups with essential hypertension and primary hypertension was also computed (Table-2).



Association of Systolic blood pressure with all the patients reported in OPD was significant (p=0.000) (Table-3).



Discussion

Hypertension, the most prevalent non-communicable diseases affecting developed countries has a spectrum of etiologies, RAAS being one of the leading causes. RAAS regulates blood pressure by regulating systemic vascular resistance and circulatory volume by water and electrolyte balance.⁷ Early diagnosis and treatment of hypertension is very important as it is a predictor of future cardiovascular events and a modifiable risk factor.³ Primary hyperaldosteronism is the most prevalent RAAS disorder in our study population which is consistent with the data presented by Tsiavos et al ¹⁰ in a study conducted in University of Athens, Greece.
Frequency of primary hyperaldosteronism in our subjects was 10% (all in males) which is very close to the prevalence documented by Rossi et al ¹⁴ which is 11.2% without gender differences and same study population characteristics (e.g. age). Douma et al¹⁷ in a study conducted in the Aristotle University of Greece reported a frequency of 11.3% of primary hyperaldosteronism in hypertensive population which is also very close to our results.
Mean age of patients having primary hyperaldosteronism in our study population was 29.25±7.1 years and those with essential hypertension was 30.97±7.1 years. However, in a study conducted by Douma et al¹⁷ the mean age for primary hyperaldosteronism was 56.7±12.3 years and that for essential hypertension was 56.3±12.3 years. This difference was because our study was conducted in young hypertensives with age from 17-40 years and specified age group selection was not a criterion in their inclusion.
Another finding in our study was that patients presenting in OPD had a significantly higher systolic blood pressure (p=0.000) as compared to those presenting in our Endocrine clinic. This was probably because of the stress and the long waiting hours that patients underwent in OPD as compared to the early morning appointment based sampling in our Endocrine clinic, without any wait. It can also be due to physical exertion and stairs climbing in hospital settings. This stress factor has been documented in a study by Artinian et al¹⁸ and Hjortskov et al.¹⁹ Another reason could be test protocol which is a fasting sample with patient comfortably seated for half-an-hour in our Endocrine clinic. Study conducted by Lutsey et al²⁰ in University of North Carolina and University of Minnesota also reported a positive association of food intake and a higher blood pressure. Similarly, another study by Tzoulaki et al²¹ in Japan, China and USA also concluded the same results.
Although study reported very important results and served as a preliminary data for future information and studies but small sample size and single centre study were the limitations. Therefore, study with greater sample size, multi-centric approach and advanced study design will be able to generate more generalised and authentic results.

Conclusion

RASS plays a key role in blood pressure regulation and mineralocorticoid excess syndrome. Primary hyperaldosteronism among all the RAAS disorders is the most common in young hypertensives, while no cases of Liddle syndrome, Gordon syndrome and apparent mineralocorticoid excess syndrome were reported in our study.

Disclaimer: None.
Conflict of Interest: None.
Source of Funding: None.

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