European Journal of Cardiovascular Medicine

Hypertension is one of the leading contributors to cardiovascular morbidity and mortality worldwide and represents a major public health challenge in India. Although most cases are essential hypertension, 5–15% result from identifiable secondary causes. The coexistence of hypertension and hypokalemia is a clinically important finding that should prompt evaluation for secondary causes, particularly disorders associated with excess mineralocorticoid activity, renal tubular dysfunction, and endocrine abnormalities.1,2

Hypokalemia, defined as serum potassium <3.5 mmol/L, is a common electrolyte abnormality that can cause muscle weakness, fatigue, and cardiac arrhythmias, while severe cases may lead to life-threatening complications.3 In hypertensive patients, common causes include diuretic therapy, renal or gastrointestinal potassium loss, and endocrine disorders. Primary aldosteronism is an important and potentially curable cause of secondary hypertension and should be considered in patients with spontaneous or diuretic-induced hypokalemia.4,5 Current guidelines recommend screening for primary aldosteronism in patients with resistant or early-onset hypertension, hypokalemia, or adrenal incidentaloma, as early diagnosis and treatment can improve blood pressure control and reduce cardiovascular and renal complications.6 Evaluation of serum electrolytes, renal function, urinary potassium excretion, and renin–aldosterone levels help identifying the underlying cause.7-9 In India, increased clinical awareness of unexplained hypokalemia and severe or resistant hypertension may facilitate earlier recognition of secondary hypertension and appropriate investigation.7,10

Despite increasing awareness, there remains limited Indian data regarding the spectrum of clinical presentation, biochemical abnormalities, and underlying etiologies among patients with hypokalemia associated with hypertension. Most available evidence originates from tertiary endocrine referral centers and may not reflect the broader patient population encountered in general medicine departments. Therefore, the present study aims to evaluate the clinical manifestations, laboratory characteristics, and etiological profile of patients presenting with hypokalemia associated with hypertension in a tertiary care hospital, thereby facilitating earlier diagnosis and appropriate management of secondary hypertension.

After obtaining Institutional Ethical Committee approval and written informed consent from all patients, this hospital-based observational cross-sectional study was conducted at a tertiary care hospital over a period of 18 months. A total of 80 patients aged ≥18 years with confirmed hypertension according to current guidelines and serum potassium levels <3.5 mEq/L were included in the study. Both newly diagnosed and previously diagnosed hypertensive patients presenting to the Outpatient Department (OPD), Inpatient Department (IPD), Intensive Care Unit (ICU), Emergency Department, or Department of Endocrinology were enrolled. Convenient sampling was used to recruit eligible participants. Patients receiving potassium-wasting diuretics such as furosemide or hydrochlorothiazide without an adequate washout period, those with chronic kidney disease stage 4 or 5, primary gastrointestinal potassium loss due to conditions such as acute diarrhoea, vomiting or intestinal fistula, and those unwilling to provide consent were excluded from the study.

The demographic and clinical information was collected using a structured proforma. Data included age, sex, height, weight, body mass index (BMI), smoking and other addictions, comorbidities, duration of hypertension, and symptoms suggestive of hypokalemia such as fatigue, muscle weakness, muscle cramps, vomiting, palpitations and other relevant complaints. A detailed general and systemic examination was performed. Vital signs were recorded, and BMI was classified according to South Asian reference criteria. Blood pressure was categorised according to the 2025 American Heart Association (AHA) guidelines.

Laboratory evaluation included serum electrolytes (potassium, sodium, calcium, magnesium and phosphorus), renal function tests (blood urea and serum creatinine), liver function tests, lipid profile, HbA1c, complete blood count, and arterial blood gas analysis when metabolic alkalosis was suspected. Spot urinary potassium-to-creatinine ratio and urinary protein were assessed to evaluate renal potassium loss. In patients suspected of having endocrine causes of hypokalemic hypertension, plasma renin activity, serum aldosterone and serum cortisol were measured. The aldosterone-renin ratio (ARR) was calculated as serum aldosterone divided by plasma renin activity and was used as a screening parameter for primary aldosteronism. Serum sodium and potassium were measured by the ion-selective electrode method. Serum calcium, phosphorus and magnesium were estimated using Arsenazo III, phosphomolybdate UV and Xylidyl Blue methods, respectively. Serum urea and creatinine were measured using the urease–GLDH and modified Jaffe kinetic methods, respectively. Liver function and lipid parameters were estimated using standard automated biochemical methods. HbA1c was measured by high-performance liquid chromatography, while plasma renin activity and serum aldosterone were estimated using chemiluminescent immunoassays. Complete blood count was performed using an automated haematology analyser based on electrical impedance, flow cytometry and light-scatter principles.

A standard 12-lead electrocardiogram (ECG) was performed for all participants to identify hypokalemia-related abnormalities, including ST-segment depression, flattened T waves, prominent U waves, QT prolongation and cardiac arrhythmias. Two-dimensional echocardiography was performed when indicated to assess left ventricular hypertrophy, left ventricular ejection fraction, chamber dimensions, diastolic function and valvular abnormalities. Ultrasonography of the abdomen was performed when clinically indicated to assess renal morphology and detect adrenal abnormalities. Adrenal computed tomography (CT) or magnetic resonance imaging (MRI) was performed in selected patients with suspected adrenal pathology or endocrine causes of hypokalemic hypertension. Renal imaging was performed when renovascular hypertension was suspected.

Statistical Analysis

Clinical and laboratory data were recorded in a structured data sheet, coded and analysed using IBM SPSS Statistics version 22. Categorical variables were expressed as frequencies and percentages, while continuous variables were summarised using appropriate measures of central tendency and dispersion. The Chi-square test was used for comparison of categorical variables, and appropriate statistical tests were applied according to the distribution and type of data. A p-value <0.05 was considered statistically significant.

Table 1 showed that the largest proportion of patients were aged 41–50 years (30.0%), followed by 31–40 years (22.5%) and 51–60 years (21.3%) with males predominated (57.5%). The majority of patients (38.8%) were overweight, while 63.7% were non-smokers. Among comorbidities, diabetes mellitus was most common (42.5%), followed by dyslipidemia (36.3%) and coronary artery disease (22.5%).

Table 1: Demographic and clinical profile of patients

The most common symptom was fatigue (70.0%), followed by muscle weakness (61.3%) and headache (55.0%). Muscle cramps were reported by 47.5% of patients, while palpitations and polyuria were present in 40.0% and 26.3%, respectively, (Figure 1).

Stage 2 hypertension was most common (41; 51.3%), followed by Stage 1 (26; 32.5%) and hypertensive crisis (13; 16.2%; p=0.002). Mild hypokalemia was predominant (39; 48.7%), followed by moderate (28; 35.0%) and severe hypokalemia (13; 16.3%).

The mean serum potassium, sodium, and magnesium levels were 2.91 ± 0.42 mEq/L, 142.8 ± 5.7 mEq/L, and 1.82 ± 0.34 mg/dL, respectively. Mean plasma renin activity, serum aldosterone, cortisol, and aldosterone–renin ratio was 3.9 ± 2.1 ng/mL/hr, 34.8 ± 14.6 ng/dL, 19.4 ± 7.2 µg/dL, and 31.6 ± 12.8, respectively, (Table 2).

Increased urinary potassium excretion (spot urine potassium-to-creatinine ratio ≥15 mEq/g) was observed in 61 (76.3%) patients, while 19 (23.7%) had a ratio <15 mEq/g. The arterial blood gas (ABG) analysis revealed that metabolic alkalosis was present in 33 patients (41.3%), while 47 patients (58.7%) had normal ABG findings.

Table 2: Laboratory Profile in patients presenting with hypertension and hypokalemia

U waves were the most common ECG abnormality (36; 45.0%), followed by ST-segment depression (17; 21.3%). Bilateral adrenal hyperplasia was the most common imaging finding (21; 26.3%), followed by adrenal adenoma (13; 16.2%) and other renovascular changes (11; 13.7%) as shown in table 3.

Table 3: ECG abnormalities and imaging findings among study participants

The primary hyperaldosteronism was the most common diagnosis (34; 42.5%), followed by renovascular hypertension (18; 22.5%) and essential hypertension with secondary hypokalemia (10; 12.5%). The overall distribution of diagnoses was statistically significant (p<0.001), (Table 4).

Table 4: Final clinical diagnosis among patients with hypokalemic hypertension

The mean aldosterone–renin ratio (ARR) was highest among patients with primary hyperaldosteronism (42.8±10.6), followed by Cushing’s syndrome (24.2±8.1) and renovascular hypertension (19.7±7.4). Lower mean ARR values were observed in pheochromocytoma (15.6±5.3) and essential hypertension (12.9±4.7). The association between ARR and final diagnosis was statistically significant (p<0.001), (Table 5).

Table 5: Association between Aldosterone–Renin Ratio and Final Diagnosis

Metabolic alkalosis was most frequently observed in primary hyperaldosteronism (24;70.6%), followed by Cushing’s syndrome (3;60.0%) and renovascular hypertension (5;27.8%). It was least common among other etiologies (1; 4.3%). The association between metabolic alkalosis and etiological diagnosis was statistically significant (χ²=27.07, df=3, p<0.001), (Figure 2).

Among 80 participants, 12 (15.0%) required ICU admission, 12 (15.0%) had abnormal LFTs, 29 (36.3%) had retinopathy, 24 (30.0%) had urinary protein, 15 (18.8%) had renal parenchymal disease, and 37 (46.3%) had concentric LVH, (Table 6). Raised ARR was observed in 39 (48.7%) compared with normal ARR in 41 (51.3%) (p=0.823). Retinopathy increased with hypertension severity, from 4 (15.4%) in Stage 1 to 16 (39.0%) in Stage 2 and 9 (69.2%) in hypertensive crisis, but the association was not significant (p=0.081).

Table 6: Clinical, laboratory and target-organ findings among study participants

The present study evaluated the clinical and laboratory profile of 80 patients with hypokalemia associated with hypertension. Most patients were aged 41–60 years (51.3%), with a male predominance (57.5%), findings comparable to those reported by Rossi et al11 and Malik SA et al12. These studies similarly observed a higher prevalence of hypokalemia among middle-aged and older adults, which may be attributed to the increasing burden of chronic diseases, medication use, and secondary hypertension with advancing age. The predominance of overweight (38.8%) and obese patients (18.7%) in the present study suggests a substantial burden of excess weight. Smokers accounted for 36.3%. Comorbidities included diabetes mellitus (42.5%), dyslipidaemia (36.3%), coronary artery disease (22.5%), and previous stroke (12.5%), indicating a high prevalence of cardiovascular risk factors, consistent with findings reported by Burrello et al13.

Regarding clinical presentation, fatigue (70.0%), muscle weakness (61.3%), and headache (55.0%) were the most common symptoms, followed by muscle cramps and palpitations. Similar clinical manifestations have been described by Funder et al6, Malik SA et al12 and Monticone et al14. These symptoms occur due to impaired neuromuscular excitability caused by potassium depletion and tend to be more pronounced in patients with severe hypokalemia.

Stage 2 hypertension was observed in 51.3% of patients, while 16.2% presented with hypertensive crisis, indicating that hypokalemia is frequently associated with advanced hypertension. Similar findings were reported by Mulatero et al15, who demonstrated that patients with primary aldosteronism generally present with higher blood-pressure levels than those with essential hypertension and that early recognition improves the likelihood of curative treatment.

Mild hypokalemia was the most common biochemical abnormality in the present study (48.7%), followed by moderate (35.0%) and severe hypokalemia (16.3%). The mean serum potassium level was 2.91±0.42 mEq/L, while serum sodium and magnesium levels remained largely within the normal range, suggesting isolated potassium depletion in most patients. The mean aldosterone-to-renin ratio (31.6±12.8) was elevated, indicating aldosterone excess in a substantial proportion of participants. 76.3% of patients had a spot urine potassium-to-creatinine ratio ≥15 mEq/g, suggesting predominant renal potassium wasting. Metabolic alkalosis was present in 33 (41.3%) patients. Electrocardiographic abnormalities were also frequently observed, with U waves present in 45.0% of patients, followed by ST-segment depression and ventricular ectopic beats, reflecting the cardiac effects of hypokalemia. These findings are consistent with the observations and recommendations of Funder et al6, Malik SA et al12 and Barche B et al16, they emphasized that hypokalemia is an important biochemical clue to underlying mineralocorticoid excess and recommended the aldosterone-to-renin ratio as the preferred initial screening test for primary aldosteronism in patients with hypertension and spontaneous hypokalemia. They also highlighted that characteristic ECG changes are common in hypokalemic patients and should prompt further evaluation for secondary causes of hypertension.

The most significant finding of the present study was that primary hyperaldosteronism accounted for 42.5% of all final diagnoses, followed by renovascular hypertension (22.5%). These results are comparable with those reported by Rossi et al11, Burrello et al13, and Monticone et al14, who identified primary aldosteronism as the most frequent cause of secondary hypertension among patients presenting with hypokalemia. Similarly, Mulatero et al15 demonstrated that systematic hormonal screening substantially increases the detection of surgically correctable primary aldosteronism.

The present study showed significant variation in ARR, metabolic alkalosis, and serum potassium levels across etiologies, consistent with findings reported by Malik et al12, Burrello et al13, and Barche et al16. ARR was highest in primary hyperaldosteronism (42.8±10.6), followed by Cushing’s syndrome (24.2±8.1), renovascular hypertension (19.7±7.4), pheochromocytoma (15.6±5.3), and essential hypertension (12.9±4.7) (p<0.001). Metabolic alkalosis was most frequent in primary hyperaldosteronism (70.6%), followed by Cushing’s syndrome (60.0%) and renovascular hypertension (27.8%) (p=0.001). Serum potassium was lowest in primary hyperaldosteronism (2.58±0.31 mEq/L) and progressively higher in Cushing’s syndrome (2.74±0.42), renovascular hypertension (2.86±0.37), pheochromocytoma (3.02±0.26), and essential hypertension (3.18±0.21) (p=0.004), supporting the diagnostic value of these parameters in differentiating secondary causes of hypokalemic hypertension.

The present study has several limitations, including its single-centre design and relatively small sample size of 80 patients, which may limit generalisability. The cross-sectional design precluded assessment of causality, long-term outcomes, treatment response, and progression of target-organ damage. Advanced confirmatory endocrine investigations were not performed uniformly because of resource constraints. Additionally, factors such as dietary potassium intake, genetic predisposition, medication adherence, and long-term hormonal variations were not assessed in detail. As a tertiary-care study, referral bias may also have resulted in overrepresentation of patients with severe or complicated diseases.

Hypokalemia associated with hypertension is an important clinical indicator of underlying secondary hypertension, particularly primary hyperaldosteronism, which was the leading etiology in this study. Most patients had Stage 2 hypertension, mild-to-moderate hypokalemia, neuromuscular symptoms, elevated aldosterone-to-renin ratios, and ECG abnormalities. A systematic clinical, biochemical, hormonal, and electrocardiographic evaluation of hypertensive patients with unexplained hypokalemia can facilitate early diagnosis and targeted management, improve blood pressure control, reduce long-term cardiovascular and renal complications, and ultimately improve patient outcomes.

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