Secondary hypertension

‍Introduction

• Secondary Hypertension is defined as hypertension due to an identifiable cause, which may be treated with specific intervention to that cause. 
• Early detection and high suspicion of secondary causes of hypertension can be curative, especially in younger patients.
• Longstanding hypertension can lead to vascular and organ damage, hence interventions earlier in life are more likely to be curative and will result in much better BP control with less medication. 
• Prevalence of secondary hypertension = 5-15% of people with hypertension.

Characteristic of patients that raise suspicion of secondary hypertension

• Younger patients (<40 years) with grade 2 hypertension or onset of any grade of hypertension in childhood
• Acute worsening hypertension in patients with previously documented chronically stable normotension
• Resistant hypertension
• Severe (grade 3) hypertension or a hypertension emergency
• Presence of extensive HMOD (Hypertension mediated organ damage)
• Clinical or biochemical features suggestive of endocrine causes of hypertension or CKD
• Clinical features suggestive of obstructive sleep apnoea
• Symptoms suggestive of phaeochromocytoma or family history of phaeochromocytoma

Causes of secondary hypertension:

Differential Diagnosis of Secondary Hypertension

1. Primary hyperaldosteronism - Clinical approach

Prevalence in hypertensive patients: 5 − 15%

Screening Indications:

• Resistant hypertension or grade 3 hypertension
• Hypokalemia (spontaneous or diuretic-induced)
• Hypertension in young patients (<40 years)
• Adrenal incidentaloma
• Family history of PA or early-onset stroke
• Atrial fibrillation without structural heart disease
• Moderate hypertension with potassium at lower end of normal range

Screening Test:

• Aldosterone-to-renin ratio (ARR)
• The diagnostic criteria suggestive of primary hyperaldosteronism on initial screening include both an elevated aldosterone-to-renin ratio (ARR) exceeding 100 pmol/ng with the plasma aldosterone level greater than 300 pmol/L
• Normal values in a screening test:

• Direct renin concentration is now preferred over plasma renin activity

Factors Affecting ARR:

• Medications:
  • Beta-blockers, central α2-agonists: increase ARR
  • Diuretics, ACE inhibitors, ARBs, dihydropyridine CCBs: decrease ARR
  • Verapamil, doxazosin, moxonidine: neutral effect
• Potassium levels: hypokalemia decreases ARR
• Sodium intake: low sodium increases ARR
• Age: advanced age increases ARR
• Renal impairment: may increase ARR
• Pregnancy: decreases ARR

Preparation for ARR Testing:

• Adjust medications if possible:some text
  • Stop spironolactone for 4-6 weeks
  • Stop diuretics for 2-4 weeks
  • Stop other interfering drugs for 2 weeks
• Correct hypokalemia (aim for 4.0 mmol/l)
• Maintain normal sodium diet (as opposed to recommendations of lifestyle changes in patients with hypertension) - low sodium intake can increase renin levels
• For menstruating women, test in early follicular phase (the early phase of menses)

Blood Sampling for ARR:

• Morning collection (before noon)
• Patient should be seated for 5-10 minutes after at least 1 hour of being upright
• Avoid prolonged tourniquet use to prevent hemolysis
• Transport at room temperature

Further Diagnosis:

• Confirmatory testing (e.g., saline infusion test) recommended after positive ARR, except in very clear cases
• CT imaging of adrenal glands
• Adrenal vein sampling to determine if PA is unilateral or bilateral

Special Considerations:

• In polymorbid patients, ARR can be measured without medication changes
• For patients unwilling to undergo further testing, treatment with mineralocorticoid receptor blockers can be initiated based on positive ARR
• Refer patients willing to consider surgery to specialized hypertension centers

Specific Therapy:

• Surgical Treatment: Adrenalectomy for unilateral disease (e.g., aldosterone-producing adenoma).
• Medical Treatment: Mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone) for bilateral adrenal hyperplasia or if surgery is not feasible.

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2. Obstructive Sleep Apnea

‍Prevalence in hypertensive patients: 5–10%

‍Suggestive symptoms and signs: 

• Snoring
• Obesity (can also be present in non-obese)
• Morning headache
• Daytime somnolence

Screening Investigations:

• Epworth score and ambulatory polygraphysome text

Consists of:

• EEG: typically using 6-8 channels for sleep staging and arousal detection
• EOG: bilateral eye movement monitoring
• EMG: submental and anterior tibialis for muscle tone and limb movements
• ECG: single or three-lead for cardiac rhythm analysis
• Respiratory monitoring: · some text
  • Oronasal airflow
  • Thoracoabdominal effort 
  • Snoring 
  • Pulse oximetry for SpO2 and pulse rate

Types of sleep apnea: 

1. obstructive - is caused by obstruction in the upper respiratory tract and respiratory effort is preserved
2. central - has its cause in the central nervous system, respiratory effort is not present;
3. mixed - is given by a combination of both previous types 

Specific therapy for OSAS:

• Lifestyle Modifications: Weight loss, avoidance of alcohol and sedatives.
• Medical Treatment: Positive airway pressure therapy (e.g., CPAP).
• Surgical Treatment: Upper airway surgery in selected cases.

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3. Renal Parenchymal Disease

Prevalence in hypertensive patients: 2–10%

Suggestive symptoms and signs: 

• Mostly asymptomatic
• Diabetes
• Haematuria
• Proteinuria
• Nocturia
• Anaemia
• Renal mass in adult polycystic CKD

Types of renal parenchymal diseases:

• Glomerular diseases:
  • Diabetic nephropathy 
  • IgA nephropathy
  • Focal segmental glomerulosclerosis (FSGS)
  • Membranous nephropathy
  • Minimal change disease
  • Lupus nephritis
  • Post-streptococcal glomerulonephritis

• Tubulointerstitial diseases:
  • Acute tubular necrosis (ATN)
  • Interstitial nephritis
  • Pyelonephritis

• Vascular diseases:
  • Hypertensive nephrosclerosis
  • Atheroembolic renal disease

• Cystic kidney diseases

• Polycystic kidney disease (ADPKD and ARPKD)
• Medullary cystic kidney disease

• Hereditary nephropathies: 
  • Alport syndrome 
  • Fabry disease

‍Screening Investigations:

• Plasma creatinine and electrolytes, eGFR
• Urine dipstick for blood and protein, urinary albumin:creatinine ratio
• Renal ultrasound
• Renal biopsy (to specify 

Specific Therapy:

• Medical Treatment: Hypertension treatment using basic antihypertensive medication (e.g., ACE inhibitors, ARBs).
• Renal Replacement Therapy: Dialysis or kidney transplant in advanced renal failure.
• Supportive Treatment: Management of complications like anemia and electrolyte imbalances.

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4. Atherosclerotic Renovascular Disease

‍Prevalence in hypertensive patients: 1–10%

‍Suggestive symptoms and signs: 

• Older
• Widespread atherosclerosis (especially PAD)
• Diabetes
• Smoking
• Recurrent flash pulmonary oedema

Screening Investigations:

• Duplex renal artery Doppler 
• CT angiography 
• MR angiography

Specific Therapy:

• Medical Treatment: Antihypertensive therapy, including ACE inhibitors or ARBs, statins, and antiplatelet agents.
• Interventional Treatment: Percutaneous transluminal renal angioplasty (PTRA) with or without stenting.
• Surgical Treatment: Renal artery bypass surgery in selected cases.

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5. Thyroid disease (hyper- or hypothyroidism)

Prevalence in hypertensive patients: 1 − 2%

Suggestive symptoms and signs: ‍

Signs and symptoms of hyperthyroidism:

• Tachycardia, palpitations
• Atrial fibrillation (especially in elderly)
• Fine tremor
• Hyperreflexia
• Anxiety, irritability
• Insomnia
• Weight loss with increased appetite
• Heat intolerance and hyperhidrosis
• Hyperglycemia (impaired glucose tolerance)
• Increased frequency of bowel movements
• Osteoporosis (in chronic cases)
• Warm, moist skin
• Exophthalmos (in Graves' disease)

Signs and symptoms of hypothyroidism:

• Bradycardia
• Diastolic hypertension
• Weight gain
• Decreased appetite
• Cold intolerance
• Periorbital edema
• Hoarseness
• Constipation
• Fatigue and lethargy
• Muscle weakness, especially proximal
• Myalgia and arthralgia
• Cognitive impairment ("brain fog")
• Depression
• Memory issues
• Non-pitting edema (myxedema)
• Hyperlipidemia (elevated total and LDL cholesterol)

‍Screening Investigations:

• Thyroid function tests
  • Routine 
    • Thyroid-Stimulating Hormone (TSH)
    • Free Thyroxine (fT4)
  • Additionalsome text
    • Thyroid antibodies (to confirm autoimmune diseases such as Hashimoto thyroiditis or Graves-Basedow disease)
    • Free Triiodothyronine (fT3) (for further investigation of elevated TSH levels)
    • Thyroglobulin (mostly used as a tumor marker)

‍Specific Therapy:

• Hyperthyroidism: Antithyroid drugs (e.g., methimazole, propylthiouracil), radioactive iodine therapy, or thyroidectomy.
• Hypothyroidism: Levothyroxine replacement therapy.
• Control of Hypertension: Beta-blockers (especially in hyperthyroidism) until euthyroid state is achieved.

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6. Phaeochromocytoma

Prevalence in hypertensive patients: <1%

‍Suggestive symptoms and signs: 

• Episodic symptoms (the 5 ‘Ps’):
  • paroxysmal hypertension
  • pounding headache
  • perspiration
  • palpitations
  • pallor
• Labile BP
• BP surges precipitated by drugs
  • (e.g. beta-blockers, metoclopramide, sympathomimetics, opioids, and tricyclic antidepressants)

Screening Investigations:

• Plasma or 24 h urinary fractionated metanephrines

• Computed tomography for adrenals
• MIBG scintigraphy 

Specific Therapy:

• Surgical Treatment: Adrenalectomy is the definitive treatment.
• Medical Treatment: Preoperative alpha-blockers (e.g., phenoxybenzamine or doxazosin) followed by beta-blockers if necessary, to control blood pressure and prevent perioperative hypertensive crises.
  • Prior to initiating beta-blocker therapy in patients with pheochromocytoma, it is essential to block alpha receptors to prevent severe hypertension. Blocking beta receptors first can lead to unopposed alpha-adrenergic receptor stimulation, which can cause a sudden and dangerous increase in blood pressure due to vasoconstriction. Alpha receptor blockade ensures that this risk is mitigated by preventing excessive vasoconstriction, thereby stabilizing blood pressure before beta-blockers are introduced.

7. Cushing’s syndrome

Prevalence in hypertensive patients: <1%

Etiology:

• Exogenous glucocorticoid use (most common cause)
• Endogenous causes:
  • ACTH-dependent (80-85%):
    • Pituitary adenoma (Cushing's disease, ~70%)
    • Ectopic ACTH syndrome (~10%)
  • ACTH-independent (15-20%):
    • Adrenal adenoma
    • Adrenal carcinoma
    • Bilateral adrenal hyperplasia

Suggestive symptoms and signs:

• Moon face, central obesity, skin atrophy, striae (especially if purplish and >1 cm wide), and easy bruising
• Hirsutism and acne in women
• Osteoporosis and pathological fractures
• Hypertension
• Diabetes mellitus or impaired glucose tolerance
• Psychiatric disturbances (depression, anxiety, cognitive dysfunction)
• Chronic steroid use history

Screening Investigations:

• 24-hour urinary free cortisol (at least two measurements)
• Late-night salivary cortisol (two measurements)
• 1-mg overnight dexamethasone suppression test
• Longer low-dose dexamethasone suppression test (2 mg/day for 48 hours)

Confirmatory tests:

• ACTH levels to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome
• CRH stimulation test
• High-dose dexamethasone suppression test
• Bilateral inferior petrosal sinus sampling (for ACTH-dependent cases)

Imaging:

• MRI of the pituitary (for ACTH-dependent cases)
• CT or MRI of the adrenal glands
• CT of chest/abdomen/pelvis (to locate ectopic ACTH-producing tumors)

Specific Therapy:

• Surgical Treatment:
  • Transsphenoidal surgery for pituitary adenomas
  • Resection of the adrenal adenoma or carcinoma
  • Removal of ectopic ACTH-producing tumor
  • Bilateral adrenalectomy (as a last resort)
• Medical Treatment:
  • Steroidogenesis inhibitors:
    • Ketoconazole
    • Metyrapone
    • Mitotane (also adrenolytic)
    • Etomidate (for acute, severe hypercortisolism)
  • Glucocorticoid receptor antagonist:
    • Mifepristone
  • Pituitary-directed medications (for Cushing's disease):
    • Pasireotide
    • Cabergoline (less effective)
• Radiation Therapy:
  • For pituitary tumors not cured by surgery

Follow-up:

• Monitor for recurrence
• Assess for and manage complications (e.g., osteoporosis, cardiovascular risk factors)
• Glucocorticoid replacement therapy may be needed post-treatment until HPA axis recovery

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8. Hyperparathyroidism

Prevalence in hypertensive patients: <1%

‍Suggestive symptoms and signs: 

• Hypercalcaemia, hypophosphatemia

Screening Investigations:

• Parathyroid hormone, Ca²⁺  

‍Specific Therapy:

• Surgical Treatment: Parathyroidectomy is the definitive treatment.
• Medical Treatment: Calcimimetics (e.g., cinacalcet) to manage hypercalcemia in patients who are not surgical candidates.
• Supportive Treatment: Ensure adequate hydration and management of any complications related to hypercalcemia.

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9. Coarctation of the aorta

Prevalence in hypertensive patients: <1%

Suggestive symptoms and signs: 

• Usually detected in children or adolescence
• Different BP (≥20/10 mmHg) between upper–lower extremities and/or between right–left arm and delayed radial-femoral femoral pulsation
• Low ABI interscapular ejection murmur
• Rib notching on chest X-ray

Etiology of hypertension in coarctation of the aorta:

• Mechanical obstruction to aortic flow
• Increased renin-angiotensin system activity
• Impaired baroreceptor sensitivity
• Altered vascular reactivity in upper body vessels
• Persistent abnormalities in vascular structure and function, even after correction

Screening Investigations:

• Echocardiogram
• Pulse palpation on upper and lower limbs as a part of screening of newborn
• Suspicion usually confirmed with CT angiography

Specific Therapy:

• Surgical Treatment: Resection of the coarctated segment with anastomosis, or use of a synthetic graft.
• Interventional Treatment: Balloon angioplasty with or without stenting.
• Medical Treatment: Antihypertensive therapy (e.g., beta-blockers, ACE inhibitors) post-repair to manage residual hypertension.

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10. Medication related secondary hypertension

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Authors: Peter Mišún, Faizan Siddiqui, Michal Pazderník

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Sources:

‍1) Bryan Williams, Giuseppe Mancia, Wilko Spiering, Enrico Agabiti Rosei, Michel Azizi, Michel Burnier, Denis L Clement, Antonio Coca, Giovanni de Simone, Anna Dominiczak, Thomas Kahan, Felix Mahfoud, Josep Redon, Luis Ruilope, Alberto Zanchetti, Mary Kerins, Sverre E Kjeldsen, Reinhold Kreutz, Stephane Laurent, Gregory Y H Lip, Richard McManus, Krzysztof Narkiewicz, Frank Ruschitzka, Roland E Schmieder, Evgeny Shlyakhto, Costas Tsioufis, Victor Aboyans, Ileana Desormais, ESC Scientific Document Group , 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH), European Heart Journal, Volume 39, Issue 33, 01 September 2018, Pages 3021–3104, https://doi.org/10.1093/eurheartj/ehy339‍

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