Secondary hypertension

Common causes and prevalence

The cause of secondary hypertension are numerous (obstructive sleep apnea, kidney disease, endocrine diseases, tumors, medication side effect, Etc.) and etiologies varies significantly with age.

Obstructive sleep apnea

Main article: Obstructive sleep apnea

Obstructive sleep apnea (OSA) is one of the most common causes; 30-50% of patients who have OSA have co-morbid secondary hypertension. OSA is prevalent in older adults and should be considered in cases of resistant hypertension, hypertension refractory to appropriate aggressive medical therapy. OSA remains an under-diagnosed cause of secondary hypertension, likely secondary many risk factors associated with OSA such as obesity, advanced age, and cigarette smoking are shared with primary hypertension. The intermittent hypoxia and resultant hypercapnia that is characteristic of OSA leads to activation of the sympathetic nervous system and leads to elevated blood pressure. As with all cases of secondary hypertension, the goal of treating patients with hypertension due to OSA is addressing the underlying cause. Therefore, weight loss and nocturnal nasal continuous positive airway pressure (CPAP) are mainstays in treating hypertension secondary to OSA. Other approaches include the mandibular advancement splint (MAS), UPPP, tonsillectomy, adenoidectomy, or septoplasty.

Kidney disorders

Renovascular disorders

Main article: Renovascular hypertension

Obstruction of the renal arteries supplying the kidney that result in elevated blood pressure is known as renovascular hypertension. It is thought that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin–angiotensin system. There are two main causes of renovascular hypertension: renal artery stenosis and fibromuscular dysplasia.

The normal physiological response to low blood pressure in the renal arteries is to increase cardiac output (CO) to maintain the pressure needed for glomerular filtration. Here, however, increased CO cannot solve the structural problems causing renal artery hypotension, with the result that CO remains chronically elevated.

Renal parenchymal disease

This includes diseases such as polycystic kidney disease which is a cystic genetic disorder of the kidneys, PKD, which is characterized by the presence of multiple cysts (hence, "polycystic") in both kidneys, can also damage the liver, pancreas, and rarely, the heart and brain. It can be autosomal dominant or autosomal recessive, with the autosomal dominant form being more common and characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts, with concurrent development of hypertension, chronic kidney disease and kidney pain. Or chronic glomerulonephritis which is a disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys.

Chronic kidney disease

Hypertension is common in chronic kidney disease.

Endocrine disorders

• Hyperaldosteronism (Conn's syndrome) – idiopathic hyperaldosteronism, liddle's syndrome (also called pseudoaldosteronism), glucocorticoid remediable aldosteronism
• Cushing's syndrome – an excessive secretion of glucocorticoids causes the hypertension
• Hyperthyroidism
• Hypothyroidism

Medication side effects

Certain medications, including NSAIDs (ibuprofen aka Motrin) and steroids can cause hypertension. Other medications include estrogens (such as those found in oral contraceptives with high estrogenic activity), certain antidepressants (such as venlafaxine), buspirone, carbamazepine, bromocriptine, clozapine, and cyclosporine. High blood pressure that is associated with the sudden withdrawal of various antihypertensive medications is called rebound hypertension. The increases in blood pressure may result in blood pressures greater than when the medication was initiated. Depending on the severity of the increase in blood pressure, rebound hypertension may result in a hypertensive emergency. Rebound hypertension is avoided by gradually reducing the dose (also known as "dose tapering"), thereby giving the body enough time to adjust to reduction in dose. Medications commonly associated with rebound hypertension include centrally-acting antihypertensive agents, such as clonidine and methyl-dopa.

Other herbal or "natural products" which have been associated with hypertension include Ephedra, St John's wort, and licorice.

Pregnancy

Few women of childbearing age have high blood pressure, up to 11% develop hypertension of pregnancy. While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary.

Uncommon causes

Other kidney disorders

Some renal tumors can cause hypertension. The differential diagnosis of a renal tumor in a young patient with hypertension includes juxtaglomerular cell tumor, Wilms' tumor, and renal cell carcinoma, all of which may produce renin.

• Renal segmental hypoplasia (Ask-Upmark kidney)

Other endocrine disorders

• Neurogenic hypertension – excessive secretion of norepinephrine and epinephrine which promotes vasoconstriction resulting from chronic high activity of the sympathoadrenal system, the sympathetic nervous system and the adrenal gland. The specific mechanism involved is increased release of the "stress hormones", epinephrine (adrenaline) and norepinephrine which increase blood output from the heart and constrict arteries. People with neurogenic hypertension respond poorly to treatment with diuretics as the underlying cause of their hypertension is not addressed.
• Pheochromocytoma – a tumor that results in an excessive secretion of norepinephrine and epinephrine, which promotes vasoconstriction.
• Hyperparathyroidism
• Acromegaly

Adrenal

A variety of adrenal cortical abnormalities can cause hypertension, In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.

Congenital adrenal hyperplasia, a group of autosomal recessive disorders of the enzymes responsible for steroid hormone production, can lead to secondary hypertension by creating atypically high levels of mineralocorticoid steroid hormones. These mineralocorticoids cross-react with the aldosterone receptor, activating it and raising blood pressure.

• 17 alpha-hydroxylase deficiency causes an inability to produce cortisol. Instead, extremely high levels of the precursor hormone corticosterone are produced, some of which is converted to 11-Deoxycorticosterone (DOC), a potent mineralocorticoid not normally clinically important in humans. DOC has blood-pressure raising effects similar to aldosterone, and abnormally high levels result in hypokalemic hypertension.
• 11β-hydroxylase deficiency, aka apparent mineralocorticoid excess syndrome, involves a defect in the gene for 11β-hydroxysteroid dehydrogenase, an enzyme that normally inactivates circulating cortisol to the less-active metabolite cortisone. At high concentrations cortisol can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney, causing hypertension. This effect can also be produced by prolonged ingestion of liquorice (which can be of potent strength in liquorice candy), by causing inhibition of the 11β-hydroxysteroid dehydrogenase enzyme and likewise leading to secondary apparent mineralocorticoid excess syndrome. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present. Cortisol induced hypertension cannot be completely explained by the activity of Cortisol on Aldosterone receptors. Experiments show that treatment with Spironolactone (an inhibitor of the aldosterone receptor), does not prevent hypertension with excess cortisol. It seems that inhibition of nitric oxide synthesis may also play a role in cortisol induced hypertension.

Yet another related disorder causing hypertension is glucocorticoid remediable aldosteronism, which is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient, causing of primary hyperaldosteronism, the Gene mutated will result in an aldosterone synthase that is ACTH-sensitive, which is normally not. GRA appears to be the most common monogenic form of human hypertension.

Compare these effects to those seen in Conn's disease, an adrenocortical tumor which causes excess release of aldosterone, that leads to hypertension.

Another adrenal related cause is Cushing's syndrome which is a disorder caused by high levels of cortisol. Cortisol is a hormone secreted by the cortex of the adrenal glands. Cushing's syndrome can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH). More than 80% of patients with Cushing's syndrome develop hypertension., which is accompanied by distinct symptoms of the syndrome, such as central obesity, lipodystrophy, moon face, sweating, hirsutism and anxiety.

Neuroendocrine tumors are also a well known cause of secondary hypertension. Pheochromocytoma (most often located in the adrenal medulla) increases secretion of catecholamines such as epinephrine and norepinephrine, causing excessive stimulation of adrenergic receptors, which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).

Other sleep disturbances

Another cause is an exceptionally rare neurological disease called Binswanger's disease, causing dementia; it is a rare form of multi-infarct dementia, and is one of the neurological syndromes associated with hypertension.

Arsenic exposure

Because of the ubiquity of arsenic in ground water supplies and its effect on cardiovascular health, low dose arsenic poisoning should be inferred as a part of the pathogenesis of idiopathic hypertension. Idiopathic and essential are both somewhat synonymous with primary hypertension. Arsenic exposure has also many of the same signs of primary hypertension such as headache, somnolence, confusion, proteinuria, visual disturbances, and nausea and vomiting.

Potassium deficiency

Due to the role of intracellular potassium in regulation of cellular pressures related to sodium, establishing potassium balance has been shown to reverse hypertension.

Other causes of secondary hypertension

• Hormonal contraceptives
• Neurologic disorders
• Liquorice (when consumed in excessive amounts)
• Scleroderma
• Neurofibromatosis
• Pregnancy: unclear cause.
• Cancers: tumours in the kidney can operate in the same way as kidney disease. More commonly, however, tumors cause inessential hypertension by ectopic secretion of hormones involved in normal physiological control of blood pressure.
• Drugs:
  • Heavy alcohol use
  • NSAIDs
  • MAOIs, SNRIs, and TCA antidepressants
  • Adrenergic stimulants, including some nasal decongestants
  • Combined methods of hormonal contraception (those containing ethinylestradiol)
  • Steroid use
  • Nicotine use
• Malformed aorta, slow pulse, ischemia: these cause reduced blood flow to the renal arteries, with physiological responses as already outlined.
  • Coarctation of the aorta
  • Atherosclerosis
• Anemia: unclear cause.
• Fever: unclear cause.
• White coat hypertension: elevated blood pressure in a clinical setting but not in other settings, probably due to the anxiety some people experience during a clinic visit.
• Perioperative hypertension is development of hypertension just before, during or after surgery. It may occur before surgery during the induction of anesthesia; intraoperatively e.g. by pain-induced sympathetic nervous system stimulation; in the early postanesthesia period, e.g. by pain-induced sympathetic stimulation, hypothermia, hypoxia, or hypervolemia from excessive intraoperative fluid therapy; and in the 24 to 48 hours after the postoperative period as fluid is mobilized from the extravascular space. In addition, hypertension may develop perioperatively because of discontinuation of long-term antihypertensive medication.

Diagnosis

The ABCDE mnemonic can be used to help determine a secondary cause of hypertension.

• A: Accuracy, Apnea, Aldosteronism
• B: Bruits, Bad Kidney
• C: Catecholamines, Coarctation of the Aorta, Cushing's Syndrome
• D: Drugs, Diet
• E: Erythropoietin, Endocrine Disorders

References

References

1. (2010-12-15). "Diagnosis of secondary hypertension: an age-based approach". American Family Physician.
2. (November 2024). "Prevalence and Risk Factors for Secondary Hypertension in Young Adults". Hypertension.
3. (November 2011). "Obstructive Sleep Apnea: The Most Common Secondary Cause of Hypertension Associated With Resistant Hypertension". Hypertension.
4. (August 2017). "Prevalence of obstructive sleep apnea in the general population: A systematic review". Sleep Medicine Reviews.
5. (2017-06-28). "Independent associations between arterial bicarbonate, apnea severity and hypertension in obstructive sleep apnea". Respiratory Research.
6. (2009). "Obstructive sleep apnea and cardiovascular disease: a perspective and future directions". [[Progress in Cardiovascular Diseases]].
7. (2013-08-13). "Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome". Journal of the American College of Cardiology.
8. (January 2002). "Treating Obstructive Sleep Apnea Improves Essential Hypertension and Quality of Life". American Family Physician.
9. Textor SC. (May 2009). "Current Approaches to Renovascular Hypertension". [[The Medical Clinics of North America]].
10. (January 2009). "[Hypertension in patients with renal artery stenosis]". [[Der Internist]].
11. (October 2008). "Renal artery stenosis and chronic ischemic nephropathy: epidemiology and diagnosis". [[Advances in Chronic Kidney Disease]].
12. (2021). "Beyond Atherosclerosis and Fibromuscular Dysplasia: Rare Causes of Renovascular Hypertension". Hypertension.
13. (April 2009). "Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease". [[Nature Reviews Nephrology]].
14. Gross P. (May 2008). "Polycystic kidney disease: will it become treatable?". [[Polskie Archiwum Medycyny Wewnȩtrznej]].
15. (2007). "Potential pharmacological interventions in polycystic kidney disease". [[Drugs (journal).
16. Chapman AB. (May 2007). "Autosomal dominant polycystic kidney disease: time for a change?". [[Journal of the American Society of Nephrology]].
17. Chapman AB. (July 2008). "Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies". [[Clinical Journal of the American Society of Nephrology]].
18. (January 2008). "Natural history of primary IgA nephropathy". [[Seminars in Nephrology]].
19. D'Cruz D. (February 2009). "Renal manifestations of the antiphospholipid syndrome". [[Current Rheumatology Reports]].
20. (February 2009). "Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis". [[Thrombosis and Haemostasis]].
21. (2011). "Hypertension in Chronic Kidney Disease: Navigating the Evidence". International Journal of Hypertension.
22. (2021). "Disease Burden of Chronic Kidney Disease Due to Hypertension From 1990 to 2019: A Global Analysis". Frontiers in Medicine.
23. (September 2010). "Australian medicines handbook 2006". Australian Medicines Handbook Pty Ltd.
24. White WB. (May 2009). "Defining the problem of treating the patient with hypertension and arthritis pain". [[The American Journal of Medicine]].
25. (2008). "Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis". [[Arthritis Research & Therapy]].
26. Berenbaum F. (2008). "New horizons and perspectives in the treatment of osteoarthritis". [[Arthritis Research & Therapy]].
27. (October 2008). "Renal consequences of prostaglandin inhibition in heart failure". [[Heart Failure Clinics]].
28. Chobanian AV. (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". [[Journal of the American Medical Association.
29. Lowenstein J. (January 1980). "Drugs five years later: clonidine". [[Annals of Internal Medicine]].
30. Robertson JI. (January 1997). "Risk factors and drugs in the treatment of hypertension". [[Journal of Hypertension Supplement]].
31. Schachter M. (August 1999). "Moxonidine: a review of safety and tolerability after seven years of clinical experience". [[Journal of Hypertension Supplement]].
32. (July 1995). "Why imidazoline receptor modulator in the treatment of hypertension?". [[Annals of the New York Academy of Sciences]].
33. (April 1995). "[Controlled hypotension]". [[Der Anaesthesist]].
34. Scholtysik G. (March 1986). "Animal pharmacology of guanfacine". [[The American Journal of Cardiology]].
35. Myers MG. (January 1977). "New drugs in hypertension". [[Canadian Medical Association Journal]].
36. (1984). "The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine". Hypertension.
37. (November 2008). "[Pre-eclampsia screening in first and second trimester]". [[Therapeutische Umschau]].
38. Marik PE. (March 2009). "Hypertensive disorders of pregnancy". [[Postgraduate Medicine]].
39. (April 2009). "[Pregnancy-related hypertension: a cardiovascular risk situation]". [[Presse Médicale]].
40. (December 2008). "Juxtaglomerular Cell Tumor of the Kidney: Case Report and Differential Diagnosis With Emphasis on Pathologic and Cytopathologic Features". Int. J. Surg. Pathol..
41. (10 April 2024). "Ask-Upmark Kidney". StatPearls Publishing.
42. (2019). "Ask-Upmark kidney: A rare cause of secondary hypertension". Indian Journal of Nephrology.
43. Samuel J Mann. (2003). "Neurogenic essential hypertension revisited: the case for increased clinical and research attention". [[American Journal of Hypertension]].
44. (15 March 2024). "Pheochromocytoma". StatPearls Publishing.
45. (2020). "Pheochromocytoma and paraganglioma: an update on diagnosis, genetics, management, and treatment". Endocrine Reviews.
46. (10 April 2024). "Hyperparathyroidism". StatPearls Publishing.
47. (15 March 2024). "Acromegaly". StatPearls Publishing.
48. (April 2009). "Management of primary aldosteronism: its complications and their outcomes after treatment". [[Current Vascular Pharmacology]].
49. (February 2018). "C-17 Hydroxylase Deficiency: Practice Essentials, Pathophysiology, Epidemiology".
50. Bailey MA. (January 2008). "A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess". [[Journal of the American Society of Nephrology]].
51. (October 2007). "11beta-hydroxysteroide dehydrogenases. Recent advances". [[Annales d'endocrinologie]].
52. Atanasov AG. (April 2007). "Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess". [[Journal of the American Society of Nephrology]].
53. Johns C. (January 2009). "Glycyrrhizic acid toxicity caused by consumption of licorice candy cigars". [[Canadian Journal of Emergency Medical Care]].
54. (February 2008). "Pseudohyperaldosteronism, liquorice, and hypertension". [[Journal of Clinical Hypertension]].
55. (Dec 2015). "Cardiovascular Consequences of Cortisol Excess". Vasc Health Risk Manag.
56. Escher G. (April 2009). "Hyperaldosteronism in pregnancy". [[Therapeutic Advances in Cardiovascular Disease]].
57. Sukor N. (August 2008). "Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families". [[Journal of Hypertension]].
58. (May 2006). "[Glucocorticoid remediable aldosteronism]". [[Nippon Rinsho]].
59. Luft FC. (October 2003). "Mendelian Forms of Human Hypertension and Mechanisms of Disease". [[Clinical Medicine & Research]].
60. (February 2004). "Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production". [[Molecular and Cellular Endocrinology]].
61. (2004). "Glucocorticoid-remediable aldosteronism". [[Cardiology in Review]].
62. (2008). "[Molecular basics of aldosterone and cortisol synthesis in normal adrenals and adrenocortical adenomas]". [[Endokrynologia Polska]].
63. Astegiano M. (March 2005). "Association between Crohn's disease and Conn's syndrome. A report of two cases". [[Panminerva Medica]].
64. Pereira RM. (October 2004). "[Childhood adrenocortical tumors]". [[Arquivos Brasileiros de Endocrinologia e Metabologia]].
65. (March 2000). "Diagnosis and treatment of adrenal incidentaloma. A cost-effectiveness analysis". [[Endocrinology and Metabolism Clinics of North America]].
66. Kumar, Abbas, Fausto. ''Robbins and Cotran Pathologic Basis of Disease, 7th ed.'' Elsevier-Saunders; New York, 2005.
67. (January 2009). "[Glucocorticoids and hypertension]". [[Der Internist]].
68. Yudofsky, Stuart C.. (2007). "The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences". American Psychiatric Pub, Inc..
69. (December 2008). "Catecholamine-induced cardiomyopathy". [[Endocrine Practice]].
70. (November 2008). "[Functional imaging in Binswanger's disease]". [[Rinsho Shinkeigaku]].
71. Arsenic trioxide drugs dot com
72. atsdr-medical management guidelines for arsenic trioxide
73. Arsenic Author: Frances M Dyro, MD, Chief of the Neuromuscular Section, Associate Professor, Department of Neurology, New York Medical College, Westchester Medical Center
74. Addison WL. (March 1928). "The Use of Sodium Chloride, Potassium Chloride, Sodium Bromide, and Potassium Bromide in Cases of Arterial Hypertension which are Amenable to Potassium Chloride". Can Med Assoc J.
75. (October 2022). "The Effects of Pain and Analgesic Medications on Blood Pressure.". Current Hypertension Reports.
76. (2021). "Antidepressant Drugs Effects on Blood Pressure.". Frontiers in Cardiovascular Medicine.
77. (August 8–22, 2005). "Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis.". Archives of Internal Medicine.
78. (2008). "Perioperative hypertension management". Vasc Health Risk Manag.
79. (2006). "Secondary Hypertension". Armenian Medical Network.