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==Causes==
==Causes==
Patients presenting with high blood pressure must conduct a complete work-up before the diagnosis of essential hypertension is considered. Work-up includes, but is not limited to, a thorough medical history and physical examination, laboratory blood and urine testing, [[electrocardiogram]], and radiological work-up<ref name="pmid17462751">{{cite journal| author=Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA et al.| title=Secondary hypertension: current diagnosis and treatment. | journal=Int J Cardiol | year= 2008 | volume= 124 | issue= 1 | pages= 6-21 | pmid=17462751 | doi=10.1016/j.ijcard.2007.01.119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17462751  }} </ref>. Further work-up may be necessary if the above raised the suspicion of secondary hypertension.
===Common Causes===
===Common Causes===


Revision as of 18:13, 4 March 2013

Hypertension Main page

Overview

Causes

Classification

Primary Hypertension
Secondary Hypertension
Hypertensive Emergency
Hypertensive Urgency

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Taylor Palmieri

Overview

The prevalence of primary hypertension is much more common than secondary hypertension, where only 5-10% of hypertension cases are diagnosed as secondary hypertension[1]. When a full evaluation yields no clear etiology for the hypertension, the latter is thus identified as primary or essential hypertension. It is considered a chronic disease that requires lifetime treatment and management. If an underlying disease is identifiable as the cause of hypertension, the latter is called secondary hypertension. Causes of secondary hypertension include obstructive sleep apnea, hyperaldosteronism, kidney diseases, excess catecholamines, coarctation, cushing syndrome among other diseases.

Causes

Common Causes

Primary Hypertension

When a full evaluation yields no clear etiology for the hypertension, the latter is thus identified as primary or essential hypertension. It is considered a chronic disease that requires lifetime treatment and management. If an underlying disease is identifiable as the cause of hypertension, the latter is called secondary hypertension. Secondary hypertension is a potentially curable condition in most of the cases[2].

The prevalence of primary hypertension is much more common than secondary hypertension, where only 5-10% of hypertension cases are diagnosed as secondary hypertension[1]. The classical age range of primary hypertension is 30-55 years[3], but age alone should never warrant an insufficient work-up by healthcare providers for patients suspected to have primary hypertension.

Secondary Hypertension

Common causes of secondary hypertension are often memorized by the mnemonic ABCDE:

Mnemonic Causes of Secondary Hypertension
A Accuracy, Apnea, Aldosteronism
B Bruit, Bad Kidneys
C Catecholamines, Coarctation, Cushing’s Syndrome
D Drugs, Diet
E Erythropoitin, Endocrine Disorders
Accuracy:

It refers to inappropriate technique to measure blood pressure. Re-measurement of blood pressures to ensure accuracy must always be performed as a first step when patients present with high blood pressure values. Appropriate measurement technique must be carefully followed. The physician in charge should check for the accuracy of home BP measurements.

Apnea:

Obstructive sleep apnea (OSA) is a respiratory disease due to repetitive narrowing or collapse of the upper airway during sleep[4] leading to apnea, hypopnea, and decreased oxygen tension at night

[5]. Symptoms and signs that might suggest OSA include daytime somnolence, obesity, snoring, and morning headaches[6]. Diagnosis is made by sleep study. Treatment relies basically on maintaining airway patency at night and includes, among others, the use of continuous positive airway pressure (CPAP).

Aldosterone:

Primary (hyporeninemic) and secondary (hyperreninemic) hyperaldosteronism result in excess sodium and water retention with excretion of potassium[7]. Patient profiles and treatment options differ significantly among the two categories. The most common cause of primary hyperaldosteronism is an aldosterone-producing adenoma, i.e. Conn’s Syndrome. Secondary hyperaldosteronism is due to overactive RAAS, as seen in renin-secreting tumors, renal artery stenosis, pheochromocytoma, and others. Diagnosis is made by measuring ratio of plasma aldosterone to plasma renin activity[8]. It is elevated in primary hyperaldosteronism and decreased/normal with elevated renin in secondary hyperaldosteronism. Treatment is etiology-dependent; including surgery for tumor resection and spironolactone, an aldosterone antagonist.

Bruit:

Renovascular hypertension is due to decreased blood supply to the kidneys secondary to renal artery stenosis. Atherosclerosis of the renal artery in older patients above 50 years of age[9] and fibromuscular dysplasia in younger patients are common etiologies. Definitive diagnosis is made by Magnetic Resonance angiography (MRA) and renal arteriography[10]. Other diagnostic methods include duplex ultrasound scanning[11], and captopril-augmented radio-isotopic renogram[12]. Treatment is targeted at the etiology and is driven by the baseline patient condition, comorbidities, and expected outcome.

Bad Kidney:

Renal parenchymal disease blunts the kidney’s physiological ability to maintain appropriate blood pressure. Significantly, hypertension is both a cause and a consequence of renal parenchymal disease; the two are closely associated and potentiate each other[13]. Diagnosis is made by demonstration of decreased GFR. The mechanisms by which renal parenchymal disease lead to the development of hypertension are many and include the activation of the local RAAS, vasoconstrictor cytokines, in addition to decreased GFR leading to inappropriate natriuresis for the blood pressure level.

Catecholamines:

Catecholamine excess is witnessed in several non-disease states, such as acute stress, medications with sympathomimetic activity, and illicit drug use such as cocaine. Nonetheless, such conditions can be ruled out by mere history taking. Pheochromocytoma is a tumor of the adrenal gland leading to hypersecretion of epinephrine in most cases, should always be considered in the differential diagnosis of secondary hypertension, classically in young patients with the triad of intermittent hypertensive episodes causing headache, sweating, and tachycardia. Nonetheless, pheochromocytoma in older adults or a presentation with sustained hypertension is not uncommon. Diagnosis of pheochromocytoma remains controversial. The most applicable tests nowadays include measurement of plasma free metanephrines and urinary fractionated metanephrines.

Diagnostic value of plasma and urinary catecholamines is of less major importance due to the very short half-life of catecholamines. Treatment is by surgical resection of the secreting tumor.[14]

Coarctation:

Coarctation of the aorta is a congenital heart defect, caused by narrowing of a segment in the ascending or descending aorta. Diagnosis in neonates or infants usually starts with a suspicious physical examination of weak femoral pulses or asymmetrically brisk brachial pulses. Hypertension occurs as a result of decreased effective circulation at the level of the kidneys; the latter respond physiologically by increasing plasma volume causing hypertension in the upper extremities. Diagnosis is by CT angiography, but is usually achieved in neonates and infants by ultrasound of the heart and the great vessels. Definitive treatment is by surgical correction.

Cushing’s Syndrome:

An endocrine disorder caused by prolonged exposure to high endogenous or exogenous cortisol levels. Hypertension in Cushing’s syndrome has been classically attributed to the mineralocorticoid effects of cortisol. It manifests as an absent fall of nocturnal blood pressure physiologically seen in normotensive subjects with associated disturbance in the adrenocorticotropic hormone-glucocorticoid system[15]. Although an ideal diagnostic test is not considered yet available, clinicians often utilize 24-hour urinary cortisol excretion[16], low-dose dexamethasone suppression test[17], late evening serum or salivary cortisol [18], and CRH after dexamethasone test for the diagnosis of the syndrome and the various entities causing it[19].

Drugs:

An extensive list of drugs cause hypertension, such as immunosuppressive agents, non-steroidal anti-inflammatory drugs, oral contraceptive pills, some weight loss agents, stimulants, monoamine oxidase inhibitors, and sympathomimetics[1].

Diet:

In addition to the association of obesity due to high-caloric diet with hypertension, the 2001 study “Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet” concluded that a high sodium diet above the recommended 100 mmol per day (2.4 g of sodium or 6 g of sodium chloride salt) is associated with hypertension. As a result, reduction of sodium levels below 100 mmol per day and following the DASH diet (rich in vegetables, fruits, with low-fat dairy products) can significantly lower BP[20].

Erythropoietin:

Elevated erythropoietin is typically seen in COPD patients who have functional anemia due to chronic hypoxia and in hematologic disorders such as polycythemia. The pathogenesis of erythropoietin-induced hypertension includes the increased hematocrit and blood viscosity, altered sensitivity to vasopressors, dysregulated vasodilatory factors, and vascular cell growth causing arterial remodeling and changes in arterial smooth musculature[21]. Diagnosis and treatment are etiology-dependent.

Endocrine:

In addition to the more common endocrine causes of hypertension such as hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma, several other endocrine changes can cause hypertension. Both hypothyroidism and hyperthyroidism can cause hypertension by volume retention and by increased cardiac output, respectively. Also, hyperparathyroidism and hypovitaminosis D can cause hypertension due to poorly understood mechanisms, where parathyroidectomy seems to significantly decrease blood pressure in patients with parathyroid disease and elevated BP[22].

Causes by Organ System

Cardiovascular Aortic regurgitation, Aortic dissection, Acute severe vascular damage, Adams Nance syndrome , Aneurysm, Aortic coarctation , Aortic stenosis, Arterial occlusive disease, progressive - -- heart defects -- bone fragility -- brachysyndactyly , Arteriosclerosis, Atheroma, Avasthey syndrome , Carotid paraganglioma ,Congenital Mitral stenosis , Eisenmenger's Syndrome , Fibromuscular dysplasia of arteries , Grange syndrome , Hemangiomatosis - familial pulmonary capillary, Hypertensive heart disease , Pulmonary artery agenesis , Vasculitis , Patent ductus arteriosus, Third degree AV block
Chemical / poisoning Acetaldehyde , Aristolochic acid poisoning , Arizona Bark Scorpion poisoning , Black widow spider envenomation , Cadmium poisoning, Cocaine, Ecstasy abuse , Ginseng , Heavy metal poisoning, Indian Tobacco poisoning, Jimsonweed poisoning , Lead poisoning , Lockwood-Feingold syndrome , Mustard tree poisoning , Nicotine addiction , Pseudoephedrine poisoning , Silicosis , Toxic mushrooms -- Psychedelic , Lobelia poisoning
Dermatologic No underlying causes
Drug Side Effect Almotriptan, Dihydroergotamine, Ergotamine, Frovatriptan, Isometheptene, Rizatriptan, Sumatriptan, Zolmitriptan, Amitriptyline, Cyclosporine, Desipramine, Doxepin, Ephedrine, Glucocorticoid resistance , Imipramine, Nasal decongestants, Nortriptyline, Combined oral contraceptive pill, Phencyclidine, Phenylpropanolamine, Protriptyline, Sedative dependence, Serotonin toxicity, Steroid abuse, Pseudoephedrine, Cocaine
Ear Nose Throat Nephrosis -- deafness -- urinary tract -- digital malformation , Fitzsimmons-Walson-Mellor syndrome
Endocrine Carcinoid Syndrome, Acromegaly , Adrenal incidentaloma , Alcohol-induced pseudo-Cushing syndrome , Apparent mineralocorticoid excess , Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency, Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, Conn's syndrome, Cushing's disease, Cushing's syndrome , Diabetes, Familial Cushing syndrome , Graves Disease , Hyperadrenalism , Hyperparathyroidism , Hyperpituitarism , Hyperthyroidism, Hypothyroidism,Isolated secretion of corticosterone, Isolated secretion of deoxycorticosterone, Mineralocorticoid excess, Multiple endocrine neoplasia type 1, Myxoedema, Pheochromocytoma, Primary aldosteronism, Primary cortisol resistance, Pseudohyperaldosteronism , Pseudohypoaldosteronism , Schroeder syndrome 1 , Hyperthyroidism, Hypoglycemia, Isolated secretion of 18-hydroxy-deoxycorticosterone, Renin-secreting tumors, Dexamethasone sensitive hypertension
Environmental No underlying causes
Gastroenterologic Hepatorenal tyrosinemia , Pancreatitis, Retroperitoneal Fibrosis
Genetic Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency, Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, Cockayne syndrome , Down Syndrome , Fabry's Disease , Isolated secretion of 18-hydroxy-deoxycorticosterone, Pierre Robin's sequence , Senior-Loken Syndrome, Turner Syndrome , Vater-like syndrome, with pulmonary hypertension, abnormal ears and growth deficiency , Von Hippel-Lindau Disease , Werner syndrome , Williams Syndrome , Gaucher disease type 3 , Mucopolysaccharidosis type I Hurler syndrome
Hematologic Atypical Hemolytic uremic syndrome, Catastrophic Antiphospholipid Syndrome , Essential mixed Cryoglobulinemia , Faye-Petersen-Ward-Carey syndrome , Hemolytic uremic syndrome , Hypereosinophilic syndrome , Liddle's syndrome, Multicentric Reticulohistiocytosis , Polycythemia , Thromboembolism , Thrombotic thrombocytopenic purpura
Iatrogenic No underlying causes
Infectious Disease Poliomyelitis, Meningitis, Post streptococcal glomerulonephritis , Renal tuberculosis, Nipah virus encephalitis
Musculoskeletal / Ortho Acrodynia , Allain Babin Demarquez syndrome , Familial Osteodysplasia - Anderson type, Paget's disease of bone , Grange syndrome , Faye-Petersen-Ward-Carey syndrome , Oculo skeletal renal syndrome , Thieffry and Sorrell Dejerine syndrome
Neurologic Guillain-Barre Syndrome, Autonomic dysreflexia syndrome , Binswanger's Disease , Brain stem encephalitis, Central sleep apnea , Choroideremia -- hypopituitarism , Disequilibrium syndrome , Dysautonomia , Hereditary sensory and autonomic neuropathy 3 , Increased intracranial pressure, Neurofibromatosis syndrome Type II , Neurogenic hypertension , Nipah virus encephalitis , Obstructive sleep apnea , Sneddon Syndrome , Upper spinal cord lesions, Wolfram's disease, Meningitis, Polyradiculitis, Quadriplegia, Adams Nance syndrome , Glycine encephalopathy - classical neonatal form, Pituitary Cancer , Fitzsimmons-Walson-Mellor syndrome
Nutritional / Metabolic Abdominal obesity metabolic syndrome , Acute intermittent porphyria , Congenital hepatic porphyria , Gaucher disease type 3, Glycine encephalopathy - classical neonatal form, Glycine synthase deficiency , Gouty nephropathy, Metabolic syndrome, Tyrosinemia , Von Gierke disease IB, Increased salt intake, Mucopolysaccharidosis type I Hurler syndrome, Fabry's Disease , Vitamin D -- adverse effects
Obstetric/Gynecologic Eclampsia , Fowler-Christmas-Chapple syndrome , Gestational hypertension, HELLP syndrome , Ovarian dysgenesis, PCOS, Pregnancy toxemia /hypertension , Twin-Twin Transfusion Syndrome
Oncologic Endothelin producing tumor, Adrenal Cancer , Familial Adrenal adenoma , Renal Cancer , Neuroblastoma

Pituitary Cancer , Renin-secreting tumors, Rhabdoid tumor , Wilms' tumor , Adrenal incidentaloma , Familial Renal cell carcinoma

Opthalmologic Isolated Ectopia lentis, Oculo skeletal renal syndrome
Overdose / Toxicity Amphetamine abuse, Almotriptan, Dihydroergotamine, Ergotamine, Frovatriptan, Isometheptene, Rizatriptan, Sumatriptan, Zolmitriptan, Amitriptyline, Cyclosporine, Desipramine, Dexamethasone sensitive hypertension, Doxepin, Ephedrine, Glucocorticoid resistance , Imipramine, Nasal decongestants, Nortriptyline, Combined oral contraceptive pill, Phencyclidine, Phenylpropanolamine, Protriptyline, Serotonin toxicity, Steroid abuse, Pseudoephedrine, Cocaine
Psychiatric Anxiety
Pulmonary Asphyxia , Bronchopulmonary dysplasia, COPD , Goodpasture syndrome , Pulmonary cystic lymphangiectasis , Pulmonary embolism , Pulmonary fibrosis /granuloma , Pulmonary veno-occlusive disease , Pulmonary Lymphangiomatosis, Respiratory acidosis , Respiratory failure , Unilateral pulmonary agenesis , Hyperventilation, Obstructive sleep apnea , Wegener's granulomatosis
Renal / Electrolyte Bartter's Syndrome, Dissection of the renal arteries, Acid-Base Imbalance , Acute Renal Failure , Albuminuria , Analgesic nephropathy syndrome , Autosomal dominant Polycystic kidney disease , Autosomal Recessive Polycystic Kidney Disease , Bilateral Renal artery stenosis , Bright's Disease , Chronic kidney disease , Chronic pyelonephritis, Congenital Membranous glomerulonephritis, Congenital stenosis of renal artery, Congenital Hydronephrosis , Diffuse mesangial sclerosis, Familial Renal cell carcinoma , Fitzsimmons-Walson-Mellor syndrome , Glomerulonephritis , Hereditary nephritis (X-linked), Hypoplastic kidney, IgA nephropathy , Kidney arteriovenous fistula , Kimmelstiel-Wilson disease, Lupus nephritis , Nephrocalcinosis , Nephrosclerosis , Nephrosis -- deafness -- urinary tract -- digital malformation , Nephrotic syndrome , Oculo skeletal renal syndrome , Pierson syndrome , Severe infantile Polycystic kidneys with Tuberous sclerosis , Post streptococcal glomerulonephritis , Renal artery thrombosis, Renal emboli, Renal segmental hypoplasia-induced Hypertension , Renal tuberculosis, Salcedo syndrome , Simple kidney cysts , Thieffry and Sorrell Dejerine syndrome , Urinary tract infections , Urinary tract obstruction, Vesicoureteral reflux , Wegener's granulomatosis , Gitelman's Syndrome, Hepatorenal tyrosinemia , Atypical Hemolytic uremic syndrome, Gouty nephropathy, Goodpasture syndrome
Rheum / Immune / Allergy Autoimmune Vasculitis , Systemic lupus erythematosus, Diffuse Systemic sclerosis , Polyarteritis nodosa , , Takayasu arteritis
Sexual No underlying causes
Trauma Electrical burns , Head injury, Skull fracture
Urologic No underlying causes
Dental No underlying causes
Miscellaneous Acquired total Lipodystrophy , After Kidney transplantation, Aging, Alcohol withdrawal, Amyloidosis , Bone cement implantation syndrome , Brachydactyly with hypertension, Carnevale-Canun-Mendoza syndrome , Codeine withdrawal , Collagen disease, Essential hypertension, Gram's syndrome , Hypothermia, Irradiation, Kashani-Strom-Utley syndrome , Lymphomatoid Granulomatosis , MSBD syndrome , Neuroleptic Malignant Syndrome , Obesity, Physical inactivity , Selye syndrome , Serotonin Syndrome , Shaken Baby Syndrome , Stress-Induced Hypertension , Type A personality, Wagener syndrome , Pain, Post-exercise, Transfusion of large blood volumes, White coat hypertension

Causes in Alphabetical Order


References

  1. ↑ 1.0 1.1 1.2 Onusko E (2003). "Diagnosing secondary hypertension". Am Fam Physician. 67 (1): 67–74. PMID 12537168.
  2. ↑ Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA; et al. (2008). "Secondary hypertension: current diagnosis and treatment". Int J Cardiol. 124 (1): 6–21. doi:10.1016/j.ijcard.2007.01.119. PMID 17462751.
  3. ↑ Dosh SA (2001). "The diagnosis of essential and secondary hypertension in adults". J Fam Pract. 50 (8): 707–12. PMID 11509166.
  4. ↑ Eckert DJ, Malhotra A (2008). "Pathophysiology of adult obstructive sleep apnea". Proc Am Thorac Soc. 5 (2): 144–53. doi:10.1513/pats.200707-114MG. PMC 2628457. PMID 18250206.
  5. ↑ Silverberg DS, Oksenberg A (1996). "Essential and secondary hypertension and sleep-disordered breathing: a unifying hypothesis". J Hum Hypertens. 10 (6): 353–63. PMID 8872797.
  6. ↑ Victor LD (1999). "Obstructive sleep apnea". Am Fam Physician. 60 (8): 2279–86. PMID 10593319.
  7. ↑ Ganguly A (1998). "Primary aldosteronism". N Engl J Med. 339 (25): 1828–34. doi:10.1056/NEJM199812173392507. PMID 9854120.
  8. ↑ Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC (1994). "High incidence of primary aldosteronism in 199 patients referred with hypertension". Clin Exp Pharmacol Physiol. 21 (4): 315–8. PMID 7923898.
  9. ↑ Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC; et al. (2002). "Distinct renal injury in early atherosclerosis and renovascular disease". Circulation. 106 (9): 1165–71. PMID 12196346.
  10. ↑ Wofford MR, King DS, Wyatt SB, Jones DW (2000). "Secondary Hypertension: Detection and Management for the Primary Care Provider". J Clin Hypertens (Greenwich). 2 (2): 124–131. PMID 11416635.
  11. ↑ AbuRahma AF, Srivastava M, Mousa AY, Dearing DD, Hass SM, Campbell JR; et al. (2012). "Critical analysis of renal duplex ultrasound parameters in detecting significant renal artery stenosis". J Vasc Surg. 56 (4): 1052–9, 1060.e1, discussion 1059-60. doi:10.1016/j.jvs.2012.03.036. PMID 22595689.
  12. ↑ Aitchison F, Page A (1999). "Diagnostic imaging of renal artery stenosis". J Hum Hypertens. 13 (9): 595–603. PMID 10482969.
  13. ↑ Soergel M, Schaefer F (2002). "Effect of hypertension on the progression of chronic renal failure in children". Am J Hypertens. 15 (2 Pt 2): 53S–56S. PMID 11866231.
  14. ↑ Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P; et al. (2002). "Biochemical diagnosis of pheochromocytoma: which test is best?". JAMA. 287 (11): 1427–34. PMID 11903030.
  15. ↑ Imai Y, Abe K, Sasaki S, Minami N, Nihei M, Munakata M; et al. (1988). "Altered circadian blood pressure rhythm in patients with Cushing's syndrome". Hypertension. 12 (1): 11–9. PMID 3397172.
  16. ↑ Contreras LN, Hane S, Tyrrell JB (1986). "Urinary cortisol in the assessment of pituitary-adrenal function: utility of 24-hour and spot determinations". J Clin Endocrinol Metab. 62 (5): 965–9. PMID 3958132.
  17. ↑ NUGENT CA, NICHOLS T, TYLER FH (1965). "Diagnosis of Cushing's Syndrome; Single Dose Dexamethasone Suppression Test". Arch Intern Med. 116: 172–6. PMID 14315650.
  18. ↑ Raff H, Raff JL, Findling JW (1998). "Late-night salivary cortisol as a screening test for Cushing's syndrome". J Clin Endocrinol Metab. 83 (8): 2681–6. PMID 9709931.
  19. ↑ Yanovski JA, Cutler GB, Chrousos GP, Nieman LK (1993). "Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states". JAMA. 269 (17): 2232–8. PMID 8386285.
  20. ↑ Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D; et al. (2001). "Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group". N Engl J Med. 344 (1): 3–10. doi:10.1056/NEJM200101043440101. PMID 11136953.
  21. ↑ Vaziri ND (1999). "Mechanism of erythropoietin-induced hypertension". Am J Kidney Dis. 33 (5): 821–8. PMID 10213636.
  22. ↑ Chopra S, Cherian D, Jacob JJ (2011). "The thyroid hormone, parathyroid hormone and vitamin D associated hypertension". Indian J Endocrinol Metab. 15 Suppl 4: S354–60. doi:10.4103/2230-8210.86979. PMC 3230087. PMID 22145139.

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