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Endocrine Hypertension: Diagnosis and Approach
Endocrine Hypertension: Diagnosis and Approach
Sushil Kumar Gupta
Professor, Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Address for correspondence: Sushil Kumar Gupta, Professor, Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences,Lucknow, Uttar Pradesh, India
E-mail: sushilguptasgpgi@gmail.com
Received: 11-11-2017; Accepted: 22-12-2017
Hypertension is a major public health problem affecting more than one-third of adults above the age of 18 years.[1] Hypertensionis one of biggest contributors to the global burden of disease and mortality.
Keywords:Aldosterone-producing adenoma , hypokalemia, adrenal hypoplasia
How to cite this article: Gupta SK. Endocrine hypertension:Diagnosis and approach. Hypertens 2018;4(1): 18-25.
Source of support: Nil
Conflict of interest: None


Hypertension is a major public health problem affecting morethan one-third of adults above the age of 18 years.[1] Hypertensionis one of biggest contributors to the global burden of diseaseand mortality. In adults, hypertension is primarily idiopathicwhile secondary hypertension occurs in 10-15% of subjects.57% of hypertensive children attending tertiary care center havesecondary hypertension while 6% have endocrine hypertension.[2]In subjects, 18-40 years attending referral hospitals, secondaryhypertension occurs in almost 30% of subjects; primaryhyperaldosteronism 7.4%, fibromuscular dysplasia 5.8%, andpheochromocytoma in 3.9% of patients.[3]

At least 15 endocrine conditions can present to clinicianas hypertension. Recognition of appropriate protocol baseddiagnosis is the key to medical or surgical cure of causativeendocrine disorder. In this article, we review the clinicalpresentation, prevalence, the case detection approach, diagnosticprotocol, and treatment.

Primary Hyperaldosteronism

Unregulated excessive production of aldosterone from adrenalgland leads to hypertension, hypokalemia, metabolic alkalosis,and suppressed renin-angiotensin axis. Primary aldosteronism(PA) causes significant cardiovascular, cerebrovascular, andrenal morbidity, which is disproportionate to the degree ofhypertension.[4] Primary hyperaldosteronism accounts for 5-10% of hypertensive subjects while in resistant hypertensivesubjects, 20% of subjects. It is now widely acknowledged thatmajority of subjects with PA are normokalemic.[5] Most patientswith PA are diagnosed during their 3-6th decades. Patients withPA also display an increased prevalence of metabolic syndromeand diabetes, osteoporotic fractures, and symptoms of depressionwith a reduced quality of life. Aldosterone-producing adenoma(APA) and bilateral idiopathic hyperaldosteronism (IHA) arethe most frequent causes of PA, accounting for 90% of cases.Primary (unilateral) adrenal hyperplasia constitutes 2% of cases,aldosterone-producing adrenocortical carcinoma constitutes< 1% of cases while familial hyperaldosteronism (FH) isconstituted by glucocorticoid-remediable aldosteronism (GRA,FH type 1, < 1%), FH type 2 (APA or IHA, < 6%), and FH type 3(germline KCNJ5 mutations, < 1%). Very rarely, ectopic APA orcarcinoma (< 0.1%) is found.


Aldosterone is synthesized from cholesterol in the zonaglomerulosa (ZG) of the adrenal cortex by a series oflocus- and orientation-specific enzymatic reaction catalyzed bydehydrogenases and mixed-function oxidases. Many of theseenzymes belong to the cytochrome P450 superfamily of hemecontainingenzymes.

Aldosterone synthesis and secretion are principally regulatedby angiotensin II (Ang II), serum K+ levels, and ACTHhormone. However, other regulators are adrenaline, vasoactive intestinal polypeptide, serotonin, ouabain, atrial natriureticpeptide, dopamine, heparin, and adrenomedullin.

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In renin-angiotensin system, renin is synthesized and releasedby the juxtaglomerular cells in the afferent arteriole of the kidneyin response to a decrease in intravascular volume detected bybaroreceptors (mediated by β-adrenoreceptor activation) andby a reduced sodium concentration at the macula densa. Renincatalyzes the hydrolysis of angiotensinogen to angiotensinI (Ang I) which is then converted to Ang II by angiotensinconvertingenzyme, presents in the lungs and vascular tissue.Ang II acts on vascular smooth muscle to cause vasoconstrictionand on the adrenal ZG to stimulate aldosterone production. Theacute adrenal response to Ang II occurs within minutes, implyingthe release of preformed aldosterone, and possibly rapid synthesisof aldosterone. Chronic stimulation by Ang II results in ZGhypertrophy and hyperplasia increased CYP11B2 expression andsubsequent aldosterone secretion. Ang II stimulates aldosteroneproduction through specific G-protein-coupled receptors (AT1receptors).

Aldosterone secretion is acutely sensitive to minute changesin extracellular K+ concentration. Increased [K+] concentrationstimulates aldosterone secretion. The effects of extracellular [K+]and Ang II are synergistic so that the prevailing [K+] determinesthe concentration/effect relationship for Ang II-mediatedaldosterone production. Ang II and K+ regulate CYP11B2transcription through common Ca2+-dependent signalingpathways and also through many common transcription factors.Acutely, ACTH stimulates aldosterone production throughcAMP-mediated pathways and multiple protein synthesisindependentmechanisms. In contrast, chronic ACTHstimulation suppresses plasma aldosterone levels in both humansand animal models. The mechanism of chronic inhibition isunclear; the postulated pathways are downregulation of Ang IIreceptors in adrenocortical cells by cAMP, transformation of ZGcells into zona fasciculate, or diversion of precursors from themineralocorticoid to the glucocorticoid pathway.

The effects of aldosterone are mediated by mineralocorticoidreceptors (MRs) located in the renal cell cytosol. Thesebelong to the nuclear receptor superfamily and are composedof several functional domains. Hormone-binding results in aconformational change resulting in dissociation of the associatedproteins, dimerization and translocation to the cell nucleus,and binding to steroid-responsive elements in the 5'UTR ofaldosterone-responsive genes that activate or repress genetranscription. The epithelial action of aldosterone consists ofearly (1-6 h) and late (>6 h) phases.

MR receptors are present in renal cytosol, salivary glands,and colon. Type 2 glucocorticoid receptors (GRs) are expressedubiquitously and have higher affinity for glucocorticoids such ascortisol and corticosterone. There is a high degree of homologybetween MRs and GRs in their DNA-binding domains (94%)and ligand-binding domains (57%), and hence, MRs have highaffinity to glucocorticoids. 1β-HSD type 2 (11β-HSD2) enzymecomplex colocalizes with MRs in target epithelial tissues. Thisenzyme catalyzes the conversion of active glucocorticoids, capable of binding with high affinity to MRs, into inactivemetabolites (in humans, this is the conversion of cortisol tocortisone). These metabolites have little affinity for the MR andso the action of 11β-HSD2 effectively protects the MR from illicitoccupation by glucocorticoids. This protective phenomenon isclinically important in syndrome of apparent mineralocorticoidexcess. It is characterized by sodium retention, hypokalemia lowrenin, and hypertension, in the absence of excessive aldosteroneor 11-deoxycorticosterone (DOC), and is due to excessiveconsumption of liquorice, a component of which - glycyrrhetinicacid - inhibits 11β-HSD2. In mutation of gene for this enzyme,which is inherited as autosomal recessive disorder, results ininactive 11#946;-HSD2 enzyme and similar picture but is successfullytreated with dexamethasone, which suppresses endogenouscortisol and does not bind to MR.

Clinical Picture

There are no specific symptoms or signs of PA; however, thereis a need for suspicion of this diagnosis in following situations;hypertension with spontaneous or diuretic-induced hypokalemia,resistant hypertension, hypertension with adrenal incidentaloma,severe hypertension (systolic >160 mmHg or diastolic pressure>100 mmHg), suspicion of secondary hypertension, and onsetof hypertension at young age (< 20 years).[6] Patients withsignificant hypokalemia can have muscle weakness, muscularcramps, headache, palpitations, polyuria, polydipsia, or tetany,either in combination or in isolation. Periodic paralysis withhypokalemia is a common presentation in Indian and subjectsfrom Southeast Asians descent but rare in Caucasians.

In general, patients with APAs have more severe hypertension,more frequent hypokalemia, higher levels of plasma aldosterone(>25 ng/dL) and urinary aldosterone (>30 µg/24 h), and areyounger (< 50 years), compared with those who have IHA.


The diagnostic approach to PA is generally considered as threestepapproaches: Case detection tests, confirmatory tests, andthen subtype evaluation tests.[6]

Case Detection

Screening for PA is usually accomplished with the estimationof the ratio of plasma aldosterone concentration (PAC, ng/dL)to plasma renin activity (PRA, ng/mL/h) by obtaining pairedrandom ambulatory morning (preferably at 8-10 am) bloodsample. Serum potassium levels should be normal at thetime of collection of blood sample. There is no indication ofstopping any antihypertensive drugs except spironolactone andeplerenone which should be stopped for at least 6 weeks beforecase screening test. Practically, PA should be suspected if thePRA is suppressed (<1.0 ng/mL/h), PAC/PRA ratio is >30, andPAC concentration is above 15 ng/dL. A high PAC/PRA ratio is a positive screening and not diagnostic test result and warrantsconfirmatory testing.

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Confirmatory Tests

Various confirmatory tests are based on suppression ofaldosterone secretion by salt loading. At the time of these tests,the subject should be normokalemic, should be on normal orhigh sodium intake diet, and should not be currently takingspironolactone or eplerenone for past 6 weeks. Many a times,vigorous replacement of potassium chloride is needed tomaintain normokalemia. Various tests are oral salt loading test,IV saline loading test, and fludrocortisone loading test.

Oral salt loading test includes administration of 12.8 g ofsodium chloride (5 g of sodium) for 3 consecutive days and thenestimation of 24 h urinary aldosterone, sodium, and creatinineon the 3rd day of administration. It is important to documentadequate sodium repletion, i.e. the 24-h urinary sodiumexcretion should exceed 200 mEq. If 24 h urinary aldosteroneexcretion exceeds 12 ug, the diagnosis of PA is confirmed. Thesensitivity and specificity of the oral sodium loading test are 96%and 93%, respectively.

Intravenous Saline Infusion Test

Normal subjects show suppression of PAC after volumeexpansion with isotonic saline; subjects with PA do not showthis suppression. The test is done after an overnight fast. 2 Lof 0.9% sodium chloride solution is infused intravenously withan infusion pump over 4 h with the patient recumbent. Bloodpressure and heart rate are monitored during the infusion. At thecompletion of the infusion, blood is drawn for the measurementof PAC. PAC levels in normal subjects decrease to < 5 ng/dL,whereas most patients with PA do not suppress to < 10 ng/dL. Post-infusion PAC values between 5 and 10 ng/dL areindeterminate and may be seen in patients with IHA.

Fludrocortisone Suppression Test

Fludrocortisone acetate is administered for 4 days (0.1 mg every6 h) in combination with sodium chloride tablets (2 g 3 timesdaily with food). Blood pressure and serum potassium levelsmust be monitored daily. In the setting of low PRA, failureto suppress the upright 10 AM PAC to < 6 ng/dL on day 4 isdiagnostic of PA. Most centers no longer use this test.

Subtype Studies

The next step is distinguishing between APA and PAH fromIHA and GRA. Unilateral adrenalectomy in patients with APAor PAH results in normalization of hypokalemia in all cases;hypertension is improved in all cases and is cured in 30-60%.In IHA and GRA, unilateral or bilateral adrenalectomy seldomcorrects the hypertension, and hence, IHA and GRA should betreated medically. The delineation of these pathologies is donein following steps.

Computed Tomography (CT) of the Adrenal Glands

Contrast-enhanced CT (CECT) of adrenal gland with 2 mmslices is usually the first step. APAs are usually small hypodenseadrenal nodules (< 2 cm in diameter) on CT while in IHAadrenal glands may be normal on CT or may show nodularchanges. Aldosterone-producing adrenal carcinomas are almostalways larger than 4 cm in diameter and have an inhomogeneousphenotype. However, many a times, CT reveals normalappearingadrenals, minimal unilateral adrenal limb thickening,unilateral microadenomas (≤1 cm), or bilateral macroadenomas.In these situations, additional testing is required to localizelaterality or the source of excess aldosterone secretion.
,br>If a solitary unilateral hypodense (HU < 10) macroadenoma(>1 cm) and normal contralateral adrenal morphologicappearance are found on CT in a young patient (< 35 years) withsevere PA, unilateral adrenalectomy without further evaluationis a reasonable therapeutic option.

Small APAs are misdiagnosed as IHA on CT on the basisof normal-appearing adrenals. Furthermore, apparent adrenalmicroadenomas may actually represent areas of hyperplasia.Unilateral PAH may be visible on CT, or the PAH may appearnormal on CT. Further, non-functioning unilateral adrenalmicro- and macro-adenomas are not uncommon in subjects>40 years age. Adrenal CT is not accurate in distinguishingbetween APA and IHA. Adrenal venous sampling is currentlythe gold standard for defining unilateral from bilateral lesionsand, hence, helps in taking the decision for surgical or medicaltreatment. In a systematic review of 38 studies including950 patients with PA, adrenal CT/magnetic resonance imaging(MRI) results did not agree with the findings from AVS in38% of subjects. 19% of these subjects could have been offeredunnecessary surgery while another 19% could have been declinecurative surgery.

Adrenal Venous Sampling

AVS is a highly specialized procedure requiring experiencedintervention radiologist, center-specific protocol, appropriatepatient selection, and meticulous data analysis. In expert hands,the AVS success rate is as high as 96%.[7]

Principally, the individual right and left adrenal arecatheterized for sampling of blood for aldosterone and cortisolwhile the patient is maximally stimulated for cortisol secretionby synthetic ACTH stimulation. In addition, peripheral sampleis collected form inferior vena cava at the level of external iliacvein for cortisol and aldosterone for peripheral concentration.The adrenal vein/IVC cortisol ratio is typically >10:1. Cortisolcorrectedratios (ratio of aldosterone and cortisol) are calculatedfrom adrenal veins samples. A cutoff point of 4.0:1 for thisratio is used to indicate unilateral aldosterone excess while aratio of < 3.0:1 suggests bilateral aldosterone hypersecretion.AVS detection of unilateral aldosterone hypersecretion (APAor PAH) has 95% sensitivity and 100% specificity. At centerswith experience with AVS, the complication rate is ≤2.5%.Complications include symptomatic groin hematoma, adrenal hemorrhage, and dissection of an adrenal vein. Some centersand clinical practice guidelines recommend that AVS shouldbe performed in all patients who have the diagnosis of PA.However, we perform AVS in all the cases with normal-appearingadrenals, adrenals with micronodularity, bilateral masses, and insubjects above the age of 35 years with unilateral hypodense,nodule >1 cm, and marked PA.

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GRA: FH Type I

GRA (FH Type I) is rare and is due to CYP11B1/CYP11B2chimeric gene and hyperaldosteronism is reversed withphysiologic suppression with glucocorticoids. Mineralocorticoidproduction is regulated by ACTH instead of by the normalsecretagogue, angiotensin II. GRA is characterized by earlyonsethypertension that is usually severe and refractory toconventional antihypertensive therapies, aldosterone excess,suppressed PRA, and excess production of 18-hydroxycortisoland 18-oxycortisol.[8] Genetic testing is a sensitive and specificmeans of diagnosing GRA. Genetic testing for GRA should beconsidered for patients with PA who have a family history ofPA, onset of PA at a young age (< 20 years), or family history ofstrokes at a young age.

FH Type II

FH Type II is an autosomal dominant PA and does not suppresswith dexamethasone, and GRA mutation testing is negative.[9]
The molecular basis for FH type II is unclear.


FH Type III is due to a point mutation in and near the selectivity filterof the potassium channel KCNJ5. This KCNJ5 mutation producesincreased sodium conductance and cell depolarization, triggeringcalcium entry into glomerulosa cells, the signal for aldosteroneproduction, and cell proliferation.[10] Various germline mutations ofKCNJ5 described are G151R and G151E. The patients have earlyonset,mild PA and may have marked adrenal hyperplasia.

Somatic Mutations in KCNJ5, ATP1A1, ATP2B3, ANDCACNA1D Genes

Somatic mutations of KCNJ5 (G151R or L168R) have beenidentified in 34-47% of APAs. They are more prevalent inwomen and associated with higher pre-operative aldosteronelevels but no significant surgical outcome.

Treatment of PA

The treatment goal in PA is to prevent the morbidity and fatalityassociated with hypertension, hypokalemia, and cardiovasculardamage. Identifying the cause of PA is to help to determine theappropriate curative surgical or lifelong medical treatment.

Surgical Treatment of APA and Unilateral Hyperplasia

Unilateral laparoscopic adrenalectomy is currently the treatmentfor patients with APA or unilateral hyperplasia. Long-term cure ofHTN in APA is 30-60%. Predictors for persistent hypertensionare family history of hypertension, use of more than twoantihypertensive drugs, old age, impaired renal functions, longduration of hypertension, and many a times are usually due tocoexistent essential hypertension.

Pharmacologic Treatment

IHA and GRA should be treated medically. Spironolactone, thedrug of choice, is initiated in dose of 12.5-25 mg/day initiallyand can be increased to 400 mg/day. Hypokalemia respondspromptly while response to hypertension takes 4-8 weeks. Thedose titration is adjusted according to serum potassium levels,to maintain it at high normal. After several months of therapy,the dosage of spironolactone often can be decreased to as littleas 25-50 mg/day. Serum potassium and creatinine shouldbe monitored frequently during the first 4-6 weeks of therapy(especially in patients with renal insufficiency or diabetesmellitus).

Eplerenone is a steroid-based antimineralocorticoid that actsas a competitive and selective MR antagonist. It is reasonableto start with a dose of 25 mg twice daily and titrated upwardwith maximum dose of 100 mg/day; the target is a high-normalserum potassium concentration without the aid of potassiumsupplements. In a randomized, double-blind trial comparingthe efficacy, safety, and tolerability of eplerenone to that ofspironolactone (100-300 mg vs. 75-225 mg, respectively) inpatients with PA found spironolactone to be superior in terms ofblood pressure lowering but to be associated with higher rates ofmale gynecomastia and female mastodynia.

Other Forms of Mineralocorticoid Excess or Effect

Endocrine hypertension associated with excess mineralocorticoideffect from DOC and cortisol should be considered if PAC andPRA are low in a patient with hypertension and hypokalemia.


Congenital Adrenal Hyperplasia

Deficiencies of 11β-hydroxylase (CYP11B1 and P450c11) or17α-hydroxylase (CYP17 and P450c17) cause hypertension andhypokalemia because of hypersecretion of DOC.

11β-hydroxylase deficiency causes impaired conversion ofDOC to corticosterone, high levels of DOC and 11-deoxycortisol;the substrate mass effect results in increased levels of adrenalandrogens. It should be suspected in girls presenting in infancyor childhood with hypertension, hypokalemia, acne, hirsutism,and virilization. Boys present in early age onset hypertension,hypokalemia, and pseudoprecocious puberty.[11] The initial screening tests include measurement of blood levels ofDOC, 11-deoxycortisol, androstenedione, testosterone, anddehydroepiandrosterone sulfate (DHEAS): All of which shouldbe increased above the upper limit of the respective referenceranges. Confirmatory testing includes germline mutation testing.

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17A-hydroxylase Deficiency

17α-hydroxylase is essential for the synthesis of cortisol and gonadalhormones, and deficiency results in decreased the production ofcortisol and sex steroid. Genetic 46, XY males present with eitherpseudohermaphroditism or as phenotypic females, and 46, XXfemales present with primary amenorrhea. Therefore, a person withthis form of CAH may not come to medical attention until puberty.Children, adolescents, and young adults present with hypertensionand spontaneous hypokalemia and low levels of aldosterone andrenin.[12] The initial screening tests include measurement of serumandrostenedione, testosterone, DHEAS, 17-hydroxyprogesterone,aldosterone, and cortisol: All of which should be either low or atthe lower quartile of the respective references ranges. The plasmaconcentrations of DOC and corticosterone should be above theupper limit of the respective reference ranges. Confirmatory testingincludes germline mutation testing.

DOC-producing Tumor

Pure DOC-producing adrenal tumors are very rare and usuallylarge and malignant.[13] Some of these adrenal neoplasmscosecrete androgens and estrogens in addition to DOC, whichmay cause virilization in women or feminization in men. Thetypical clinical presentation would be that of relatively rapidonset of marked hypertension associated with hypokalemia andlow blood levels of aldosterone and renin. A high level of plasmaDOC or urinary tetrahydrodeoxycorticosterone and a largeadrenal tumor seen on CT confirms the diagnosis.

Primary Cortisol Resistance

Increased cortisol secretion and plasma cortisol concentrationswithout evidence of Cushing syndrome are found in patients withprimary cortisol resistance (or glucocorticoid resistance), a rarefamilial syndrome caused by genetic defects in the glucocorticoidreceptor and the steroid-receptor complex.[14] The syndrome ischaracterized by hypokalemic alkalosis, hypertension, increasedplasma concentrations of DOC, and increased adrenal androgensecretion. It usually presents in childhood with hypertensionand spontaneous hypokalemia and low levels of aldosterone andrenin. The initial screening tests include measurement of bloodlevels of cortisol, DOC, 11-deoxycortisol, androstenedione,testosterone, and DHEAS - all of which should be increasedabove the upper limit of the respective reference ranges. Inaddition, 24-h urinary cortisol excretion is above the upper limitof the reference range, and serum ACTH is not suppressed.Confirmatory testing includes germline mutation testing.

Apparent Mineralocorticoid Excess Syndrome

Apparent mineralocorticoid excess is the result of impairedactivity of the microsomal enzyme HSD11B2, which normallyinactivates cortisol in the kidney by converting it to the inactivecompound, cortisone. Decreased HSD11B2 activity may behereditary, or it may be secondary to pharmacologic inhibitionof enzyme activity by glycyrrhizic acid, the active principleof licorice root (Glycyrrhiza glabra). Congenital apparentmineralocorticoid excess typically presents in childhood withhypertension, hypokalemia, low birth weight, failure to thrive,hypertension, polyuria and polydipsia, and poor growth.[15]Acquired apparent mineralocorticoid excess due to licorice rootingestion presents with hypertension and hypokalemia - thecause becomes evident when a good medical history isobtained. The diagnosis of apparent mineralocorticoid excessis confirmed by demonstration of an abnormal (high) ratio ofcortisol-to-cortisone in a 24-h urine collection. The ratio ofcortisol-to-cortisone is typically increased 10-fold above thenormal value.

Liddle Syndrome

Liddle syndrome is caused by autosomal dominant mutationsin the β- or γ-subunit of the amiloride-sensitive epithelialsodium channel resulting in enhanced activity of the epithelialsodium channel. It presents similar to PA with hypertension,hypokalemia, increased renal sodium reabsorption, andinappropriate kaliuresis but with low PRA and aldosteronelevels.[16] It presents in children or young adults with hypertensionand spontaneous hypokalemia and the presence of family historystrongly supports the diagnosis. After exclusion of anotherdiagnosis, a treatment trial with amiloride or triamterene shouldbe considered. Liddle syndrome can easily be distinguishedfrom apparent mineralocorticoid excess based on the goodclinical response to amiloride or triamterene combined witha sodium-restricted diet, lack of efficacy of spironolactone anddexamethasone, and normal 24-h urine cortisone/cortisol ratio.Clinical genetic testing is available.


Catecholamine-secreting tumors from chromaffin cells ofthe adrenal medulla and the sympathetic ganglia are called aspheochromocytomas and catecholamine-secreting paragangliomas,respectively. The prevalence of pheochromocytoma has beenestimated at 0.1-0.6% in subjects attending tertiary care centers forhypertension. It is important to suspect, confirm, localize, and resectthese tumors because (1) the associated hypertension is curablewith surgical removal of the tumor, (2) a risk of lethal paroxysmexists, (3) at least 10% of the tumors are malignant, and (4) 40%of these tumors are familial and their detection in the proband mayresult in early diagnosis in other family members.

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Clinical Presentation

Pheochromocytoma presents with equal frequency in bothmales and females, usually in 3-5th decade. Classically, theypresent with sustained or paroxysmal hypertension or acombination of both. Typically, the paroxysm presents asepisodic palpitation, pallor, tremor, headache, and diaphoresis,the symptoms complex usually lasting for < 30 min.[17] Paroxysmsare either spontaneous or can be precipitated by posturalchange, anxiety, medications (e.g. β-adrenergic antagonists,metoclopramide, and anesthetic agents), exercise, or maneuversthat increase intra-abdominal pressure. Additional clinicalsigns of pheochromocytoma include hypertensive retinopathy,cardiomyopathy, orthostatic hypotension, angina, nausea,constipation, megacolon, hyperglycemia, diabetes mellitus,hypercalcemia, Raynaud phenomenon, livedo reticularis,erythrocytosis, painless hematuria, and mass effects from thetumor. Rarely, pheochromocytoma can present as suddenhypotension or can be simply asymptomatic. With increasing theuse of imaging, nowadays, 50% of adrenal pheochromocytomaare discovered as incidentaloma on imaging.

Syndromic Forms of Pheochromocytoma and

Pheochromocytoma and paraganglioma can occur in isolationor as a part of inherited syndrome complex. Since 1990, 16pheochromocytoma/paraganglioma susceptibility genes havebeen reported: NF1, RET, VHL, SDHD, SDHC, SDHB, EGLN1(PHD2), EGLN2 (PDH1), KIF1B, SDHAF2, IDH1, TMEM127,SDHA, MAX, HIF2A, and FH.[18] Various syndromes associatedwith pheochromocytoma are multiple endocrine neoplasia(MEN) 2A (primary hyperparathyroidism, medullary thyroidcarcinoma, pheochromocytoma, cutaneous lichen amyloidosis,very rarely Hirschsprung disease), MEN 2b (pheochromocytoma,mucocutaneous neuromas, marfanoid habitus, myelinated cornealnerves, and intestinal ganglioneuromas), von Hippel-Lindau disease(pheochromocytoma or paraganglioma, hemangioblastomainvolving the cerebellum, spinal cord, or brainstem, retinal angioma,clear cell renal cell carcinoma, pancreatic neuroendocrine tumors,endolymphatic sac tumors of the middle ear, serous cystadenomasof the pancreas, and papillary cystadenomas of the epididymisand broad ligament), neurofibromatosis 1 (NF1, neurofibromas,multiple cafe au lait spots, axillary and inguinal freckling, irishamartomas [Lisch nodules], bony abnormalities, centralnervous system gliomas, macrocephaly, and cognitive deficits),and Carney triad or syndrome (gastrointestinal stromal tumor,pulmonary chondroma, catecholamine-secreting paraganglioma,esophageal leiomyoma, and adrenal adenoma). Most cases offamilial paraganglioma are caused by mutations in the succinatedehydrogenase subunit genes (SDHB, SDHC, SDHD, SHDA, andSDHAF2), which make up portions of mitochondrial complex II.As of 2014, a total of 403 different germline mutations in the SDHgenes associated with pheochromocytoma/paraganglioma werereported in the literature; 62.52% in SDHB, 35% in SDHD, 10% in SDHC, 2% in SDHA, and 1% in SDHAF2. 78 mutations werefound in malignant tumors: 76% in SDHB, 19% in SDHD, and 5%in SDHC. In addition, sporadic pheochromocytoma (unilateraladrenal tumor with negative family history), 2% have TMEM127mutations. MAX germline mutations and germline mutations in theFH gene encoding fumarate hydratase have been seen in sporadicpheochromocytoma. In view of variety of mutation, genetictesting has been advocated in following situations: Genetic testingshould be considered if a patient has one or more of the following:(1) Paraganglioma, (2) bilateral adrenal pheochromocytoma,(3) unilateral adrenal pheochromocytoma and a family historyof pheochromocytoma/paraganglioma, (4) unilateral adrenalpheochromocytoma with onset at a young age (< 45 years), or (5)other clinical findings suggestive of one of the previously discussedsyndromic disorders. A sequential genetic testing algorithm, basedon biochemical phenotype, age, and tumor, has been proposed.However, next-generation sequencing now being widely availableand more cost-effective, it is now proposed to be more helpful.

Diagnostic Investigation


Pheochromocytoma should be suspected in patients whohave one or more of the following: Hyperadrenergic spells,resistant hypertension, a familial syndrome that predisposesto catecholamine-secreting tumors (e.g. MEN2, NF1, VHL,and Carney triad), family history of pheochromocytoma, anincidentally discovered adrenal mass with imaging characteristicsconsistent with pheochromocytoma, pressor response duringanesthesia, surgery, or angiography, onset of hypertension at ayoung age (< 20 years), and idiopathic dilated cardiomyopathy.


The diagnosis must be confirmed biochemically by the presenceof increased concentrations of fractionated metanephrines andcatecholamines in urine or plasma.[19] Most laboratories nowmeasure fractionated catecholamines (dopamine, norepinephrine,and epinephrine) and fractionated metanephrines (metanephrineand normetanephrine) by high-performance liquidchromatography with electrochemical detection or tandem massspectrometry. Measurements of fractionated metanephrines andcatecholamines in a 24-h urine collection have high sensitivity(98%) and specificity (98%). In addition, measurement of plasmafractionated metanephrines is a good first-line test for children,because obtaining a complete 24-h urine collection is difficultin pediatric patients. In normotensive laboratory volunteers,the 95th percentiles are 428 ug for normetanephrine and 200 ugfor metanephrine. Usually, the values are 2-3 times of normalrange in subjects with pheochromocytoma. The 24-h urinaryVMA excretion has poor diagnostic sensitivity and specificitycompared with fractionated 24-h urinary metanephrine.Certain drugs (e.g. tricyclic antidepressants, antipsychotics,beta-blockers, centrally acting α2-adrenergic receptor agonist like clonidine, etc.,) and clinical situations (acute stress/illness,e.g. stroke, myocardial infarction, congestive heart failure, andobstructive sleep apnea) should be avoided during the collectionof urine or plasma collections. Chromogranin A is not specific forpheochromocytoma, and is, in fact, a marker of neuroendocrinetumor.

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Localization studies for pheochromocytoma must be initiatedonly after biochemical confirmation. CECT or spin echo MRIof the abdomen and pelvis is the initial imaging with sensitivityof >95% and specificity of >65%. Pheochromocytoma hascontrast enhancement with intravenous. High signal intensityon T2-weighted MRI, cystic and hemorrhagic changes, andvariable size.[20] The tumor may be bilateral approximately 85%of these tumors are found in the adrenal glands, and 95% arefound in the abdomen and pelvis. The most common locationsof catecholamine-secreting paragangliomas include superiorabdominal para-aortic region, 46%; inferior abdominal paraaorticregion, 29%; urinary bladder, 10%; mediastinum, 10%;head and neck, 3%; and pelvis, 2%.

123I-MIBG scintigraphy is indicated when CT or MRIis negative. This radionuclide accumulates preferentially incatecholamine-producing tumors. The sensitivity and specificityare 80% and 99%, respectively. AVS for catecholamines ismisleading and, hence, not advised.


Complete surgical resection, either laparoscopic or openlaparotomy, is indicated in all the subjects with pheochromocytomaand the success rates are 98-100% with cures of hypertension.Pre-operative preparation with alpha blockers (prazosin,terazosin, doxazosin, and phenoxybenzamine) and fluid and saltreplacement for 7-14 days is crucial for smooth perioperativehemodynamic stability.[21] Adequate blockade of catecholamineeffect is achieved when target blood pressure is < 120/80 mmHgin the seated position, with systolic blood pressure >90 mmHg(standing), and absence of paroxysms and postural hypotension.The β-adrenergic antagonist should be administered only afterα-adrenergic blockade is effective with target to achieve heartrate 60-80/min. Metyrosine inhibits catecholamine synthesisby blocking the enzyme tyrosine hydroxylase and is used ininoperable metastatic pheochromocytoma. Calcium channelblocker, especially nicardipine, which blocks norepinephrinemediatedcalcium transport into vascular smooth muscle,has been used successfully at several centers. Approximately1-2 weeks after surgery, 24-h urinary fractionated catecholaminesand metanephrines should be measured. If the levels arenormal, the resection of the pheochromocytoma should beconsidered complete. The survival rate after removal of a benignpheochromocytoma is almost equal to that of age- and sexmatchednormal control subjects.

Other Endocrine Disorders Associated with

Cushing Syndrome

Hypertension occurs in 75-80% of patients with Cushingsyndrome.[22] The mechanisms of hypertension include increasedproduction of DOC, enhanced pressor sensitivity to endogenousvasoconstrictors (e.g. epinephrine and angiotensin II), increasedcardiac output, activation of the RAA system by increased hepaticproduction of angiotensinogen, and cortisol activation of the MR.Diagnosis is established by demonstration of lack of suppressionof cortisol on overnight dexamethasone suppression, and lowdosedexamethasone suppression, elevated midnight salivarycortisol, and 24-h urinary cortisol excretion, along with serumACTH estimation.

Thyroid Dysfunction


Thyrotoxic patients usually have tachycardia, high cardiacoutput, increased stroke volume, decreased peripheral vascularresistance, and increased systolic blood pressure.[23] Thehypertension is due to enhanced catecholamine sensitivity dueto excess thyroid hormones. Treatment is etiology specific andbeta-blockers.


Hypertension is usually diastolic and is due to increased systemicvascular resistance and extracellular volume expansion.[24]Thyroxine replacement decreases blood pressure in most patientswith hypertension and normalizes blood pressure in one-third ofthem.

Hypercalcemia and Primary Hyperparathyroidism

Hypertension is observed in 10-60% of subjects withprimary hyperparathyroidism.[25] The pathogenesis is stillunclear. Hypertension may or may not remit after successfulparathyroidectomy.


Hypertension occurs in 20-40% of the patients withacromegaly[26] and is associated with sodium retention andextracellular volume expansion and its remits after cure ofhypersomatotropism.

  1. Beaney T, Schutte AE, Tomaszewski M, Ariti C, Burrell LM,Castillo RR, et al. May measurement month 2017: An analysis ofblood pressure screening results worldwide. Lancet Glob Health2018;6:e736-e743.

24 Hypertension Journal, January-March, Vol 4, 2018

Endocrine hypertension Gupta

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  2. Camelli S, Bobrie G, Postel-Vinay N, Azizi M, Plouin PF,Amar L. LB01.11: Prevalence of secondary hypertension inyoung hypertensive adults. J Hypertens 2015;33 Suppl 1:e47.
  3. Galati SJ. Primary aldosteronism: Challenges in diagnosis andmanagement. Endocrinol Metab Clin North Am 2015;44:355-69.
  4. Vaidya A, Malchoff CD, Auchus RJ, AACE Adrenal ScientificCommittee. An individualized approach to the evaluationand management of primary aldosteronism. Endocr Pract2017;23:680-9.
  5. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M,Shibata H, et al. The management of primary aldosteronism:Case detection, diagnosis, and treatment: An endocrinesociety clinical practice guideline. J Clin Endocrinol Metab2016;104:1889-916.
  6. Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M,Plouin PF, et al. An expert consensus statement on use of adrenalvein sampling for the subtyping of primary aldosteronism.Hypertension 2014;63:151-60.
  7. Halperin F, Dluhy RG. Glucocorticoid-remediable aldosteronism.Endocrinol Metab Clin North Am 2011;40:333-41, viii.
  8. Torpy DJ, Gordon RD, Lin JP, Huggard PR, Taymans SE,Stowasser M, et al. Familial hyperaldosteronism Type II:Description of a large kindred and exclusion of the aldosteronesynthase (CYP11B2) gene. J Clin Endocrinol Metab1998;83:3214-8.
  9. Monticone S, Tetti M, Burrello J, Buffolo F, De Giovanni R,Veglio F, et al. Familial hyperaldosteronism Type III. J HumHypertens 2017;31:776-81.
  10. White PC. Steroid 11 beta-hydroxylase deficiency and relateddisorders. Endocrinol Metab Clin North Am 2001;30:61-79, vi.
  11. Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies,genetic and pharmacologic. J Steroid Biochem Mol Biol2017;165:71-8.
  12. Gupta S, Melendez J, Khanna A. Deoxycorticosterone producingtumor as a cause of resistant hypertension. Case Rep Med2010;2010:372719.
  13. Charmandari E, Kino T. Chrousos syndrome: A seminalreport, a phylogenetic enigma and the clinical implicationsof glucocorticoid signalling changes. Eur J Clin Invest2010;40:932-42.
  14. Funder JW. Apparent mineralocorticoid excess. J SteroidBiochem Mol Biol 2017;165:151-3.

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  2. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP,Grebe SK, Murad MH, et al. Pheochromocytoma andparaganglioma: An endocrine society clinical practice guideline.J Clin Endocrinol Metab 2014;99:1915-42.
  3. Shuch B, Ricketts CJ, Metwalli AR, Pacak K, Linehan WM.The genetic basis of pheochromocytoma and paraganglioma:Implications for management. Urology 2014;83:1225-32.
  4. van Berkel A, Lenders JW, Timmers HJ. Diagnosis of endocrinedisease: Biochemical diagnosis of phaeochromocytoma andparaganglioma. Eur J Endocrinol 2014;170:R109-19.
  5. Blake MA, Kalra MK, Maher MM, Sahani DV, Sweeney AT,Mueller PR, et al. Pheochromocytoma: An imaging chameleon.Radiographics 2004;24 Suppl 1:S87-99.
  6. Naranjo J, Dodd S, Martin YN. Perioperative managementof pheochromocytoma. J Cardiothoracic Vasc Anesth2017;34:1427-39.
  7. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, et al. Treatment of cushing's syndrome: Anendocrine society clinical practice guideline. J Clin EndocrinolMetab 2015;100:2807-31.
  8. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P,Maia AL, et al 2016 american thyroid association guidelinesfor diagnosis and management of hyperthyroidism and othercauses of thyrotoxicosis. Thyroid 2016;26:1343-421.
  9. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I,Mechanick JI, et al. Clinical practice guidelines forhypothyroidism in adults: Cosponsored by the americanassociation of clinical endocrinologists and the americanthyroid association. Endocr Pract 2012;18:988-1028.
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