Endocrine Hypertension: The Urgent Need for Greater Global Awareness

Hypertension affects about 1.28 billion adults globally, and significantly increases the risk of chronic morbidity and mortality among sufferers. About 15% of these individuals have secondary hypertension, the majority of whom have dysfunction of one or more endocrine systems as the cause of hypertension. Although adrenal disorders are often identified as the cause of endocrine hypertension, extra-adrenal disease and pituitary disorders also can cause the disease. Timely diagnosis is of paramount importance, because of the potential for a surgical cure or optimal disease control with pharmacotherapy to prevent hypertensive complications. Even with its relatively high prevalence compared with many other chronic illnesses, the diagnosis of endocrine hypertension is often delayed or never made because of poor awareness about the disease among physicians. This review attempts to provide an overview of the disease, with some practical aspects of diagnosis and management of a few of the important disorders causing endocrine hypertension.


H
ypertension affects about 1.28 billion adults globally, and significantly increases the risk of chronic morbidity and mortality among sufferers.About 15% of these individuals have secondary hypertension, the majority of whom have dysfunction of one or more endocrine systems as the cause of hypertension.Although adrenal disorders are often identified as the cause of endocrine hypertension, extra-adrenal disease and pituitary disorders also can cause the disease.Timely diagnosis is of paramount importance, because of the potential for a surgical cure or optimal disease control with pharmacotherapy to prevent hypertensive complications.Even with its relatively high prevalence compared with many other chronic illnesses, the diagnosis of endocrine hypertension is often delayed or never made because of poor awareness about the disease among physicians.This review attempts to provide an overview of the disease, with some practical aspects of diagnosis and management of a few of the important disorders causing endocrine hypertension.
Hypertension affects up to 40% of the adult population worldwide, 1 and according to the World Health Organization's 2021 estimates, globally 1.28 billion adults between 18 and 79 years are affected. 2Of these, 85% have essential hypertension 3 and the remainder have secondary hypertension, which is potentially curable with timely diagnosis and treatment. 3The prevalence of secondary hypertension is around 50% in hypertensive children, 4 and 30% in young adults under the age of 40 years 4,5 indicating that children and young adults should undergo secondary hypertension workup, even outside the resistant hypertension range.
Secondary hypertension often presents as resistant hypertension, which is defined as blood pressure that remains above 140/90 mmHg despite the use of three antihypertensive medications (of which one is a diuretic) of different classes at the maximum tolerated doses. 6The prevalence of secondary hypertension is only 5-15% in the non-selected hypertensive population, whereas it can be around 30% in patients with resistant hypertension. 7Hence, working up patients with resistant hypertension is crucial to identifying a potential secondary cause. 8docrine causes of secondary hypertension (endocrine hypertension) have been increasingly identified in recent years in parallel with improvement in our diagnostic armamentarium.They are now among the most frequent causes of secondary hypertension, the other common causes of secondary hypertension being renal parenchymal or renovascular disease, coarctation of the aorta and obstructive sleep apnoea (OSA).With the recognition of the increased prevalence of primary aldosteronism, they could represent up to 20% of patients with hypertension. 9The main causes of endocrine hypertension are summarized in Table 1. 10 In this article, we will mainly focus on three important causes of endocrine hypertension (primary aldosteronism, Cushing's syndrome and pheochromocytoma), as the more common causes such as thyroid and parathyroid diseases, are already familiar to most readers.
Investigating the cause of endocrine hypertension can be highly rewarding for both patients and physicians, as identifying a treatable endocrine disease can greatly improve the outcome, although this requires a high index of suspicion.However, the diagnosis is often delayed, or even never made due to inadequate awareness among physicians.Moreover, the clinical presentation of some of these disorders can be vague, mimicking other systemic diseases. 11

Monogenic hypertension
Essential hypertension is a polygenic trait and over 900 genetic variants have been known to contribute to its development, together with several environmental factors.In contrast, many causes of secondary hypertension are monogenic, that is, they are associated with single gene alterations with a Mendelian pattern of inheritance. 12An overview of monogenic hypertension is DOI: http://doi.org/10.17925/EE.2023.19.2.11  touchREVIEWS in Endocrinology given in Figure 1.The typical presentation of monogenic hypertension is childhood-onset, severe or resistant hypertension and a positive family history.However, due to incomplete penetrance, some genetic carriers show milder hypertension, or even normotension.Moreover, typical electrolyte abnormalities may not be present in all carriers.
Accompanying syndromic features, including brachydactyly, should trigger the performance of genetic tests.Measurement of renin and aldosterone levels coupled with genetic testing is indicated if monogenic hypertension is suspected. 12

Primary aldosteronism
PA is the most common cause of curable endocrine hypertension, with an estimated prevalence of >10% among hypertensive patients and 20% among those with resistant hypertension. 13Biochemically overt PA diagnosed with urinary aldosterone levels greater than 12 μg/24 h can be seen in 15.7%, 21.6% and 22.0% of patients with stage 1 hypertension, stage 2 hypertension and resistant hypertension, respectively. 14In PA, excessive aldosterone production inappropriate to the sodium levels leads to increased sodium reabsorption, plasma volume expansion and, as a result, hypertension. 13This is associated with increased potassium and hydrogen ion excretion and may lead to hypokalemic metabolic alkalosis.
The PA diagnostic pathway involves screening, confirmatory and subtyping tests.Early detection and specific therapy are crucial as undiagnosed/untreated PA is associated with raised renal, cardiovascular, cerebrovascular, and metabolic morbidity and mortality through direct target organ damage independent of hypertension. 16Inappropriate mineralocorticoid receptor (MR) activation can cause endothelial dysfunction, myocardial fibrosis and microalbuminuria. 13Glucose metabolism is impaired, and the increased prevalence of diabetes and metabolic syndrome further increases cardiovascular risk. 16Though early detection of PA is vital, screening for PA is reported in only 8-9% of those with hypertension, and general practitioners demonstrate a surprisingly little knowledge about PA and its diagnostic guidelines. 17     it allows sample handling at room temperature.However, they are less reliable and reproducible, especially at the lower limit of the reference range.PRA therefore remains the preferred approach. 20e ARR is highly determined by renin.In the presence of very low renin values, the ARR may be elevated even when the PAC values are very low and not compatible with PA.To avoid a falsely high ARR, the lowest level of renin is fixed at 0.2 ng/ml/h for PRA and 2 mUI/l for DRC. 19This is especially important in people with low renin levels, including the elderly and people of African origin. 21Some guidelines use a minimum PAC threshold of >277 pmol/L (>10 ng/dL) 22 within the screening criteria to avoid these false high ARR values.Others use a higher PAC threshold of >416 pmol/L (>15 ng/dL). 19Others still use a lower PAC threshold of >162 pmol/L (5.8 ng/dL), the normal suppression after a seated saline suppression test, when measured by LC-MS/MS. 20Including a "PAC threshold" has been shown to increase the specificity but reduce the sensitivity of the ARR. 23Therefore, a PAC threshold is not widely accepted in PA screening.However, the PAC should be above the cut-off for the subsequent confirmatory test.
As people of African origin are very sensitive to aldosterone, PA can manifest with only mild PAC elevations and, therefore, different ARR and PAC cut-offs might be used. 19Moreover, normal PAC levels seen in PA patients should be considered as inappropriately normal in the face of suppressed renin levels which, in subjects without PA, should have caused low PAC levels. 20Finally, the sexually dimorphic relationship between ARR and blood pressure in young adults indicates that sexspecific ARR cut-offs are needed in young adults. 24ble 3 summarizes the preparations for an ideal ARR test.The natural history of PA starts with normotension and renin suppression, progressing to stage 2 or 3 and/or resistant hypertension. 25,26Some authors suggest considering ARR in all hypertensives at the time of diagnosis before commencing antihypertensive drugs. 27This would avoid confounding drug effects and permit the earlier introduction of specific therapy.
Restricting screening to hypertension with hypokalaemia is inappropriate as this would miss up to 80% of PA. 27 OSA is common in PA, resulting from PA-induced fluid retention causing upper airway soft tissue oedema.PA therapy, either with mineralocorticoid receptor antagonists (MRAs) or adrenalectomy, achieves a significant reduction in neck circumference and apnoea-hypopnoea index. 28Similarly, PA is common in OSA due to the hypoxia-mediated rise in plasma endothelin-1 levels increasing the aldosterone secretion. 29 the renin and PAC are measured using varied assays, and the results are available in different units from different laboratories, it is not possible to establish a rigid diagnostic threshold for ARR.The performance of ARR, especially the sensitivity, differed markedly based on the study population and diagnostic threshold.Some recommend concentrating on the actual PAC and renin values that generated the ARR rather than the ARR itself.
When renin is measured as PRA, one of the best ARR threshold values   touchREVIEWS in Endocrinology is ≥30 with PAC in ng/dL and PRA in ng/mL/h with a PAC threshold of >10.This is equivalent to an ARR threshold of ≥830 with PAC in pmol/L and PRA in ng/mL/h with a PAC threshold of >277. 30Selecting an ARR threshold of ≥40 and a PAC threshold >15 ng/dl would be less sensitive but more specific. 30When renin is measured as DRC, one of the best ARR threshold values is ≥2.4 when PAC is in ng/dL and DRC is in mU/L or ≥70 when PAC is in pmol/L and DRC is in mU/L. 31 an Italian study, where renin is measured as DRC using CLIA, an ARR threshold of 2.06 ng/dl per mU/L, which is equivalent to 20.6 ng/mU, provided a sensitivity of 92%, a specificity of 92% and an overall accuracy of 97.4%. 32The same study observed that, when renin is measured as PRA using RIA, an ARR threshold of 38.7 ng/dL per ng/mL/h provided a sensitivity of 80% and a specificity of 92%.In a similar Spanish study, where renin is measured as DRC using CLIA, an ARR threshold of 2.3 ng/ dl per mU/L (equivalent to 23 ng/mU) provided a sensitivity of 100% and a specificity of 90.9%. 33When renin is measured as PRA using RIA, an ARR threshold of 48.9 ng/dL per ng/mL/h provided a sensitivity of 100% and a specificity of 93.6%.
Significant within-individual variability in PAC (22-25%), DRC (41-42%) and ARR occurs in a large volume of patients investigated for PA. 31 Nearly 38% had at least one ARR below the threshold, indicating that ARR needs to be done a minimum of twice before PA is excluded or confirmed.As per the Endocrine Society's recommendations, those who have a persistently raised ARR should undergo one or more of the confirmatory tests, the exception being those with hypokalaemia, and those with suppressed renin below the detection limits plus with PAC >20 ng/dL (550 pmol/L). 18ditionally, markedly raised ARR (e.g.>45 ng/mU) increases the probability of PA, with significantly low false-positive rates. 34Hence, among patients with markedly raised ARR, those who are surgical candidates can undergo adrenal venous sampling (AVS) even without doing confirmatory tests, reflecting the quantitative importance of ARR.
The higher the ARR and the PAC threshold, the greater the number of patients established to be truly positive for PA.At an ARR >30 ng/dL per ng/ml/h and a PAC >10 ng/dL, 42.7% of the ARR were true positives. 30 an ARR >20 ng/dL per ng/ml/h with PAC ≥10 ng/Dl, 33.3% were true positives. 35Finally, at an ARR >20 ng/dL per ng/ml/h and PAC >15 ng/dL, only 28.6% were true positives. 36ARR, as a screening test, has a better discriminating ability in patients with hypokalaemia.Hence, ARR alone may be sufficient for diagnosis in these patients and confirmatory tests can be skipped. 37On the other hand, among normokalaemic hypertensives, there is a considerable overlap in ARR between those with PA and essential hypertension.Hence, caution should be exercised before considering skipping confirmatory tests in this setting. 37nfirmation of PA depends on the demonstration of autonomous aldosterone secretion in the presence of dynamic procedures that are designed to suppress aldosterone levels, so that false-positive diagnoses and thereby inappropriate adrenal venous sampling and surgery are avoided.The available confirmatory tests include the fludrocortisone suppression test (FST), saline infusion test (SIT), and oral sodium loading test (OSLT), all of which are meant to expand the plasma volume and suppress renin.The remaining available confirmation tests include the captopril challenge test (CCT), which is meant to suppress the aldosterone through inhibition of angiotensin-converting enzyme, losartan suppression test and furosemide upright test. 30rrently, there is no universal gold standard confirmatory test.
Fludrocortisone suppression test (FST), though considered to have maximum reliability, requires hospital admission for 5 days and is laborious, hence it is rarely done nowadays.Originally, SIT was done with the patient in the recumbent position.However, performing SIT in the seated position results in marked improvement in sensitivity, while retaining the specificity.The confirmatory tests that are meant to expand the plasma volume are contraindicated in severe hypertension, and in renal or cardiac dysfunction. 13In these patients, though the captopril challenge test can be used, this test has a low discriminatory power; moreover, it can cause symptomatic hypotension.It is therefore sensible to directly proceed to subtyping (imaging or AVS) or to consider a trial of medical treatment. 30A recent systematic review and meta-analysis that evaluated the performance of various confirmatory tests observed that the routine use of these tests should be reconsidered due to large variations in the way they were performed, interpreted and verified. 38is should be followed by PA subtyping, initially with either a triple-phase adrenal computed tomography (CT) or adrenal magnetic resonance imaging (MRI), followed by AVS.Adrenal CT can identify unilateral or bilateral adrenal adenomas, micronodular/macronodular adrenal hyperplasia or, rarely unilateral adrenocortical carcinoma. 30 Although AVS is the gold standard investigation for subtyping, it is a challenging technique as it is not widely available, is poorly standardized, and must be performed only by an experienced interventional radiologist. 30In experienced hands, the success rate can be above 95% where it can successfully localize the source of aldosterone overproduction as unilateral or bilateral. 30 The gold standard therapy for unilateral APA is unilateral adrenalectomy, where the laparoscopic approach is preferred. 20 PA is a major public health issue that needs to be addressed.Based on the 24 h urinary aldosterone excretion (UEA) test as a measure of aldosterone status, the prevalence of PA seems to be 3-5 times greater than the currently recognized number of 5-10% of hypertensives. 39tients with inadequately treated PA have a threefold greater cardiovascular risk than that of matched essential hypertensives.Finally, <1% of hypertensives are ever screened for PA, increasing the risks associated with untreated PA on top of those for hypertension per se. 39diagnostic and management approach to a hypertensive patient with suspected PA is shown in Figure 2.
Untreated CS is associated with infections, cardiovascular complications, malignancies and increased mortality.Patients with CS have a four-to fivefold higher risk of developing cardiovascular disease in comparison with the general population, and the risk factors include hypertension, dyslipidaemia, diabetes mellitus, obesity and hypercoagulability. 41though early treatment can achieve a significant reduction in the mortality associated with CS, it cannot fully mitigate the risk.This could partly be due to recurrent or residual disease in some patients.However, the risk continues even in those with apparently successful treatment.
The risk of long-term excess mortality associated with CS seems to vary depending on the aetiology of CS, and most patients with ectopic Review Cardiovascular Risk touchREVIEWS in Endocrinology CS have a poorer prognosis, followed by treated Cushing's disease in comparison to cases of treated adrenal CS. 40,41 CS is an uncommon cause of secondary hypertension.In general outpatient clinics, the prevalence of CS is around 0.5% in the hypertensive population and <1% in patients with resistant hypertension. 40Only hypertensive patients with other clinical features of CS should undergo screening tests for CS. 40Endogenous CS can either be ACTH-dependent (80% of all cases) or ACTH-independent (20%).ACTH-dependent CS includes ACTH-secreting pituitary adenoma (known as Cushing disease; CD), and ectopic ACTH or CRH (corticotrophin-releasing hormone) producing tumour (known as ectopic ACTH secretion or EAS).On the other hand, ACTH-independent CS includes adrenal glucocorticoid excess (adrenal CS).
Endogenous CS is a rare disease with an incidence of 1.2 to 2.4 per million/year and a prevalence of 40 per million population. 43On the contrary, CS due to exogenous glucocorticoid exposure is much more common.Hence, ruling out exogenous cortisol (injection, oral, inhaler or topical) is the first step in all patients in whom CS is suspected.This should be followed by confirmation of the cortisol excess with one of the following tests: either at least two measurements of 24 h urinary free cortisol excretion (UFC), two late-night salivary cortisol measurements (LNSC), or an overnight dexamethasone suppression testing (ODST). 40,41ese screening tests utilize three cardinal features of endogenous CS, and these include the increased cortisol production (UFC), the loss of normal circadian rhythm in cortisol production (LNSC), and the failure to suppress the autonomous cortisol secretion by the exogenously administered glucocorticoids (DST). 41
Paragangliomas (PGLs) -neuroendocrine tumors that originate from the paravertebral sympathetic ganglia in the chest, abdomen, or pelvis, or the parasympathetic ganglia in the neck and skull base -constitute around 15-20% of PPGL. 45,46The PPGL has an incidence of 6.6 cases per million/year and a prevalence of 65 per 100,000 people.Among patients with an adrenal incidentaloma, pheochromocytoma accounts for around 7%, whereas in the general hypertensive population, PPGL is rare accounting for <1%.However, this diagnosis should not be missed due to the negative impact associated with a delayed or missed diagnosis.
Either germline mutation (in up to 40%) or somatic mutation (in around 30-40%) in one of the predisposition genes is identified in up to 70% of patients with PPGL. 47 The cluster 3 is less explored.
The classic PPGL triad including palpitation, headache, and diaphoresis are found in only 20% of patients.The most common sign found in up to 95% of PPGL patients is hypertension, which can be sustained (more with cluster 1 tumors that secrete norepinephrine; constitute 50% of PPGL), episodic or paroxysmal (more with cluster 2 tumors that secrete epinephrine; constitute 45% of PPGL).Normotension is also seen (more with cluster 1A -SDHx -tumors that secrete dopamine together with norepinephrine; constitute 5-15% of PPGL). 47GLs secreting predominantly or exclusively dopamine are very rare, and most occur with concomitant norepinephrine overproduction.In these patients, the vasodilatory effect of dopamine counteracts the vasoconstrictor effect of norepinephrine.Dopamine-secreting PGLs are mostly found incidentally on imaging or found because of pressure effects; these are generally larger, and often metastatic at diagnosis.
Based on the clinical features, a scoring system has been proposed to establish the pretest likelihood of the disease, with a score ≥3 associated with a 5.8-fold pretest probability of PPGL 48 (Table 4).The biochemical testing for PPGL using plasma free metanephrines or urinary fractionated metanephrines is indicated in patients with the features given in Table 5. 49 Plasma free metanephrines and urinary fractionated metanephrines have very high negative predictive value (above 99%) and comparable specificity (around 94%) provided appropriate precautions (at least 20 min of supine rest, avoidance of strenuous exercise and potentially interfering medications sufficiently before testing) are taken.Thus, a negative test virtually rules out a PPGL except in those with very small tumors or in those with non-functional head and neck PGLs. 49In patients at low risk, both plasma and urine metanephrines have the same diagnostic accuracy.However, in those at high risk (adrenal incidentaloma and surveillance screening), plasma has superior diagnostic accuracy.
Many medications are associated with falsely high metanephrines due to pharmacodynamic (antidepressants, MAO inhibitors, levodopa, sympathomimetics, phenoxybenzamine) or analytical (acetaminophen, sotalol) interference.The analytical interference is minimal for LC-MS/MS and hence it is the preferred method.As some foods can interfere with the measurement of 3-methoxytyramine (3MT), overnight fasting and avoidance of these foods are important for 3MT estimation.
Patients with a 2-fold rise of a single metabolite or simultaneous rise in 2 or more metabolites (metanephrine, normetanephrine, and/or 3MT) are less likely to be false-positive and hence can proceed with imaging.
On the contrary, patients with <2 fold rise of a single metabolite without any potential for a false-positive result (including heart failure, OSA, inappropriate sampling, drug interference, and incorrect cut-off value) can undergo a clonidine suppression test if the pretest probability for PPGL was high.However, further tests are not needed for patients with <2 fold rise of a single metabolite with a low pretest probability for PPGL. 49aging studies should be done only after biochemical testing except in critically ill patients and/or patients in the intensive care setting, and when non-secretory tumors are suspected.Anatomical imaging by dedicated contrast-enhanced CT or MRI is enough to locate a   an upright heart rate of 70-80 bpm. 45,46blockers should be started at least 7-14 days before surgery with gradual dose escalation until expected targets are reached. 45,46Choices include phenoxybenzamine, a nonselective and noncompetitive α-blocker, or doxazosin, a selective and competitive α1adrenergic blocker.There is no demonstrable superiority of one over another, though phenoxybenzamine was associated with better per-operative hemodynamic stability, but without any better clinical outcomes.After achieving adequate α-blockade (usually after 3-5 days), the β-blockade can be started, to improve blood pressure control and to minimize the α-blockade induced undesirable tachycardia.β-blocker should never be used as monotherapy as this would cause unopposed α-adrenoceptor stimulation causing pheochromocytoma crisis.Calcium channel blockers may be added to optimize blood pressure control. 45,46In some difficult PPGL resection or PPGL cases with anticipated large catecholamine release (e.g., chemotherapy), metyrosine, a tyrosine hydroxylase inhibitor may be used.Sadly, metyrosine is not available in many countries and is very costly.α-blockade is not indicated in dopamine-secreting PPGLs because of severe hypotension risk.
Co-secretion of aldosterone and cortisol from an adrenal tumour can lead to the development of Connshing (CoSh) syndrome. 60ACTH dependent and independent CS can rarely co-exist. 61Though the common components of Multiple Endocrine Neoplasia 2 (MEN2) are primary hyperparathyroidism, PCC, and medullary thyroid cancer, it can rarely cause ACTH dependent CS (both Cushing' disease and ectopic ACTH or CRH secretion). 62Finally, ACTH production by some PCCs can cause ACTH independent CS via a paracrine action on the ipsilateral adrenal cortex causing subclinical or even clinical CS. 63 The principles that we have discussed in this article can also be applied in the investigation and management of patients with adrenal incidentaloma.
Adrenal lesions from PCC are often larger in comparison to PA or CS.Apart from the adrenal causes of hypertension discussed, many other endocrine pathologies can present with hypertension including growth hormone excess and deficiency. 64hyperparathyroidism, thyroid hormone excess or deficiency, 65 and OSA. 66We have not discussed them here as other recent literature elaborates these conditions in detail. 11,20gure 3 shows an algorithm for screening and work up of patients with suspected endocrine causes of hypertension at primary, secondary and tertiary-care levels.

Conclusion
Although endocrine hypertension is common with a prevalence of about 10% among hypertensive individuals and about 20% of those with resistant hypertension, the diagnosis is often missed because of poor awareness among healthcare workers and the subtle symptoms in individuals with the disease.Prompt early diagnosis and appropriate management often result in a cure of the disease or at least better control of hypertension and the likelihood of end-organ complications.
As some of these disorders are inherited, proper genetic testing with methods such as NGS can optimize the care of patients with the disease.
There is an urgent need to increase global awareness among medical professionals to improve the diagnosis and management of endocrine hypertension.q PA remains largely under-recognized due to underestimation of its prevalence, the complexity of the diagnostic tests, and the lack of familiarity with the interpretation of the diagnostic test results.

Figure 1 :
Figure 1: The classification of monogenic hypertension
During the first touchREVIEWS in Endocrinology postoperative day, blood pressure and potassium must be rigorously checked.Discontinuation of MRA and potassium supplement should be considered to prevent hypotension/hypokalaemia. 20Medical therapy of PA is recommended in bilateral adrenal hyperplasia, bilateral APA, unilateral APA with aldosterone-producing cell clusters (APCCs), familial hyperaldosteronism, and in patients with unilateral APA who refuses surgery or in whom surgery is contraindicated. 20FH-I (GRA or glucocorticoid-remediable aldosteronism) is treated with low dose glucocorticoids with the least mineralocorticoid activity (ideally dexamethasone 0.125-0.25 mg nocte).The side effects of spironolactone can be lessened by low doses or with co-administered epithelial sodium channel (ENaC) inhibitors.
glucocorticoids of either exogenous or endogenous origin.Patients with Cushing's syndrome often have central fat accumulation, hypertension, diabetes mellitus, fatigue, menstrual abnormalities, hirsutism, decreased libido, dorsocervical fat pad, supraclavicular fullness, mood disturbances and peripheral oedema.However, the above-mentioned clinical picture is often nonspecific and may be seen commonly in the general population (Cushingoid appearance) because of the increase in global obesity prevalence.Clinical features with a high specificity for CS include facial plethora, spontaneous bruising, broad

Figure 2 :
Figure 2: Diagnostic and management approach to a patient with suspected primary aldosteronism Several surrogate markers are used to determine the metastatic potential of PPGLs which contribute to various scores including the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), the Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP), and the Composite Pheochromocytoma-paraganglioma Prognostic Score (COPPS).
All subjects with PCCs and PGLs should be involved in the discussion about genetic testing, irrespective of age or tumor location.53Although clinical and biochemical features can suggest a specific causal gene, they do not always predict the underlying genotype.The genetic testing should ideally be performed using the targeted next-generation sequencing (NGS) which would enable testing of several genes in one panel from the DNA acquired either from the peripheral blood, the buccal swab, or, more recently, from the tumor tissue.The latter enables the detection of not only the germline mutations found in the tumorous and peripheral DNA but also the somatic mutations found only in tumorous DNA.

Figure 3 :
Figure 3: Algorithm for screening and work up of patients with suspected endocrine hypertension at primary, secondary and tertiary-care levels

Table 2
gives a summary of hypertensive patients who should undergo screening for PA.

Table 1 :
The main causes of endocrine hypertension

Table 3
If ARR is non-diagnostic, withdraw even the drugs with lesser effect on ARR for at least 2 weeks: β-blockers, clonidine, α-methyldopa, and NSAIDs Antihypertensive drugs with the least effect on ARR (hydralazine, moxonidine, α1selective adrenergic blockers, or slow-release verapamil) are recommended for BP control if needed β-blockers, clonidine, α-methyldopa, and NSAIDs can cause false-positives ARR ACEi, ARBs, diuretics (all) and dihydropyridine CCBs can cause false-negative ARR ARR that is done while on interfering drugs can still be important Normal ARR while on β-blockers would make PA unlikely; raised ARR with suppressed renin while on ACEi, ARBs or diuretics (not β-blocker) would make PA very likely Premenopausal women should have the ARR test in the follicular phase, as the luteal phase or OCP/HRT affects DRC ARR with DRC, but not PRA is associated with false-positive ARR

Table 4 :
48proposed scoring system for the pretest probability of48pheochromocytoma and paraganglioma

Table 5 :
49commendations for biochemical testing for pheochromocytoma and paraganglioma49

Table 6 :
Summary of clinical characteristics of various adrenal causes of endocrine hypertension 45,46Moreover, severe, and refractory hypotension can develop from sudden catecholamine withdrawal after PPGL resection.Hence, adequate preoperative preparation is needed even in normotensive PPGL patients with normal metanephrine levels before surgery.Liberal fluid and salt intake are advised in the pre-operative period to restore the catecholamine excess mediated volume contraction, which would lessen the volume expansion that occurs after PPGL removal.Preoperative targets are seated blood pressure <130/80 mmHg, upright systolic blood pressure >90 mmHg, seated heart rate of 60-70 bpm, and