Adv Exp Med Biol - Advances in Internal Medicine DOI 10.1007/5584_2016_26 # Springer International Publishing Switzerland 2016

Endocrine Hypertension: A Practical Approach

Joseph M. Pappachan and Harit N. Buch

Abstract Elevated blood pressure resulting from few endocrine disorders (endo- crine hypertension) accounts for a high proportion of cases of secondary hypertension. Although some features may be suggestive, many cases of endocrine hypertension remain silent until worked up for the disease. A majority of cases result from primary aldosteronism. Other conditions that can cause endocrine hypertension are: congenital adrenal hyperplasia, Liddle syndrome, pheochromocytomas, Cushing’s syndrome, acromeg- aly, thyroid diseases, primary hyperparathyroidism and iatrogenic hor- mone manipulation. Early identification and treatment of the cause of endocrine hypertension may help to reduce morbidity and mortality related to these disorders. This article gives a comprehensive and practical approach to the diagnosis and management of endocrine hypertension.

Keywords Endocrine hypertension • Primary aldosteronism • Congenital adrenal hyperplasia • Liddle syndrome • Pheochromocytoma • Cushing’s syndrome • Acromegaly • Thyroid disease • Primary hyperparathyroidism

1 Introduction hypertension is approximately 40 % among adults over the age of 25 years and contributes Hypertension is a chronic condition with multi- to 45–50 % of deaths due to heart disease and system involvement and is associated with high stroke (World Health Organization. Obesity and morbidity and mortality. The prevalence of overweight 2015). Although the prevalence of hypertension is high in the general population, only in around 10 % of cases an underlying spe- cific cause can be identified (secondary hyperten- J.M. Pappachan (*) and H.N. Buch Department of Endocrinology & Diabetes, New Cross sion), of which the majority are related to renal Hospital, The Royal Wolverhampton Hospital NHS Trust, and endocrine disorders (Young 2015). If sec- Wolverhampton WV10 0QP, UK ondary hypertension is suspected, it is important e-mail: [email protected] J.M. Pappachan and H.N. Buch to identify the cause, as treatment of the primary However, in a high proportion of patients, an condition may lead to complete or partial cure of endocrine cause may not be obvious, and all hypertension. patients suspected to have secondary hyperten- A multitude of endocrine disorders can pres- sion should be evaluated for an endocrine cause ent with secondary hypertension, collectively unless an alternative aetiology for hypertension termed here as endocrine hypertension. Some of is obvious from the initial clinical and laboratory these disorders may present with unique clinical picture. features while the others may be asymptomatic and identified during work-up of resistant hyper- tension (refractory to standard anti-hypertensive 3 Causes of Endocrine therapy), or a hypertension-related complication. Hypertension Early diagnosis and appropriate management of the primary illness often result in marked A number of endocrine conditions can result in improvement or cure of hypertension. In this hypertension although only a few of them are chapter, we describe a comprehensive and prac- common in clinical practice. A detailed discus- tical approach to endocrine hypertension. sion of individual disorders, the clinic- pathological features and diagnostic evaluation is elaborated below. 2 When to Suspect Endocrine Hypertension?

Secondary hypertension is suspected in patients 4 Primary Mineralocorticoid who present with: hypertension at an early age, Excess sudden onset of uncontrolled hypertension, loss of control over previously well-controlled blood Mineralocorticoids are steroid hormones that pressure and a hypertensive emergency (Velasco control the water and salt balance in the body. and Vongpatanasin 2014; Weber et al. 2014; Aldosterone is the principal endogenous miner- Thomas et al. 2015). alocorticoid hormone in the body although other Endocrine hypertension is the second most hormones including glucocorticoids and sex common cause of secondary hypertension after steroids may exert mineralocorticoid effects. renal disease, and forms a major aetiological Aldosterone is synthesised by the zona factor for resistant hypertension. A diagnosis of glomerulosa cells of the adrenal cortex, and is endocrine hypertension may be obvious when under control of angiotensin II, plasma potas- patients present with typical clinical features of sium levels, and to a lesser extent adrenocorti- the underlying condition like acromegaly, cotrophin (ACTH). Cushing syndrome, hyperthyroidism, hypothy- Clinical conditions in which primary mineral- roidism and features of virilisation in congenital ocorticoid excess can occur are: overproduction adrenal hyperplasia (Young 2015). They may of mineralocorticoid hormones as in primary present with a typical history e.g. paroxysmal aldosteronism (PA) and congenital adrenal palpitations and orthostatic hypotension in hyperplasia (CAH), or increased effect of miner- phaeochromocytoma (Pappachan et al. 2014; alocorticoid hormones as in Liddle syndrome, Desai et al. 2009; Kiernan and Solo´rzano 2016). syndrome of apparent mineralocorticoid excess Occasionally routine laboratory tests in a patient (AME), pseudohypoaldosteronism type with hypertension may raise the suspicion of an 2 (Gordon syndrome) and Geller syndrome. endocrine cause e.g. hypokalemia in These conditions are elaborated in the sections mineralcorticoid excess (Thomas et al. 2015). below. Endocrine Hypertension

4.1 Hypermineralocorticoidism corresponding increase in the water absorption results in an increase in blood volume and blood Overproduction of aldosterone occurs in PA or pressure and the loss of hydrogen ions and potas- CAH, and these disorders are elaborated in the sium results in a state of hypokalemic metabolic following sections. alkalosis in some but not all patients (Thomas et al. 2015; Mulatero et al. 2004). A reduction of plasma renin levels is classical of PA. Apart from 4.1.1 Primary Aldosteronism (PA) the usual complications related to essential PA is one of the most common disorders that hypertension, PA is found to be associated with causes secondary hypertension and forms the elevated risk of cardiac hypertrophy and fibrosis, majority of cases of endocrine hypertension. vascular endothelial dysfunction, albuminuria The disease accounts for 5–13 % of cases in and nephrocalcinosis. people with age of onset of hypertension between 30 and 60 years (Thomas et al. 2015; Young Clinical Presentation 2007). About 10 % of cases in hypertension Although the classical presentation of PA is with clinics, 4 % in the community (Hannemann and resistant hypertension and hypokalemia (some- Wallaschofski 2012; Boulkroun et al. 2015), and times symptomatic), it is not often observed in nearly 20 % with resistant hypertension are clinical practice (Thomas et al. 2015; Funder estimated to be resulting from PA (Boulkroun et al. 2008). The following categories of cases et al. 2015). The variability in the reported inci- should be considered for screening: hypertension dence is related to the use of different definitions, inadequately controlled with three or more anti- biochemical tests and cut-offs. Nearly 60–65 % hypertensive medications, hypertension with an of cases of PA are from idiopathic hyperaldos- adrenal incidentaloma, hypertension in young teronism (IHA) and 30–35 % result from an adults, or those presumed to have secondary aldosterone producing adrenal adenoma (APA) hypertension (Thomas et al. 2015; Young (Thomas et al. 2015; Young 2007). Roughly 5 % 2007). Apart from these categories, the 2008 of cases of PA are familial (familial hyperaldos- American Endocrine Society Guidelines also teronism type I, II and III [FH-I, II and III]) with suggest screening for: hypertensives with clear genetic background (Zennaro et al. 2015a). diuretic-induced hypokalemia, patients with family history of early-onset hypertension or Pathophysiology stroke before 40 years of age and hypertensive PA results from aldosterone over-production patients with a first degree relative having PA with a consequent suppression of plasma renin, (Thomas et al. 2015; Manolopoulou et al. 2015). and manifests with hypertension, retention of sodium, and over-excretion of potassium that Diagnostic Approach may lead to hypokalemia (Funder et al. 2008). Although many of the complex molecular, cellu- Initial Screening Patients with suspected PA lar and genetic mechanisms involved in these should be tested with an estimation of plasma pathways have been recently elucidated aldosterone and renin levels with the calculation (Boulkroun et al. 2015; Zennaro et al. 2015a; of aldosterone to renin ratio (ARR). The assay Piaditis et al. 2015), they are beyond the scope should be ideally performed in the morning after of this chapter. Excess production of aldosterone the individual has been out of bed for 2 h and in PA has multiple biologic and pleiotropic seated for 5–15 min (Thomas et al. 2015; Funder effects in human body that results in the et al. 2008). Different laboratories use different manifestations and complications of the disease. units and cut off values for ARR depending on Aldosterone causes retention of sodium from the assay, and a practical approach could be the distal renal tubules and collecting ducts in following the local guidelines. A recent study exchange for hydrogen and potassium ions. The using a method-specific ARR cut-off of 1.2 J.M. Pappachan and H.N. Buch

(ng/dl)/(μIU/ml), determined with direct, Biochemical Confirmation Although a raised automated chemi-luminescence immunoassays ARR in a clinically relevant scenario is highly allowing the simultaneous measurement of suggestive of PA, one of the four confirmatory plasma aldosterone and renin concentrations, tests is recommended by the American Endo- provided 98.9 % sensitivity and 78.9 % specific- crine Society Guidelines (Funder et al. 2008). ity (Manolopoulou et al. 2015). These results have These tests are: oral sodium loading with mea- been reproduced by other studies but method- surement of urinary aldosterone excretion, intra- specific cut off needs to be derived. Different venous saline infusion with measurement of centres use renin activity or renin concentration, plasma aldosterone levels (levels suppressed in and the ratio cut-off is significantly affected by absence of PA), fludorcortisone suppression test this and other laboratory-based variables. An and captopril challenge test. The latter two tests absolute cut-off value for aldosterone concentra- are not routinely used now, and severe uncon- tion (also method-specific) is often used as an trolled hypertension and heart failure are relative additional criterion to make ARR more specific. contraindications to the former two (Thomas Aldosterone antagonists and beta-blockers should et al. 2015). The former two confirmatory tests be withdrawn prior to the test as they dispropor- may become necessary in cases with mild PA, tionately affect the ARR. where the ARR is only marginally elevated in the absence of severe hypertension or heart failure. A Confounders Several antihypertensive medi- detailed description and interpretation of the con- cations can interfere with the screening results firmatory tests and results are beyond the scope to a varying extent because of interference with of this chapter and are freely available to the the renin-angiotensin-aldosterone (RAA) system readers in the full text of the American Endocrine causing high false-positive and false-negative Society Guidelines (Funder et al. 2008). rates, with betablockers and diuretics being the main culprits. Hypokalemia, and treatment with Adrenal Imaging Computed tomography antihypertensive medications such as (CT) scan of the adrenal glands is recommended dihydropyridine group of calcium channel in all cases of PA for localisation of the disease blockers, angiotensin convertase enzyme and to exclude the small possibility of an adreno- inhibitors and angiotensin II receptor blockers, cortical carcinoma (Thomas et al. 2015; Funder can cause false negative results of ARR in et al. 2008). Adrenal CT is preferred over mag- patients with mild PA. Discontinuation of netic resonance imaging (MRI) as an imaging interfering medications for sufficient time period modality for localisation purpose because it is may be considered if feasible. For example, more economical and has better spatial resolu- diuretics and aldosterone antagonists should be tion. However, adrenal imaging had a low sensi- withdrawn 4 weeks prior to, and the other tivity of 58.6 % to detect unilateral disease (Lim antihypertensives described above, 2 weeks et al. 2014). prior to the intended ARR estimation (Funder et al. 2008). Antihypertensives such as verapamil Adrenal Venous Sampling (AVS) AVS is the (slow release), hydralazine and alpha-adrenergic gold standard test for detection of the source of blockers possess minimal effects on RAA system aldosterone excess, and is recommended in most and are recommended for control of hypertension cases for lateralisation of the abnormal adrenal before ARR measurement if other antihyperten- gland if a surgical cure is contemplated. The sive drugs are to be discontinued (Thomas technical difficulty with the procedure, lack of et al. 2015; Funder et al. 2008). However, in availability in many centres and relatively higher patients with severe hypertension resistant to complication rates (about 5 %) are the main conventional medications, switching to these concerns in the routine performance of AVS. A drugs may not be easy, considering the recent expert consensus statement recommends anticipated hypertensive complications. avoiding AVS in the following situations: age Endocrine Hypertension is < 40 years with marked PA in presence of a life, and possibly all-cause mortality were typical unilateral adrenal adenoma and normal observed after surgery, although without an appearance of the opposite adrenal on CT, suspi- observed benefit on cardiovascular cion of adrenocortical carcinoma from adrenal complications. imaging, high risk cases for adrenalectomy, Laparoscopic adrenalectomy is the preferred proven cases of FH-I and FH-III (Thomas surgical procedure because of lower morbidity, et al. 2015; Rossi et al. 2014). shorter length of hospital stay and faster recovery compared to open adrenalectomy. Partial adre- Tests for Familial Hyperaldosteronism (FH) nalectomy may be an option in selected case of FH-I (GRA) is screened by a low-dose dexa- unilateral PA. Both hypertension and hypokale- methasone suppression test with serial mia should be well controlled pre-operatively, measurements of blood pressure and plasma and levels of plasma aldosterone and renin aldosterone levels (Mussa et al. 2012; Korah should be measured postoperatively to assess and Scholl 2015). Normalisation of blood pres- the biochemical response (Thomas et al. 2015; sure and suppression of aldosterone are Funder et al. 2008). Withdrawal of potassium characteristics of FH-I. In addition, urinary supplements and mineralocorticoid receptor 18-oxocortisol and 18-hydroxycortisol are usu- (MR) antagonist are usually possible on the first ally elevated in patients with FH-I (Mussa postoperative day after successful surgery, with et al. 2012). In patients with FH-II, blood pres- reduction/discontinuation of antihypertensive sure is un-responsive to glucocorticoid challenge medications within 1–6 months in most cases. and aldosterone suppression is partial or absent Bilateral adrenalectomy may be necessary in (Mussa et al. 2012). Urinary 18-oxocortisol and FH-III to control the disease (Mussa et al. 2012). 18-hydroxycortisol levels are normal/moderately elevated. Blood pressure is unresponsive/ Medical Therapy Medical treatment is the increases with a paradoxical increase in aldoste- option in a majority of cases of PA with bilateral rone levels occurs in cases of FH-III during disease and in cases not appropriate for adrenal- dexamethasone suppression test (Mussa ectomy. MR antagonist spironolactone is the first et al. 2012). The urinary 18-steroid metabolites line of treatment. With a starting dose of are very high in FH-III. Genetic testing confirms 12.5–25 mg, the dose is gradually up-titrated to the autosomal dominant gene mutations in all the optimise the dose (usually up to 100 mg daily) to three forms of FH (Korah and Scholl 2015; get adequate control of BP and potassium levels. Zennaro et al. 2013). Eplerenone, a selective MR antagonist, is started at a dose of 25 mg once or twice daily. Caution must be taken in chronic kidney disease stage Management of PA 3 and above while using these drugs. Amiloride/triamterene are useful alternative Surgical Management Surgical management is medications if MR antagonists are not tolerated/ possible only in selected cases of PA where there contra-indicated (Funder et al. 2008). is a clear evidence of lateralisation of the aldo- sterone excess to the side of an adrenal adenoma PA resulting from FH-I (GRA) should be as described above. A recent systematic review managed with glucocorticoids in adults and MR showed that adrenalectomy for unilateral disease antagonists in paediatric cases (because of the was associated with normalization of blood pres- effect of steroids on growth retardation) until sure in about 42 % (range 20–72) and cure of PA they reach adulthood. Starting dose of dexameth- in 96–100 % with a mean complication rate of asone is 0.125–0.25 mg or prednisolone is 4.7 % among 1056 patients (Muth et al. 2015). 2.5–5 mg at night and the doses are titrated to Compared to medical therapy, use of fewer anti- partially suppress the ACTH levels to optimise hypertensive drugs, improvement of quality of the aldosterone levels and BP control (Funder J.M. Pappachan and H.N. Buch et al. 2008). FH-II is managed with MR Zennaro et al. 2015b). Plasma renin and aldoste- antagonists +/ amiloride to optimise BP rone levels will be low. Definitive diagnosis is control. proved with genetic testing for the mutation. 17-α-hydroxylase deficiency results in elevated 4.1.2 Congenital Adrenal Hyperplasia levels of DOC, ACTH and gonadotropins with (CAH) with Mineralocorticoid suppressed levels of androgens and estrogen Excess (Zennaro et al. 2015b; Kim and Rhee 2015). CAH is the most common inborn error of adrenal Unlike the classical and non-classical forms of gland function (Speiser 2015; Sahakitrungruang CAH, levels of 17-hydroxyprogesterone levels 2015; Miller and Auchus 2011). There are differ- are low and the levels do not rise with ACTH ent forms of CAH depending on the type of challenge. Genetic testing establishes the diagno- genetic mutations and the related enzyme defect sis with identification of the related mutations. in the adrenocortical hormone synthesis that cause these disorders. Two types of enzyme Management defects cause mineralocorticoid excess in CAH, The mainstay of management in patients with viz. 11-β-hydroxylase deficiency (11OHD) and 11OHD is glucocorticoids that normalise 17-α-hydroxylase deficiency (Sahakitrungruang ACTH, the driving force for DOC overproduc- 2015). tion, with improvement of hypertension About 5–8 % of cases of CAH among (Zennaro et al. 2015b). Addition of MR Caucasians and about 15 % among Middle- antagonists such as spironolactone or eplerenone Eastern populations results from 11OHD may be necessary in some cases to treat hyper- (Sahakitrungruang 2015; Miller and Auchus tension. Patients with 17-α-hydroxylase defi- 2011). The enzyme deficiency causes decreased ciency should be treated with glucocorticoids cortisol production with accumulation of and sex steroids when necessary (Zennaro 11-deoxycortisol and 11-deoxycorticosterone et al. 2015b; Kim and Rhee 2015). The genital (DOC; a mineralocorticoid precursor). The dis- abnormalities related to virilisation should be ease is transmitted as an autosomal recessive trait managed by appropriate surgical procedures. with more than 80 mutations described already (Zennaro et al. 2015b). Hypertension and varying Increased Mineralocortocoid Action degrees of virilisation and precocious puberty in Even with normal levels of mineralocorticoid both sexes are the results of 11OHD clinically. hormones, mineralocorticoid-related hyperten- 17-α-hydroxylase deficiency results in a sion can result from rare genetic disorders from reduction of cortisol synthesis with overproduc- exaggerated actions of the hormone at the tion of corticosterone, and deoxycorticosterone receptor/effecter-tissue levels. These disorders (mineralocorticoid). Hypertension, hypokalemia are briefly discussed in the following section. and sexual infantilism secondary to hypergona- dotropic hypogonadism are the common clinical 4.1.3 Liddle Syndrome features of this disorder. Inheritance pattern is This is an autosomal dominant genetic disorder autosomal recessive with more than 90 gene associated with hypertension, hypokalemia, met- mutations described to date (Zennaro abolic alkalosis, and low plasma renin and aldo- et al. 2015b). sterone levels. Because of similarity to the clinical presentation of PA, the condition is Diagnostic Approach to CAH (with termed “pseudoaldosteronism” (Wang Mineralocorticoid-Induced Hypertension) et al. 2015). Liddle syndrome results from gain- Diagnosis of 11OHD is established by elevated of-function mutations in genes encoding the baseline levels of DOC and 11-deoxycortisol subunits of epithelial sodium channel (ENaC) with significant increase in the levels following that cause increased sodium re-absorption and ACTH challenge (Sahakitrungruang 2015; potassium loss from the kidney and hypertension Endocrine Hypertension

(Zennaro et al. 2015b; Wang et al. 2015; MR antagonists +/ thiazide diuretics along with Melcescu et al. 2012). small doses of dexamethasone. Diagnosis is considered in hypertensives with a family history of early-onset hypertension, 4.1.5 Pseudohypoaldosteronism Type hypokalemia, low levels of renin and aldoste- 2 (Gordon Syndrome; Familial rone, and prompt response to ENaC antagonists Hyperkalemic Hypertension) such as amiolride and triamterine without This is a rare genetic disorder associated with response to MR antagonists (Zennaro hypertension, hyperkalemic-hyperchloremic et al. 2015b; Wang et al. 2015; Melcescu metabolic acidosis, low renin and normal or ele- et al. 2012). Confirmation of the diagnosis is by vated levels of aldosterone (Zennaro et al. 2015b; screening for mutations in the genes encoding the Melcescu et al. 2012). Multiple genetic β and γ subunits ENaC. Patients are managed by mutations are identified (in the genes WNK1, a low sodium diet and ENaC antagonists. WNK4, KLHL3 and CUL3) that modulate the thiazide-sensitive Na-Cl cotransporter in the kid- 4.1.4 Syndrome of Apparent ney leading to increased re-absorption of sodium Mineralocorticoid Excess (AME) and chloride from the kidney with the resultant AME is an autosomal recessive disorder biochemical and clinical manifestations of the characterised by hypertension, hypokalemia, disease. metabolic alkalosis with low levels of plasma Diagnosis is based on the biochemical renin and aldosterone levels (Zennaro abnormalities described above and the genetic et al. 2015b; Melcescu et al. 2012). It is caused testing for different culprit gene mutations by mutations in the HSD11B2 gene coding for (Zennaro et al. 2015b; Melcescu et al. 2012). the enzyme 11β-Hydroxysteroid dehydrogenase Management of the disease is with dietary 2 (HSD11B2) on chromosome 16 (Zennaro sodium restriction and thiazide diuretics. et al. 2015b; Melcescu et al. 2012). This enzyme is responsible for the inter-conversion of cortisol 4.1.6 Geller Syndrome to cortisone in aldosterone-selective tissues This disorder results from a mutation activating including kidneys liver, colon, salivary glands, the mineralocorticoid receptor (MR) that was lungs, placenta and some neural tissues. Around first described by Geller et al. in 2000 (Geller 40 different types of mutations are described in et al. 2000). The index case presented with early- the gene already (Zennaro et al. 2015b). onset severe hypertension associated with low Severe form of the disease is usually plasma renin and aldostereone, and exacerbation diagnosed in early childhood with hypertension, of hypertension during pregnancy. So far, only polyuria, polydypsia, hypokalemia, metabolic one family has been identified with a p. alkalosis and failure to thrive in presence of Ser810Leu mutation, located in the ligand bind- suppressed plasma renin and aldosterone levels ing domain of the MR (Zennaro et al. 2015b; (Zennaro et al. 2015b; Melcescu et al. 2012). Melcescu et al. 2012). Amiloride may be effec- Short stature, renal cysts and nephrocalcinosis tive in the correction of the biochemical may be present in some cases (Zennaro abnormalities and improvement of hypertension, et al. 2015b; New et al. 2005). Milder forms but spironolactone has to be avoided as it is a may present during adult life. Biochemical diag- potent agonist of the mutant receptor (Zennaro nosis of AME is based on measurement of the et al. 2015b). ratio of urinary metabolites of cortisol to corti- A flow chart depicting the algorithm for work sone (high ratio in cases) (Zennaro et al. 2015b; up and management of primary mineralocorti- New et al. 2005). Confirmation of the diagnosis coid excess states is shown in Fig. 1. is by genetic testing. Management is usually by J.M. Pappachan and H.N. Buch

Fig. 1 An algorithm for diagnostic evaluation and man- mineralocorticoid antagonist, ACTH Adrenocorticotropic agement of primary mineralocorticoid excess states (HTN hormone, DST dexamethasone suppression test, CAH hypertension, CT computed tomography, MRI magnetic congenital adrenal hyperplasia, FH familial hyperaldos- resonance imaging, K+ potassium, Cl chloride, ENaC teronism, Culprit genes* WNK1, WNK4, KLHL3 and epithelial sodium channel, HSD11B2 11β-Hydroxysteroid CUL3, (AVS)** adrenal venous sampling may be avoided dehydrogenase 2, AME apparent mineralocorticoid in certain situations as mentioned in the text) excess, IHA idiopathic hyperaldosteronism, MRA

from the extra-adrenal autonomic ganglia 5 Pheochromocytomas (PGLs). and Paragangliomas Pathophysiology Pheochromocytomas (PCC) and paragangliomas Increased production and release of (PGL) are rare neuroendocrine tumours arising catecholamines (epinephrine, norepinephrine from the chromaffin tissues of the embryonic and dopamine) by the tomors to circulation result neural crest cells that become the adrenal in the clinico-pathological manifestations of medulla and autonomic neural ganglia in adult PCCs and PGLs. Catecholamines cause intense life. With an estimated annual incidence of 2–8 vasospasm and hypertension through per million, these tumors account for 0.2–0.6 % α-adrenergic effect, and vasodilatation, diapho- of hypertension in the community (Pappachan resis and tachycardia from the β-adrenergic et al. 2014; Kasperlik-Zaluska et al. 2006). effect (Pappachan et al. 2014). Severe orthostatic About 85 % of pheochromocytomas arise from hypotension with syncopal episodes can occa- the adrenal medulla (PCCs) and the remainder sionally result from unbalanced effects of α- Endocrine Hypertension and β-adrenergic receptors in different vascula- drug-induced hypertensive crisis (with beta- ture in the body (Pappachan et al. 2014; Desai blockers or monoamine oxidase inhibitors), and et al. 2009). new-onset diabetes in an young lean hyperten- The paroxysmal nature of the catecholamine sive are some of the atypical clinical release may explain the episodic nature of presentations of the disease (Pappachan symptoms in PCCs/PGLs. Recurrent surge of et al. 2014). these hormones may cause a (reversible) form of cardiomyopathy called catecholaminergic car- Diagnostic Approach diomyopathy (Pappachan et al. 2014; Desai et al. 2009). 10–15 % of PCCs and 20–50 % of PGLs can be malignant, and as there is no clear- Biochemical As in any other endocrine disease cut histological criteria to determine malignancy biochemical confirmation of the diagnosis is the in resected tumors, life-long follow up for recur- first-line approach to the diagnosis of PCCs/ rence in an appropriate clinical scenario is PGLs. Plasma free metanephrines or urinary recommended by many authorities (Parenti fractionated metanephrines is the screening et al. 2012; Tsirlin et al. 2014; Lenders investigation of choice for suspected cases et al. 2014). Several genetic mutations have with very high sensitivity and good specificity been recently described in PCCs/PGLs (Pappachan et al. 2014; Lenders et al. 2014). (Pappachan et al. 2014) that may be associated Intake of multiple medications and other with malignant potential and inheritance to suc- chemicals before testing can interfere with the cessive generations, and the recent endocrine results reducing the positive predictive value of society guidelines in 2014 recommend appropri- this screening assay. A detailed list of these ate testing and follow up algorithm of the disease medications can be found in the relevant (Lenders et al. 2014). literature (Pappachan et al. 2014;Lenders et al. 2014). Therefore, raised levels 3–4 Clinical Features times the laboratory reference range should be Although the classical clinical presentation is interpreted with caution to avoid un-necessary with headaches, palpitations and sweating with work up because of a false positive test. A hypertension, many of these tumours present clonidine suppression test may be useful in with protean manifestations including prolonged such situations (Lenders et al. 2014;Eisenhofer periods of clinical silence. <1 % of resistant et al. 2003). hypertension cases are related to PCCs/PGLs (Rimoldi et al. 2014). With the increasing use Anatomical Imaging Imaging studies for of cross sectional abdominal imaging for medical localisation should only be undertaken after the diagnostics, many cases of PCCs/PGLs are biochemical diagnosis is proven. CT scan and diagnosed in the recent years while evaluating Magnetic Resonance Imaging (MRI) have excel- adrenal incidentalomas. About 4 % of adrenal lent sensitivity and reasonable specificity for incidentalomas are reported to be PCCs anatomical localisation of these tumours. (Kasperlik-Zaluska et al. 2006). Few multi- Non-ionic contrast is preferred for CT scan organ endocrine neoplastic syndromes such as because of the risk of hypertensive crisis (Lenders Multiple Endocrine Neoplasia (MEN) 2A and et al. 2014). MRI is preferred over CT in patients 2B, Von Hippel-Lindau (VHL) disease and neu- in whom where radiation needs to be avoided and rofibromatosis type 1 can have PCCs/PGLs as in patients suspected to have metastatic disease disease manifestations (Pappachan et al. 2014; (Pappachan et al. 2014; Lenders et al. 2014). Desai et al. 2009). Hypertensive crisis during emergency surgery, general anaesthesia or con- Functional Imaging Once the anatomical diag- trast radiography, unexplained heart failure, nosis is established with an initial imaging J.M. Pappachan and H.N. Buch modality, functional imaging is usually Management Surgery is the preferred definitive recommended to prove the diagnosis, and to management option for all cases of PCCs/PGLs exclude the possibility of metastasis and multi- unless contraindicated. Complete resection of the site disease in cases of PGLs. 123I-metaiodoben- tumor often results in cure of the disease zylguanidine (MIBG) scitigraphy is the usual although improvement in hypertension depends functional imaging modality utilized in most on other factors too. centers. The sensitivity and specificity of 123I- MIBG scintigraphy is around 85 % in PCCs. A Peri-Operative Management variety of different radio-pharmaceutical agents Prompt control of hypertension and appropriate can be used for functional imaging in cases with preoperative preparation is a must as manipula- a negative 123I-MIBG scintigraphy (Pappachan tion of the tumour during surgery results in et al. 2014; Lenders et al. 2014). hypertensive crisis because of the massive release of catecholamines to circulation. Ade- Genetic Testing The recommendations for quate control of hypertension with non-selective genetic testing and the testing algorithm can be α-adrenergic blockers such as found in the 2014 Endocrine society guidelines phenoxybenzamine (10 mg BD to a maximum (Lenders et al. 2014). of 1 mg/kg/day) or α-1 selective agent doxazosin An algorithm for diagnostic work up of (2–32 mg/day) 10–14 days prior to the surgery clinically suspected PCCs/PGLs is shown in along with liberal intake of fluids and salt to Fig. 2. replenish volume depletion is recommended in

Fig. 2 Diagnostic evaluation of pheochromocytomas emission computed tomography, 123I-MIBG 123Iodine- (PCCs) and paragangliomas (PGLs) (CT Computed Meta-iodo-benzyl-guanidine. Reproduced with permis- tomography, MRI Magnetic resonance imaging, PET sion from Pappachan et al. (2014)) Positron emission tomography, SPECT Single photon Endocrine Hypertension all cases (Pappachan et al. 2014; Lenders Follow Up The follow up care of patients with et al. 2014). Addition of a β-adrenergic blocker PCCs and PGLs is detailed in the 2014 guidelines such as propranolol or atenolol to counteract the of the Endocrine Society (Lenders et al. 2014). reflex tachycardia and postural hypotension An algorithm for management and follow up associated with α-blockers may be necessary of PCCs/PGLs is shown in Fig. 3. after few days of starting α-blockers. Other anti- hypertensive medications such as calcium chan- nel antagonists and metyrosine may be necessary 6 Glucocorticoid Excess for optimal control of BP in some cases (Cushing’s Syndrome) (Pappachan et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). The target BP control Glucocorticoids are hormones from the zona should be < 130/80 mm Hg while seated and fasciculata of the adrenal cortex. Although physio- > 90 mm systolic while standing and a heart logical levels are critically important for homeo- rate 70–80 per minute (Pappachan et al. 2014; stasis in normal subjects, excess production of Tsirlin et al. 2014; Lenders et al. 2014). Appro- glucocorticoids in the body (endogenous hypercor- priate modifications in these targets may be made tisolism) or prolonged administration of the hor- in the presence of cardiovascular disease. mone in high doses (iatrogenic hypercortisolism) result in a pathologic state known as Cushing’s Operative Management Surgeon and anaes- syndrome (CS) that is associated with protean thetist with sufficient experience with the man- manifestations including secondary hypertension. agement of these rare tumors should perform The disease is associated with excess morbidity, the surgery to optimise safe outcomes. mortality and poor quality of life, and an early Laparoscopic adrenalectomy is the preferred diagnosis and appropriate management may miti- surgery in most cases of PCCs. Large tumors, gate this natural history (Nieman 2015). The clini- PGLs and suspected metastatic disease are cal picture of CS cases varies depending on the indications for an open surgery (Pappachan extent and duration of cortisol excess. et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). Intra-operative BP changes should Pathophysiology be closely monitored with administration of A majority of cases of CS results from an ACTH intravenous α-adrenergic blockers (phentol- producing pituitary adenoma that is otherwise amine or phenoxybenzamine) for hypertensive known as Cushing’s disease. Ectopic production episodes during surgery, and intravenous of ACTH accounts for a significant proportion of crystalloids and vasopressors to manage the cases other than pituitary Cushing’s, followed by postoperative hypotension in an intensive care cortisol-secreting adrenal adenomas and unit may be necessary to manage cases carcinomas, and adrenal nodular hyperplasia. (Pappachan et al. 2014; Tsirlin et al. 2014). Exogenous steroid administration for therapeutic purposes results in iatrogenic CS in many patients. Postoperative Care Withdrawal of the antihy- Carney complex, a rare genetic disorder (autosomal pertensive medications and hypoglycemic agents dominant), characterized by pigmented skin and (if secondary diabetes was present mucosal lesions, cardiac and cutaneous myxomas, pre-operatively) may be possible in some cases. and multiple endocrine and non-endocrine Testing plasma (or urinary) metanephrines neoplasms is an uncommon cause of CS (Correa 10 days after the surgery to ensure complete et al. 2015). Another rare cause for CS is ectopic removal of the tumor is recommended in all CRH (corticotropin releasing hormone) producing cases (Pappachan et al. 2014; Tsirlin tumors. Subclinical CS, results from alterations in et al. 2014; Lenders et al. 2014). Regular endo- the hypothalamus–pituitary–adrenal (HPA) axis crine follow up of the patients with appropriate without overt signs or symptoms of hypercor- long-term care plan is also mandatory. tisolism (Di Dalmazi et al. 2015). J.M. Pappachan and H.N. Buch

Fig. 3 Management and follow up care of pheochromocytomas (PCCs) and paragangliomas (PGLs) (Reproduced with permission from Pappachan et al. (2014))

Hypertension in CS may be multi-factorial, of skin, acne, hirsutism, thinning of scalp hair, and the exact mechanisms still remain elusive. weight gain with truncal obesity, buffalo hump Several putative mechanisms have been and supraclavicular fatty pad (due to ectopic identified including imbalance between fat distribution), labile mood and sometimes vasodilatory and vasoconstrictor chemicals such frank psychosis, menstrual irregularities, prox- as prostacyclin, nitric oxide and endothelins, the imal myopathy, growth failure in children, sex- mineralocorticoid receptor activation ual dysfunction (and even impotence), (Di Dalmazi et al. 2015; Anagnostis et al. 2009; hypertension, hypokalaemia, glucose intoler- Mihailidou et al. 2009; De Leo et al. 2010; ance or frank diabetes, osteoporosis, metabolic Rizzoni et al. 2009), endothelial abnormalities syndrome, and susceptibility to infections due (Di Dalmazi et al. 2015; Anagnostis to suppressed immunity. However, these clas- et al. 2009), and development of metabolic syn- sical manifestations are less frequently drome (Di Dalmazi et al. 2015; Anagnostis observed these days because of wide availabil- et al. 2009; Ferrau and Korbonits 2015). ity of investigations and awareness of the dis- ease among physicians. In up to 15 % of adults Clinical Features with CS, the clinical manifestations may occur A wide variety of clinical manifestation may only periodically, a condition known as cycli- be seen in a classical case of overt CS (Nieman cal Cushing’s syndrome (Alexandraki 2015). These include facial plethora, fragility et al. 2009). Endocrine Hypertension

Diagnostic Approach pituitary surgery although controversy still Although the American Endocrine Society remains among endocrinologists on size criteria Guidelines on diagnostic evaluation of CS is (Florez et al. 2013). A high-dose DST (using slightly old (Nieman et al. 2008), most of the 2 mg QDS for 48 h) and/or CRH stimulation recommendations are still valid for work up of tests is recommended by some centers if the suspected cases. An exclusive meeting to discuss pituitary mass is smaller or absent, in presence about CS, held in Germany in October 2014 with of raised ACTH levels. A suppressible cortisol wide participation from global experts, compiled with high-dose DST or 20 % rise in cortisol further evidence on the diagnostic and manage- following CRH administration indicates ment algorithms of the disease (Reincke 2015). A pituitary-driven corticotrophin excess although detailed discussion of the diagnostic approach to overlap with ectopic source is well recognised. CS can be found in these published literature and Bilateral inferior petrosal sinus sampling only a brief account is given here. (BIPSS) with baseline and CRH-stimulated A thorough history of extraneous steroid ACTH measurements is the next step. If BIPSS administration should be obtained in all cases of is negative, imaging of thorax and/or abdomen clinically suspected CS before biochemical test- and pelvis should be performed to identify an ing. The Endocrine society recommends testing ectopic source of ACTH. Finally, an octreotide for CS in patients with multiple clinical features scan may be necessary if all other confirmatory described above, children with growth retarda- tests are negative. A useful algorithm for diag- tion with abnormal weight gain, illnesses uncom- nostic work up of CS can be found in the full-test mon in younger age-groups such as hypertension article (freely available) by Florez et al. (2013). and osteoporosis, and adrenal adenomas (Nieman et al. 2008). Management In suspected cases of CS, one of the following Management of CS can be complex in many screening investigations should be performed cases, and the mortality related to the disease initially: 24-hour urinary free cortisol (at least is reported to be higher than in normal 2 samples), late night salivary cortisol, 1-mg age-matched controls even in treated cases overnight dexamethasone suppression test (Clayton et al. 2011; Graversen et al. 2012). (DST) or low-dose DST (0.5 mg QDS for 48 h) Complete cure of the disease may not be always (Nieman et al. 2008). Further evaluation by an possible, and management of disease endocrinologist is recommended in cases with at manifestations shall be the only options in least one positive test and in those with negative such cases. Whenever feasible, surgical removal screening tests and clinically suspected cyclical of the cause of excess cortisol/ACTH is the most CS. Random plasma cortisol measurement has appropriate and potentially curable manage- no value for screening cases of CS because of ment option. the marked variability of levels depending of many factors. Medical Therapy Even in curable cases, medi- Confirmation of CS in suspected cases needs cal management should bridge the definitive sur- detailed endocrine work up. Measurement of gery for adequate preparation of the patient. First- corticotrophin (ACTH) levels is the next step in line agent widely used is metyrapone, a diagnosis. Suppressed level of ACTH indicate an 11-β-hydroxylase enzyme inhibitor (dose range adrenal/iatrogenic source of hypercortisolism. If 1–4 g/day in divided doses). The drug has been adrenal source is suspected a contrast CT scan of found to be very effective for short- and long- the adrenal glands should be done. If ACTH term control of endogenous steroid excess in a levels are high or high normal, an MRI of pitui- recent multicenter study (Daniel et al. 2015). tary should be done. A pituitary mass 1cm However, the drug can increase the adrenal syn- may be an indication of Cushing’s disease and thesis of steroids with mineralocorticoid activity J.M. Pappachan and H.N. Buch that worsens hypertension (Ferrau and Korbonits Hypophysectomy with or without pituitary 2015). Other cortisol-lowering medications such radiotherapy is usually associated with multiple as ketoconazole (Nieman 2002), mitotane pituitary hormone insufficiencies that (Donadille et al. 2010) and mifepristone (Fleseriu necessitates lifelong hormone replacement with et al. 2012) also have beneficial effects on hyper- endocrine follow up. Sometimes bilateral adre- tension in CS, although careful monitoring for nalectomy may be necessary for patients with side effects of these agents is necessary. Recent intractable CS where source of ACTH excess is guidelines from the Endocrine Society and rec- irremovable (Reincke et al. 2015). This surgery ommendation from the European Medicines is reported to be relatively safe and highly effec- Agency suggest ketoconazole as highly effective tive in such cases. Patients need lifelong steroid option for medical management of CS when used and mineralocorticoid replacement and Nelson’s judiciously (European Medicines Agency 2016; syndrome is a possible consequence of this sur- Nieman et al. 2015). Combination therapy with gery in CS due to the growth of the pituitary ketoconazole and metyrapone may be necessary adenoma in absence of feedback inhibition from to obtain rapid control hypercortisolism in some corticosteroids. cases (Nieman et al. 2015). Pasireotide alone (Colao et al. 2012), or in combination with cabergoline and ketoconazole (Feelders 7 Acromegaly et al. 2010) also have been reported to benefit treatment of hypertension in CS. Recently, Acromegaly results from prolonged growth hor- retinoic acid (Pecori Giraldi et al. 2012) and mone (GH) excess in adults. GH exerts its hor- LCI699 have been shown to be effective in treat- monal effect in the body through the protein ment of CS and disease-related hypertension molecule Insulin-like Growth Factor-1 (IGF-1) (Bertagna et al. 2014; Daniel and Newell-Price secreted from liver. The classical cases of acro- 2015). Along with medical measures to manage megaly with all the phenotypic features are less hypercortisolism, conventional antihypertensive often encountered currently in clinical practice treatment also needs to be administered for con- owing to better investigation facilities and trol of BP in patients with CS. heightened awareness of the disease among physicians that result in early diagnosis of the Surgery Transphenoidal hypophysectomy is disease. The estimated prevalence of the disease the preferred surgical treatment in Cushing’s dis- is 30–60 cases/one million population and arte- ease although cure is not guaranteed in all cases rial hypertension is encountered in 40 % of the owing to the difficulty in removal of the entire cases (Capatina and Wass 2015). tumour tissue in some cases, especially small adenomas. Pituitary radiotherapy may be neces- Pathophysiology sary in selected cases with residual tumour In over 95 % of cases, acromegaly results from a although associated with higher long-term com- GH-secreting somatotroph adenoma of pituitary plication rates including pan-hypopituitarism. causing GH and IGF-1 overproduction (Melmed Functional imaging of the pituitary with (11)C- 2009; Katznelson et al. 2014). Majority of these methionine positron emission tomography- are macroadenomas (size > 1 cm). Less than computed tomography (PET-CT) scan is recently 5 % of cases results from a hypothalamic tumour reported to be an excellent tool to localise resid- or a neuroendocrine tumour secreting Growth ual disease after previous hypophysectomy for Hormone Releasing Hormone (GHRH) or rarely targeted therapy (Koulouri et al. 2015). GH overproduction from a hemopoeitic or Removal of the source of ectopic ACTH- abdominal tumor (Katznelson et al. 2014). driven CS may be easy if precise tumour GH-producing tumours may be a consequence localisation is possible pre-surgically. of the genetic MEN-1 syndrome. Endocrine Hypertension

Overstimulation from the excess GH in circu- may have prognostic significance (enhanced lation results in raised plasma levels of IGF-1 response to somatostatin receptor ligand [SRL] produced from liver that causes overgrowth of therapy) (Katznelson et al. 2014; Puig-Domingo somatic tissues culminating in the clinical et al. 2010). Visual field testing is recommended manifestations of acromegaly. Disfigurement of in all cases with a pituitary macroadenoma in the facial skeleton and enlargement of limbs the MRI. If pituitary imaging is negative, result from prolonged hyper-stimulation of GHRH levels should be measured to exclude IGF-1. The clinical manifestations of the disease rare location of the disease in hypothalamus or are related to overgrowth of tissues and the met- other tissues with appropriate imaging when abolic abnormalities related to excess circulating necessary (Capatina and Wass 2015). IGF-1 levels. Management Clinical Features The disease affects most body organs and the Surgery All resectable tumors in the pituitary common manifestations are headache, coarse facial should be removed through a transphenoidal features (frontal bossing and prognathism), hypophysectomy if possible. Some large tumors enlargement of hands and feet, hypertension and may need a trans-cranial or combined approach. diabetes, osteoarthritis, entrapment neuropathies, Sometimes surgical de-bulking improves the sleep apnoea, visual field defects and heart failure. medical treatment outcome later if complete A detailed account of the disease and its clinical removal of the tumor is impossible (Katznelson features can be found in the recent article (available et al. 2014; Katznelson 2010). Repeated surgery free in the web) by Capatina et al. (2015). may be necessary if initial procedure did not clear the entire tumor. Postoperative measure- Diagnostic Approach ment of GH and IGF-1 levels give evidence for All patients with clinically suspected acromegaly clearance of tumor during surgery and pituitary and typical features should undergo testing for imaging is necessary for anatomical assessment. IGF-1 levels. Those with some of the features These are usually done after 12 weeks of surgery without a definite clinical picture may also need (Katznelson et al. 2014). IGF-1 testing when some of disease-associated features such as sleep apnoea, type 2 diabetes, Medical Treatment Medical management hypertension, carpel tunnel syndrome, becomes necessary when tumors are inoperable debilitating arthritis or hyperhidrosis are present or when surgery is incomplete with residual dis- (Katznelson et al. 2014). IGF-1 levels also ease. SRLs and pegvisomant are the two classes should be measured in patients with a pituitary of drugs with good activity against acromegaly. mass to exclude the disease. Biochemical confir- 2 forms of SRLs are commercially available mation of acromegaly in patients with elevated or widely (Octreotide LAR [long acting release] equivocal IGF-1 levels is by a glucose tolerance and lanreotide depot/autogel). Pasereotide is a test to show lack of suppression of GH levels novel SRL with enhanced activity and confers during hyperglycemia (Capatina and Wass better tumoral response to treatment (Capatina 2015; Katznelson et al. 2014). and Wass 2015; Katznelson et al. 2014; Colao In biochemically confirmed cases, disease et al. 2014). Pegvisomant possess better treat- localisation should be done by an appropriate ment response than SRLs in patients with acro- imaging study. An MRI of the pituitary detects megaly (Katznelson et al. 2014; van der Lely a macroadenoma in about 77 % cases et al. 2012). Monitoring of response to treatment (Katznelson et al. 2014; Mestron et al. 2004), and dose adjustments are done with serial and a hyper-intense T2-weighted MRI signal measurements of IGF-1 and pituitary imaging. J.M. Pappachan and H.N. Buch

Mild disease may respond to dopamine agonists Bradycardia, mild hypertension, narrow pulse such as cabergoline. Combinations of different pressure, and muffling of heart sounds are the drug classes in different multi-drug regimes may most common signs of overt hypothyroidism be necessary in some cases for enhanced (Klein and Ojamaa 2001). Positive correlation response to treatment (Capatina and Wass 2015; between serum thyrotropin levels and hyperten- Katznelson et al. 2014). Pituitary radiotherapy sion was observed in children and adolescents, may also be necessary in cases with residual suggesting a linear relationship between even disease when medical therapy fails to control subclinical hypothyroidism and BP, in two large the disease. cohort studies among two populations with Management of multi-system entirely different genetic backgrounds (Chen manifestations of the disease such as diabetes, et al. 2012; Ittermann et al. 2012). High serum hypertension, entrapment neuropathy and heart thyrotropin levels were positively associated with disease should be as per the individual needs of systolic and diastolic blood pressure, in children the patient. In general, acromegaly cases are and adolescents with Odds ratios 1.12 and 1.19 managed in a multi-disciplinary team environ- respectively (p < 0.05 in both) (Ittermann ment involving endocrinologists, surgeons, et al. 2012). Appropriate control of hypothyroid biochemists and anaesthesiologists with signifi- state with thyroid hormone replacement results in cant expertise in the management of this uncom- normalisation of blood pressure as many of the mon disease. other abnormalities related to the disease.

8 Thyroid Diseases 8.2 Hyperthyroidism

Thyroid disorders are the second most common Hyperthyroidism results from excessive causes of endocrine disease after diabetes circulating levels of thyroid hormones. Primary mellitus. Although not associated with severe hyperthyroidism from diseases of the thyroid hypertension, both hypothyroidism and hyper- gland is usually autoimmune. Subclinical hyper- thyroidism can cause high BP in some patients. thyroidism, a state of suppressed thyrotropin levels and normal thyroid hormones, is seen in up to 1 % of men and 1.5 % of women older than 60 years (Ittermann et al. 2012; Helfand 2004). The clinical 8.1 Hypothyroidism features of hyperthyroidism are mostly opposite to hypothyroidism, familiar to most physicians, and Hypothyroidism is a common endocrine disease therefore, not described here. with higher prevalence towards older Hyperthyroidism increases cardiac output by age-groups. Subclinical hypothyroidism (without 50–300 % because of a decrease in systemic overt symptoms and signs) affects about 3-8 % vascular resistance, an increase in heart rate, of adult population that reaches around 10 % by increase in left ventricular output, and an the sixth decade of life (Hollowell et al. 2002; increase in the blood volume (Klein and Ojamaa Fatourechi 2009). Overt hypothyroidism presents 2001). Therefore, systolic hypertension with a with multiple clinical features such as lethargy, widened pulse pressure (opposite to the hypothy- constipation, cold intolerance, menstrual roid state) is the usual clinical manifestation in abnormalities, weight gain, dry skin, hair loss, hyperthyroidism. Prompt resolution of hyperten- hoarseness of voice, psychomotor retardation, sion is usually observed in patients with hyper- neuropsychiatric abnormalities, bradycardia and thyroidism after full control of the disease by in severe cases, myxedema and coma. medical or surgical intervention. Endocrine Hypertension

9 Primary Hyperparathyroidism (Nainby-Luxmoore et al. 1982; Ringe 1984; Broulik et al. 2011), while others without a posi- Primary hyperparathyroidism (PHPT) results tive effect (Rapado 1986; Lind et al. 1991). from increase in secretion of parathyroid hor- Although improvement of the substantial cardiac mone (PTH) from the parathyroid glands. The and vascular dysfunction related to symptomatic estimated incidence of PHPT in the United States PHPT was observed in patients after parathyroid- from 1993 to 2001 was approximately 22 cases ectomy (Agarwal et al. 2013), PHPT-related per 100,000 person years (Wermers et al. 2006; hypertension is not an indication for surgery Marcocci and Cetani 2011). Prevalence of PHPT currently. can be as high as 2.1 % on older individuals (Lundgren et al. 1997). Many cases are asymp- tomatic, and the diagnosis is often made while 10 Iatrogenic Hormone investigating patients for the cause of mild Manipulation hypercalcemia. Sometimes patients may present with severe hypercalcemia, renal stones, osteo- Therapeutic administration of hormones for dif- porosis and fractures, acute kidney injury, and ferent medical conditions can result in develop- chronic renal impairment. ment of/or worsening of hypertension. Frequent association between PHPT and Glucocorticoid administration is the most com- hypertension is well documented even among mon cause for drug-induced endocrine hyperten- patients with mild PHPT (Silverberg sion. Prevalence of Steroid-induced hypertension et al. 2009). Mean 24-h BP (both systolic and increases with age, and new-onset hypertension diastolic) obtained by ambulatory monitoring was observed in 22 % of cases receiving long- was significantly higher, with a higher preva- term steroids for giant-cell arteritis (Proven lence of hypertension in 47 % of patients with et al. 2003). Studies on the effect of hormone PHPT compared to controls (Letizia et al. 2005). replacement on hypertension in post-menopausal Plasma ionised calcium levels was found to be an women showed conflicting results with positive independent risk factor for elevated BP in multi- (Preston 2009), and negative effects (Akkad ple linear regression model in this study. The et al. 1997). Although testosterone can theoreti- probable mechanism of hypertension in PHPT cally increase BP by the effects of vasoconstric- is increased arterial stiffness in these patients. A tion and stimulation of renin-angiotensin- recent large community-based cohort study aldosterone system (Kienitz and Quinkler indicated that plasma calcium levels were inde- 2008), testosterone replacement resulted in pendently associated with higher arterial stiff- improvement of the parameters of metabolic syn- ness, and the PTH levels with arterial blood drome including hypertension in hypogonadal pressures (Hagstrom€ et al. 2015). men (Janjgava et al. 2014). Generally, mild cases of PHPT are not treated A classification of different endocrine by parathyroid surgery, and the follow up is with disorders causing hypertension, their common regular monitoring of calcium, renal function and clinical presentations, important diagnostic bone mineral density assessments in the endo- features and treatment are summarized in crine outpatient clinics. Hypertension is managed Table 1. by conventional antihypertensive drugs as in a normal case. Thiazide diuretics should be avoided as antihypertensives because of the risk 11 Conclusions of worsening hypercalcemia. There is conflicting data on the improvement of hypertension in Endocrine hypertension is a cause of secondary patients undergoing parathyroidectomy for hypertension in a significant proportion of cases. PHPT with some studies showing benefit Some clinical characteristics of the patients may Table 1 The causes of endocrine hypertension, their common clinical characteristics, diagnostic features & treatment Common clinical Clinical condition characteristics Diagnostic features Treatment Primary Hypermineralocorticoidism Primary Aldosterone Resistant HTN & Raised ARR, CT – Adenoma removal/MR mineralocorticoid aldosteronism producing adenoma adrenal adenoma adrenal adenoma, AVS antagonist Excess (APA) – lateralisation to side of adenoma Idiopathic Resistant HTN Raised ARR, CT MR antagonist hyperaldosteronism adrenal – negative Type 1 familial Resistant HTN and Raised ARR; HTN & Glucocorticoid therapy hyperaldosteronism strong family history aldosterone suppressed (FH-I) by dexamethasone Congenital 11-β-hydroxylase HTN, virilisation and Elevated DOC & Glucocorticoids; adrenal deficiency precocious puberty 11-deoxycortisol. (MR antagonists in hyperplasia Abnormal genes some cases) 17-α-hydroxylase Hypokalemia, HTN & High ACTH, DOC & Glucocorticoids & sex deficiency sexual infantilism gonadotropins, low steroids when necessary androgens, estrogens. Abnormal genes Increased Liddle syndrome (pseudo- HTN, hypokalemia & Low aldosterone & Low sodium minrealocorticoid action aldosteronism) alkalosis with family rennin, ENaC gene diet + amiloride or history mutation triamterine Syndrome of apparent Hypokalemia, HTN, & Low aldosterone & MR antagonists +/ mineralocorticoid excess (AME) alkalosis. Severe renin, high ratio of urine thiazide diuretics & disease: growth failure cortisol/cortisone small doses of and short stature in metabolites & dexamethasone

children HSD11B2 gene Buch H.N. and Pappachan J.M. mutation Pseudohypoaldosteronism type HTN, hyperkalemic- low renin, normal or Dietary sodium 2 (Gordon syndrome) hyperchloremic elevated aldosterone restriction and thiazide metabolic acidosis level, abnormal gene diuretics mutations Geller syndrome Early onset HTN & Low plasma aldosterone Sodium restriction & worsening of HTN & renin & activating amiloride for HTN during pregnancy mutation of MR norn Hypertension Endocrine

Pheochromocytomas and paragangliomas (PCC & PGL) Episodic symptoms with High plasma and Tumor removal with HTN. Adrenal urinary metanephrines. surgical precautions. incidentaloma PCC or PGL on imaging Long-term follow up Glucocorticoid excess (Cushing’s syndrome) HTN with cushingoid High plasma and Metyrapone, appearance, diabetes, urinary cortisol, ACTH antihypertensives, metabolic syndrome, – high in central & surgery to remove infection susceptibility ectopic; low in adrenal ACTH source or & osteoporosis Cushing’s. Imaging adrenalectomy evidence of source of high ACTH or adrenal disease. Acromegaly Coarse body features High levels of insulin- Pituitary adenoma with facial & limb like growth factor 1 & removal by surgery if enlargement, HTN, growth hormone (GH), possible. GH diabetes, sleep apnoea, lack of GH suppression suppression by SRL visual field defects & on glucose tolerance test therapy & arthritis & pituitary adenoma on antihypertensives imaging Thyroid diseases Hypothyroidism Diastolic HTN, weight High levels of Thyroid hormone gain & coarse features thyrotrophin with low/ replacement low-normal level of thyroid hormones Hyperthyroidism Systolic HTN with Low levels of Antithyroid drugs, weight loss thyrotrophin with high/ thyroidectomy/radio- high-normal level of iodine therapy thyroid hormones Primary hyperparathyroidism HTN, asymptomatic Hypercalcemia with Parathyroidectomy in disease in many, raised parathyroid selected cases. Close fractures & hormone level and monitoring & periodic osteoporosis, acute/ parathyroid adenoma or evaluation in mild cases chronic renal failure hyperplasia Iatrogenic hormone manipulation HTN with history of History and blood Antihypertensives and hormone treatment pressure elevation withdrawal of hormone if feasible HTN hypertension, ARR aldosterone to renin ratio, MR mineralocorticoid receptor, ENaC epithelial sodium channel, CT computed tomography, ACTH adrenocorticotrophin J.M. Pappachan and H.N. Buch help clinician to suspect an endocrine cause for Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, hypertension. Primary aldosteronism is the most Maldonado M et al (2012) A 12-month phase 3 study of pasireotide in Cushing’s disease. New Engl J Med common cause for endocrine hypertension. The 366:914–924 Endocrine society guidelines on individual Colao A, Bronstein MD, Freda P et al (2014) Pasireotide diseases that cause endocrine hypertension may versus octreotide in acromegaly: a head-to-head supe- help clinician to appropriately evaluate and riority study. J Clin Endocrinol Metab 99:791–799 Correa R, Salpea P, Stratakis C (2015) Carney complex: manage patients. an update. Eur J Endocrinol 173:M85–M97 Daniel E, Newell-Price JD (2015) Therapy of endocrine disease: steroidogenesis enzyme inhibitors in References Cushing’s syndrome. Eur J Endocrinol 172:R263– R280 Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert Agarwal G, Nanda G, Kapoor A, Singh KR, Chand G, K et al (2015) Effectiveness of metyrapone in treating Mishra A et al (2013) Cardiovascular dysfunction in Cushing’s Syndrome: a retrospective multicenter symptomatic primary hyperparathyroidism and its study in 195 patients. 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