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Fig. 9.1 Adrenal steroid pathway. The adrenal cortex produces three major types of steroids: mineralocorticoids, glucocorticoids, and
androgen precursors. Each group is produced in distinct layers of the adrenal cortex, which are organized concentrically. Adrenocorticotropic hormone (ACTH) and angiotensin II (Ang II) prompt steroidogenesis by increasing the expression and activating the steroidogenic
acute regulatory (StAR). StAR mobilizes cholesterol to the inner mitochondrial membrane where it is then converted to pregnenolone by
the cholesterol side-chain cleavage enzyme (CYP11A1). The enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) inactivates
cortisol to cortisone in peripheral tissues, including the kidney. HSD3B2, 3β-Hydroxysteroid dehydrogenase type 2; CYP17A1, 17αhydroxylase or 17,20-lyase; CYB5A, cytochrome b5 type A; SULT2A1, sulfotransferase type 2A1.
Box 9.1 Causes of Glucocorticoid Hypertension
Glucocorticoid Excess (Cushing
Syndrome)
• Pituitaryadenoma
Impairment of HSD11B2
• Apparentmineralocorticoidexcesssyndrome
• LicoriceandotherHSD11B2inhibitors
• EctopicACTHsyndrome
• EctopicCRH-producingtumors
• Adrenalcorticaladenomas/carcinomas
• Bilateralmacronodularadrenalhyperplasia
• Primarypigmentednodularadrenalhyperplasia
• Iatrogenic
ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormones ; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2.
• EctopicCRH-producingtumors:<1%
ACTH-independent: 20%
• Adrenalcorticaladenoma:14%
• Adrenalcorticalcarcinoma:4%
• Bilateralmacronodularadrenalhyperplasia:<2%
• Primarypigmentednodularadrenalhyperplasia:<1%
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7. Describe the clinical manifestations in Cushing syndrome.
The clinical manifestations depend on the severity and the duration of hypercortisolism but most commonly occur
gradually. The manifestations are most severe in patients with ectopic ACTH production, typically from a neuroendocrine tumor located in the lungs. Conversely, patients with adrenal adenomas often have mild hypercortisolism
with subtle clinical manifestations. Staple physical signs found in Cushing Syndrome include central obesity; moon
face; dorsocervical adiposity (also known as “buffalo hump”); wide, purple striae, commonly on the abdomen,
thighsand/oraxillaryareas;ecchymoses;andproximalmuscleatrophy.
Common cushingoid features:
• Centralobesity:70%to85%
• Muscleweakness/atrophy:45%to82%
• Moonface:81%to89%
• Violaceousstriae:44%to72%
• “Buffalohump”:51%to53%
Other manifestations
• Acne:19%to27%
• Hirsutism:75%
• Bruising:21%to52%
• Menstrualirregularities:78%
• Decreasedlibido:24%
• Boneloss/fractures:40%to70%
• Hyperglycemia:45%to70%
• Hypertension:70%to85%
• Insomnia:29%
• Impairedcognition:22%
• Hypokalemia:22%to33%
• Venousthromboembolism:20%
• Immunosuppression/opportunisticinfections:21%to51%
8. Who should be tested for Cushing syndrome?
The diagnosis is typically pursued when some of the manifestations listed earlier come to the attention of medical
providers, patients, or family members. In addition, patients with incidentally found adrenal nodules are commonly
screened for mild adrenal cortisol excess. Family members of those affected by genetic conditions known to
predispose to Cushing Syndrome have a higher medical scrutiny for this disease.
9. How do we test for Cushing syndrome?
When a clinical suspicion exists, the initial step is to exclude exposure to exogenous glucocorticoids. Next, the
diagnosis is established by hormonal tests. Because normal hormonal fluctuations can be caused by many different conditions, at least two of three abnormal tests are required to establish the diagnosis. The following tests are
conducted when Cushing Syndrome is suspected:
• 1-mgdexamethasonesuppressiontest.Administer1mgbetween11:00p.m.andmidnight,thendraw8:00
a.m. serum cortisol. This test is commonly used as an initial screening test, particularly in patients with incidentally found adrenal nodules.
• 24-hoururinaryfreecortisolexcretion(thistestisoftennormalinpatientswithmildhypercortisolism).
• Late-nightsalivarycortisol.
• Late-nightserumcortisol.
10. What is pseudo-Cushing syndrome?
Cortisol is a stress hormone, and several conditions can lead to hypercortisolism due to overactivation of the
hypothalamus-pituitary-adrenal axis: chronic exercise, severe physical illness, morbid obesity, malnutrition,
alcoholism, and poorly controlled diabetes mellitus. When such conditions are associated with clinical features
common to Cushing Syndrome, they are referred to as “pseudo-Cushing Syndrome.”
11. What are some other caveats of hypercortisolism testing?
Testing should take into account the possibility of circadian rhythm disruptions (such as night-shifts or recent
travel across time zones).
Many medications can influence testing for Cushing Syndrome:
• Estrogensandmitotaneincreasecortisol-bindingglobulinlevelsandcauseanelevatedtotalserumcortisol.
Free cortisol, as measured in saliva or urine, is not impacted.
• CYP3A4inducers(e.g.,phenobarbital,carbamazepine,rifampin,etc.)acceleratethemetabolismofdexametha-
sone and lead to false positive results with dexamethasone suppression tests. Measurement of serum dexamethasone level is useful to ascertain if an incompletely suppressed cortisol might be a true or false positive
result.
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Fig. 9.2 Algorithm for establishing the etiology of Cushing syndrome. In patients with adrenocorticotropic hormone (ACTH)-depen-
dent Cushing syndrome, pituitary MRI, 8-mg dexamethasone suppression test (DST), and inferior petrosal sinus sampling (IPSS) can be
used in conjunction to distinguish between Cushing disease (pituitary adenoma) and ectopic ACTH-producing tumors. CT, Computed
tomography; MRI, magnetic resonance imaging.
Box 9.2 Medical Treatment for Cushing Syndrome
Adrenal Enzyme Inhibitors
• Ketoconazole
• Metyrapone
Adrenolytic
• Mitotane
12. How is the etiology of Cushing Syndrome established?
Once endogenous cortisol excess is established as described previously, the next step is to obtain an ACTH, which
will guide the subsequent steps in localizing the source of cortisol excess (Fig. 9.2). When ACTH is suppressed,
adrenal imaging is obtained. When ACTH is not suppressed, that indicates a pituitary or ectopic ACTH (or, rarely,
CRH)-producing tumor. The evaluation of such cases is summarized in Fig. 9.2.
13. What are the treatment options for Cushing syndrome?
• SurgeryisthepreferredandonlycurativetreatmentforallformsofendogenousCushingSyndrome:
• pituitary surgery for Cushing disease;
• adrenalectomy for cortisol-producing adenomas or carcinomas;
• resection of the ACTH- or CRH-producing tumor in ectopic Cushing Syndrome;
• when the primary source of Cushing Syndrome is not found or fully resectable and the clinical manifesta-
tions are severe, bilateral adrenalectomy can be done.
• RadiationtherapyisreservedforunresectableorresidualCushingdiseaseoradrenalcorticalcarcinomas.
• Medicaltreatment(Box 9.2) is used to control hypercortisolism and its complications prior to surgery while
awaiting the effects of radiation or for occult ectopic Cushing Syndrome.
Glucocorticoid Receptor Inhibitor
• Mifepristone
Others (for Cushing disease only)
• Pasireotide
• Cabergoline
APPArenT minerALoCorTiCoid eXCess syndrome
14. What is apparent mineralocorticoid excess syndrome?
Apparent mineralocorticoid excess (AME) syndrome is an autosomal recessive disease characterized by defects
in the gene encoding HSD11B2. In these rare inherited HSD11B2 deficiencies, cortisol is not inactivated by target
tissues expressing MRs, including the kidneys, allowing physiological concentrations of cortisol to activate MR.
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15. Describe the clinical and laboratory features of AME syndrome.
AME syndrome shares several clinical and laboratory features with primary aldosteronism: hypertension, hypokalemia, metabolic alkalosis, and low renin. In contrast with primary aldosteronism, however, plasma aldosterone
concentration is low. Affected patients typically present with early-onset severe hypertension accompanied by
low birth weight, failure to thrive, renal insufficiency, and hypercalciuria. A milder phenotype occurs in adults with
compound heterozygous mutations.
16. How is AME syndrome diagnosed?
When the diagnosis of AME syndrome is suspected based on clinical and initial laboratory features described earlier,
a24-hoururinemeasurementofcortisol-to-cortisoneratioisusefulinmakingthediagnosis.InthepresenceofHSD11B2defects,thenormal24-hoururinecortisol/cortisoneofapproximately0.3to0.5isippedinfavorofcortisol,
whichcannotbeappropriatelyinactivated.Typical24-hoururinarycortisol-to-cortisoneratiosare5inchildrenand
18 in adults with AME syndrome. AME syndrome can also be confirmed with commercially available genetic testing.
17. What treatment options are available for patients with AME syndrome?
The primary treatment strategy in AME syndrome is to counteract the MR activation by cortisol. MR antagonists,
such as spironolactone and eplerenone, are preferred. Amiloride and triamterene, which block the ENaCs in the
distal convoluted tubules and collecting ducts of the nephrons, are other alternatives. Suppression of endogenous
cortisol synthesis with low-dose dexamethasone, a synthetic glucocorticoid with negligible mineralocorticoid activity, has also been suggested. Dexamethasone, however, is a potent glucocorticoid with propensity for systemic
side effects, including persistence of hypertension and hypokalemia. A thiazide diuretic can be used for patients
with AME syndrome and hypercalciuria. Renal transplant has also been reported to cure AME syndrome.
18. Are there nongenetic forms of HSD11B2 dysfunction?
Several exogenous and endogenous compounds can inhibit HSD11B2, leading to hypertension in a similar manner
to AME syndrome.
19. What are the most common inhibitors of HSD11B2?
The most recognized HSD11B2 inhibitors are glycyrrhetinic acid, which is a compound found in licorice, and carbenoxolone, a derivative of glycyrrhetinic acid. Licorice extracts are used in sweets, particularly in the Middle East
and in parts of Europe and Asia. Chronic consumption of licorice leads to an AME syndrome–like phenotype.
Several other exogenous and endogenous compounds have HSD11B2-inhibitory effects and collectively are
termed glycyrrhetinic acid–like factors (GALFs). Endogenous GALFs might serve as regulators of sodium and blood
pressure. Several antifungal agents (itraconazole and posaconazole) and carbenoxolone also inhibit HSD11B2 (see
Chapter 13: Drug-Induced Hypertension).
KEY POINTS
1. Cortisol circulates in higher concentrations than aldosterone; whereas cortisol and aldosterone have similar
affinity for the MRs, the enzyme HSD11B2 serves as a gatekeeper by inactivating cortisol to cortisone.
2. In Cushing syndrome, supraphysiological concentrations of cortisol lead to activation of both glucocorticoid
and MRs due to the saturation of HSD11B2. This leads to sodium and water retention, intravascular volume
expansion, and hypokalemia.
3. AME syndrome is a rare inherited disease that displays clinical manifestations similar to primary aldosteronism,
except that plasma aldosterone concentrations are low. AME syndrome is caused by defects in the HSD11B2
gene, which prevent the inactivation of cortisol in target tissues and allow cortisol to overactivate the MRs.
4.ExogenousglucocorticoidsandseveralinhibitorsofHSD11B2,includinglicorice,alsoleadtoMR–mediated
hypertension.
BiBLiogrAPhy
Adamidis A, Cantas-Orsdemir S, Tsirka A, et al. Apparent mineralocorticoid excess in the pediatric population: report of a novel
pathogenic variant of the 11β-HSD2 gene and systematic review of the literature. Pediatr Endocrinol Rev.2019;16(3):335–358.
Athimulam S, Lazik N, Bancos I. Low-renin hypertension. Endocrinol Metab Clin North Am.2019;48(4):701–715.
FareseJrRV,BiglieriEG,ShackletonCH,etal.Licorice-inducedhypermineralocorticoidism.N Engl J Med.1991;24(32517):1223–1227.
Isidori AM, Graziadio C, Paragliola RM, et al. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on
cardiovascular complications. J Hypertens.2015;33(1):44–60.
Ma X, Lian QQ, Dong Q, et al. Environmental inhibitors of 11β-hydroxysteroid dehydrogenase type 2. Toxicology. 2011;29(2853):83–89.
Morris DJ, Latif SA, Hardy MP, et al. Endogenous inhibitors (GALFs) of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2:
derivatives of adrenally produced corticosterone and cortisol. J Steroid Biochem Mol Biol.2007;104(3–5):161–168.
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NiemanLK,BillerBM,FindlingJW,etal.ThediagnosisofCushing’ssyndrome:anEndocrineSocietyclinicalpracticeguideline.J Clin
Endocrinol Metab.2008;93(5):1526–1540.
NiemanLK,BillerBM,FindlingJW,etal.TreatmentofCushing’ssyndrome:anEndocrineSocietyclinicalpracticeguideline.J Clin
Endocrinol Metab. 2015;100(8):2807–2831.
Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab.2003;88(6):2384–2392.
SharmaST,NiemanLK,FeeldersRA.Cushing’ssyndrome:epidemiologyanddevelopmentsindiseasemanagement.Clin Epidemiol.
2015;17(7):281–293.
PHEOCHROMOCYTOMA AND
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PARAGANGLIOMA
Anand Vaidya, MD, MMSc
QUESTIONS
1. What are pheochromocytoma and paraganglioma?
• Pheochromocytomasandparagangliomasaredifferentiatedbasedonanatomicallocation.
• Pheochromocytomasareneuroendocrinetumorsthatarisefromtheadrenalmedulla.
• Paragangliomasareneuroendocrinetumorsthatarisefromextraadrenalsympatheticorparasympathetic
paraganglia.Thereforeparagangliomascanbefoundanywherefromthebaseoftheskulltothepelvis.
2. What are the differences between pheochromocytoma and paraganglioma?
• Beyondtheanatomicaldifferencesdescribedearlier,pheochromocytomaandparagangliomacanexhibit
biochemicaldifferences.
• Catecholaminesaresynthesizedfromatyrosinesubstrate,whichisultimatelytransformedtoproducedopamine,norepinephrine,andepinephrine.
• Catecholaminestypicallycirculateinlowconcentrationsandhavepulsatileandvariablelevelsandshort
half-lives.
• Catecholaminesarefurthermetabolizedtoinactivemetabolitesthathavelongandstablecirculating
half-lives.Thesemetabolitesaretermed“metanephrines.”Norepinephrineismetabolizedtonormetanephrine,
andepinephrineismetabolizedtometanephrine.Together,thesetwometabolitesarereferredtoas
metanephrines.Whenorderingtestingformetanephrines,theresultsappearasfractionatedconcentrationsof
normetanephrineandmetanephrine.Thisterminologycanbeconfusingasthesingularandpluraldistinctions
impartdifferentmeanings.
• Dopamineismetabolizedtotheinactivemetabolitetermed“methoxytyramine”;however,theuseofthis
metaboliteisnotcommoninclinicalcare,andthismeasurementisnotwidelycommerciallyavailable.
• Theadrenalmedullaexpressestheenzymaticmachinerytosynthesizeallthecatecholamines.Therefore
pheochromocytomascanexhibitabiochemicalphenotypethatincludeselevatednormetanephrineand/or
elevatedmetanephrine(i.e.,apheochromocytomacansecretenorepinephrineand/orepinephrine).
• Incontrast,paragangliomasdonotexpresstheenzymethatconvertsnorepinephrinetoepinephrineand,
therefore,donotsecreteepinephrine(i.e.,paragangliomascansecretedopamineand/ornorepinephrine).
• Therefore,inpractice,elevatednormetanephrinelevelscouldsignifyapheochromocytomaoraparaganglioma,
whereaselevatedmetanephrinelevelscouldindicateapheochromocytomabutnotaparaganglioma.
• Finally,itisworthrememberingthatpheochromocytomasandparagangliomascanbenonfunctional(i.e.,
neuroendocrinetumorsthatdonotsecretecatecholaminesormetanephrines).
1
CHAPTER 10
3. What causes pheochromocytoma and paraganglioma?
• Wenowunderstandthat35%to40%ofallpheochromocytomaandparagangliomaareattributedtoaninheritable(i.e.,germline)pathogenicgeneticmutation.
• Morethanadozengeneticmutationshavebeenassociatedwithpheochromocytoma-paragangliomasyndromes.Beyonddevelopingtheseneuroendocrinetumors,somegeneticsyndromespredisposetodeveloping
othertumorsandcancersaswell.
• Forthisreason,itisrecommendedthatallpatientswithpheochromocytomaandparagangliomabeadvisedto
considergenetictesting.Thediscoveryofageneticmutationoftendictatesatumorsurveillanceprogramthat
involvesimaging.
• Thefollowingaregenesassociatedwithpheochromocytoma-paragangliomasyndromes:
• VHL(von-HippelLindausyndrome)
• RET(multipleendocrineneoplasiatype2)
• NF1(neurobromatosistype1)
• SDHA(succinatedehydrogenasesubunitA)
• SDHB(succinatedehydrogenasesubunitB)
• SDHC(succinatedehydrogenasesubunitC)
1–4
1,5
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• SDHD(succinatedehydrogenasesubunitD)
• SDHAF2(succinatedehydrogenasesubunitAF2)
• TMEM127(transmembraneprotein127)
• MAX(myc-associatedfactorX)
• FH(fumaratehydratase)
• EPAS1(hypoxiainduciblefactor2a)
• Itisimportanttonotethatthemajorityofpatientswithagermlinemutation,orhereditarypheochromocytomaparagangliomasyndrome,donotdisplayspecicphenotypicfeaturestohelpguidegenetictesting.Therefore
unlessthereareobviousphenotypicfeaturesindicativeofaspecicgeneticsyndrome(seeTable),genetic
testingshouldbeconductedusingacomprehensiveandunbiasedapproach(i.e.,genepanels).
• Forpatientswhoarefoundtohaveapathogenicgermlinemutation,screeningoffamilymembersshouldbe
recommended.Inaddition,animagingandbiochemicalsurveillanceprogramshouldberecommendedto
monitorforpheochromocytoma,paraganglioma,andotherrelatedtumors.
1,5
• Patientsshouldbemanagedbyamultidisciplinaryteamwithexpertiseingenetictestingandimagingsurveillanceprotocols.
4. What other tumors are associated with hereditary pheochromocytoma-paraganglioma
syndromes?
• Alistofthemostcommongermlinemutationsandthetumorsthatcanoccurarelistedinthefollowingtable.
Notably,thetumorsincludebothbenignandmalignantentities.
Gene Syndrome Key Features and Associated Tumors
VHL
VonHippel-Lindau Pheochromocytoma(PHEO),paraganglioma(PGL),
hemangioblastoma,renalcellcarcinoma(RCC),renal
andpancreaticcysts,endolymphaticsactumor,
neuroendocrinetumors
SDHA
NA PHEO,PGL,gastrointestinalstromaltumors(GIST),possible
pituitaryadenoma,andRCC
SDHB
SDHC
SDHD
SDHAF2
HIF2A
PHD2
FH
NF1
PGL4 PHEO,PGL,GIST,RCC,possiblepituitaryadenoma
PGL3 PHEO,PGL,GIST,RCC,possiblepituitaryadenoma
PGL1 PHEO,PGL,GIST,RCC,possiblepituitaryadenoma
PGL2 PHEO,PGL, possiblyothers
Familialerythrocytosis
Zhuang-Pacaksyndrome
Familialerythrocytosis
Hereditaryleiomyomatosis
andrenalcellcancer
Neurobromatosis,
type1
3
PHEO,PGL,polycythemia,somatostatinoma
4
PHEO,PGL,polycythemia
PHEO,cutaneousleiomyomata,uterineleiomyomata
(broids),RCC
PHEO,PGLneurobromas,opticgliomas,malignant
peripheralnervesheathtumors,astrocytomas,leukemia,
breastcancer,boneylesions,shortstature,relative
macrocephaly,developmentaldelaysinsomeindividuals
RET
Multipleendocrineneoplasia,
type2a
Multipleendocrineneoplasia,
type2b
PHEO,PGL,medullarythyroidcarcinoma,parathyroid
hyperplasia/adenoma
PHEO,PGL,medullarythyroidcarcinoma,oralmucosal
neuromas,marfanoidhabitus,distinctfacialfeatureswith
largelips,gastrointestinalganglioneuromas
TMEM127
MAX
NA PHEO,possibleRCC
NA PHEO,RCC,possiblyothers
5
5. What are the symptoms and signs of pheochromocytoma and paraganglioma?
• Excessivecatecholamineproductioncaninduceepisodichyperadrenergicsymptoms.Patientsmaydescribe
episodicpalpitations,sweating,headaches,anxiety,orpanicattacks.Patientsmayhavepallor(dueto
vasoconstriction).
• Flushingisnotasymptomorsignofcatecholamineexcess.
• Bloodpressuremaybechronicallyelevatedand,ifcheckedduringanepisode,maybeveryelevated.However,
itisworthnotingthatlabilebloodpressureattributabletocausesotherthanapheochromocytomaorparagangliomaisfarmorecommon.Thus,althoughpheochromocytomaandparagangliomaareconsidered“secondary
causesofhypertension,”itisworthnotingthatmostcausesoflabilehypertensionarenotpheochromocytoma
orparaganglioma.
• Hyperglycemiaorworseningofglycemiccontrolmaybeobserved.
• Orthostatichypotensioncanbeobserved.Catecholamineexcesscancauseanatriuresisandvolumedepletion,
whichmayresultinbloodpressuredecreaseswithuprightposture.Althoughorthostatichypotensionmaybe
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seeninmoreseverecasesofpheochromocytomaandisoftenconsideredtobeaclassicnding,mostcases
inthecurrenteraarediagnosedatarelativelyearlystage(orincidentally)andusuallydonothaveappreciable
orthostatichypotension.
• Importantly,theincidenceofasymptomaticpheochromocytomaandparagangliomaisincreasingasthese
tumorsarefrequentlydetectedincidentallyoncross-sectionalimagingpriortothedevelopmentofclinical
symptoms.
6. Which patients should be tested for pheochromocytoma and paraganglioma?
• Patientswithepisodichyperadrenergicsignsorsymptoms,describedpreviously.
• Patientswithanadrenalmassthatappearslipid-poor(unenhancedHounseldunits[HU]>10oncomputed
tomography[CT]ornolossofsignalonin-and-out-of-phasemagneticresonanceimaging[MRI]).
• Patientswithlabileand/orseverehypertensionthatisnotattributabletomedicationnonadherenceorother
secondarycausesofhypertension.
• Patientswhodevelopahypertensiveoradrenergicepisodetriggeredbycertainmedications(inductionof
anesthesia,opioids,metoclopramide,andothers).
• Patientswithaknowninheritablesyndromeorgeneticmutationassociatedwithpheochromocytomaorparaganglioma.
7. How are pheochromocytoma and paraganglioma diagnosed?
• Currently,themajorityofpheopchromocytomasarediagnosedincidentallyoncross-sectionalimagingin
asymptomaticindividuals.Theimagingfeaturesareoftenthemostdiagnosticinthesecases.
• Thediagnostictestofchoiceinpatientswhoexhibithyperadrenergicsymptomsorepisodesistomeasure
fractionatedmetanephrinesineithertheplasmaortheurine.
6
• Measuringplasmametanephrinesor24-hoururinarymetanephrinesarebothappropriateandhavesimilar
diagnosticaccuracy.Thesensitivityis∼97%,andthespecicityis∼90%.Thereforethelikelihoodofmissing
atruesymptomaticpheochromocytomaorparagangliomaisverylow;however,theriskoffalse-positivetestingisnottrivial.
6
• Thenegativepredictivevalueofbothtestsisveryhigh.
• Plasmacatecholaminesarenotreliableandarenottypicallyrecommended.
• 24-hoururinaryfractionatedcatecholaminescanbemeasuredreliablyandmayprovideausefuladjunctwhen
measuring24-hoururinarymetanephrines.
• Ingeneral,measuringplasmametanephrinesisthequickestandeasiestwaytoinitiatethediagnosticevaluationasitinvolvesonlyphlebotomy.
• Metanephrinesshouldideallybemeasuredbylaboratoriesthatuseliquidchromatographywithtandemmass
spectroscopy.
8. Can false-positive testing results occur?
• Yes.False-positivetestingisoneofthemostcommonpitfallsintheevaluationofpheochromocytomaand
paraganglioma.
• Theupperlimitofthereferencerangeofmetanephrinesdoesnotrepresentahardandxedbiologicalboundaryof“normal”versus“abnormal;”rather,itmustbeinterpretedinthecontextoftheclinicalscenarioand
expectedphysiology.
• Atruesymptomaticpheochromocytomaorparagangliomaalmostalwaysexhibitsmarkedelevationsinlevels
ofmetanephrines.Inmostcases,afunctionaltumorcausingsymptomswillexhibitfourfoldorgreaterelevationsinmetanephrineand/ornormetanephrineabovetheupperlimitofthereferencerange.Rarely,atrue
functionaltumorwillexhibittwofoldorgreaterelevations.
• False-positiveelevationsinmetanephrinesoccurin∼10%to15%ofthepopulationandaregenerallyless
thantwofoldabovetheupperlimitofthereferencerange.Rarely,false-positivecanbeseentoriseashighas
three-tofourfoldtheupperlimitofthereferencerange.
• Themostcommoncauseoffalse-positiveelevationsinmetanephrinesarefactorsthatincreasesympathoadrenergicactivity.Thesefactorscanincludepain,stress,anxiety,illness(includinghospitalization),upright
posture(includingseatedpostureduringphlebotomy),theuseofsympathomimeticagents(includinglevodopa
andvasopressors),andtheuseofcatecholamine-reuptakeinhibitorsfordepression.
• Medicationsfordepressionoranxietythatinhibitthereuptakeofcatecholaminesareaverycommon
causeoffalse-positiveelevationsinmetanephrines.Theseincludenorepinephrine-reuptakeinhibitorsand
selective-serotoninreuptakeinhibitors.Attimes,thesemedicationscancausetwo-tofourfoldelevationsin
metanephrines.Itisimportanttorecognizethispotentialsourceofafalse-positivebeforeundertakingtesting.
• Thenegativepredictivevalueofmetanephrinesisveryhigh.Thereforemetanephrinelevelsthatreturninthe
normalreferencerangeprovidestrongreassurancethatthesignsandsymptomsarenotattributabletoa
functionalpheochromocytomaorparaganglioma.
• Incidentallydiscoveredpheochromocytomasareincreasinglycommonwiththeuseofcross-sectionalimaging.
Often,incidentalpheochromocytomasaredetectedbeforetheonsetofclinicalsymptoms(i.e.,subclinicalor
nonfunctional).Thediagnosisshouldinvolvetheuseofradiographiccharacteristics(describedearlierandlater)
incombinationwithmetanephrines.
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9. When and how should imaging be used in the evaluation of pheochromocytoma and paraganglioma?
• Thediagnosisofasymptomaticpheochromocytomaorparagangliomaisbiochemical.Imagingshouldnotbe
pursueduntilabiochemicaldiagnosisisconrmed.Therefore,inmostinstances,imagingshouldbeconsideredalocalizationtest,notadiagnostictest.
• Pheochromocytomaandparagangliomasmayalsobedetectedincidentallyonimaging,inwhichcase
biochemicaltestingshouldfollow.Incidentaldiscoveryofthesetumorsoncross-sectionalimagingissteadily
increasing.
• PheochromocytomasandparagangliomasexhibithighattenuationonunenhancedCTimaging.Typicallythese
tumorswillmanifestashavinggreaterthan10HUattenuationonCTdonewithoutcontrastandwilloften
enhancetogreaterthan75HUfollowingintravenouscontrast.Lowunenhancedattenuation(<10HU)provides
strongevidenceagainstapheochromocytoma.OnMRI,thesetumorsoftenexhibitT2hyperintensityandalack
ofsignaldropoutonin-and-out-of-phaseimaging.
• Pheochromocytomasandparagangliomasareusuallyuorodeoxyglucose-avid.However,themostspecic
tracerandmetabolitewhenpositronemissiontomography(PET)imagingisusedisnowDOTATATE,whichhas
thehighestsensitivityandspecicityforneuroendocrinetumors.
• Whennuclearimagingisneeded,metaiodobenzylguanidinehaslargelybeenreplacedbyG68-DOTATATE-PET
imaging.
10. What is the treatment for pheochromocytoma and paraganglioma?
• Surgeryisthetreatmentofchoiceforsymptomaticandfunctionalpheochromocytomasandparagangliomas.
• Giventheepisodicnatureofcatecholaminesecretionandtheriskofintraoperativehemodynamicinstability
thatcouldinducehypertensiveorhypotensivecrises,surgeryshouldbecoordinatedwithanexperiencedteam
thatincludesanendocrinologist,asurgeon,andananesthesiologist.Interdisciplinaryteamswithlargeexperiencebaseshavelowerratesofadverseoutcomes.
• Preoperativealpha-andbeta-adrenergicblockadeshouldbeimplemented,and,whennecessary,theuseof
calciumchannelblockersandmetyrosine(tyrosinehydroxylaseinhibitor)canalsobeeffective.
11. What should I do if I think I have diagnosed a pheochromocytoma or paraganglioma?
• Consultwithanexperiencedendocrinologistand/oradrenalsurgeontoensurethatthediagnosisiscorrect,
thatthelocalizationproceduresareappropriate,andthatanadequatemedicalandsurgicaltreatmentplanis
developed.
• Diagnosisandtreatmentoutcomesareoptimizedwhenpatientsarecaredforbyexperiencedmultidisciplinary
teams.
8
1
4
6
KEY POINTS
• Pheochromocytomaandparagangliomaareneuroendocrinetumorsarisingfromtheadrenalmedullaor
autonomicnervoussystem,respectively,thatarecapableofsecretingcatecholamines.
• Thediagnostictestofchoiceistomeasureplasmaand/orurinarymetanephrines.Symptomaticandfunctional
pheochromocytomasandparagangliomashavesubstantialelevationsinmetanephrinelevels,oftenmultiple
timestheupperlimitofthereferencerange.False-positiveelevationsinmetanephrinesarecommon.
• Imagingisusedtolocalizethepheochromocytomaorparagangliomaafterbiochemicalconrmation;however,
incidentallydiscoveredtumorsareincreasinginincidence.
RefeRences
1. NeumannHPH,YoungJrWF,EngC.Pheochromocytomaandparaganglioma.N Engl J Med.2019;381:552–565.
2. CronaJ,TaiebD,PacakK.Newperspectivesonpheochromocytomaandparaganglioma:towardamolecularclassication.Endocr
Rev.2017;38:489–515.
3. DahiaPL.Pheochromocytomasandparagangliomas,geneticallydiverseandminimalist,allatonce!.Cancer Cell.2017;31:159–161.
4. FishbeinL,LeshchinerI,WalterV,etal.Comprehensivemolecularcharacterizationofpheochromocytomaandparaganglioma.Cancer
Cell.2017;31:181–193.
5. RanaHQ,RainvilleIR,VaidyaA.Genetictestingintheclinicalcareofpatientswithpheochromocytomaandparaganglioma.Curr Opin
Endocrinol Diabetes Obes.2014;21:166–176.
6. LendersJW,DuhQY,EisenhoferG,etal.Pheochromocytomaandparaganglioma:anendocrinesocietyclinicalpracticeguideline.J
Clin Endocrinol Metab.2014;99:1915–1942.
7. NearyNM,KingKS,PacakK.Drugsandpheochromocytoma—don’tbefooledbyeveryelevatedmetanephrine.N Engl J Med.
2011;364:2268–2270.
8. VaidyaA,HamrahianA,BancosI,FleseriuM,GhayeeHK.Theevaluationofincidentallydiscoveredadrenalmasses.Endocr Pract.
2019;25:178–192.
OTHER ENDOCRINE CAUSES OF
https://t.me/med1917
HYPERTENSION
James M. Luther, MD MSCI, and Craig Sussman, MD
QUESTIONS
1. How does acromegaly cause hypertension, and when should it be suspected?
Acromegaly is caused by hypersecretion of growth hormone (GH) usually from the pituitary with peripheral target
organ mediation through the excess production of insulin like growth factor 1 (IGF-1). In addition to the classical
features of this disease like acral growth, jaw prognathism, and gigantism, IGF-1 causes hypertrophy and growth
of multiple other tissues. The heart muscle, adrenal glands, endothelial cell, and kidneys are all targets for excess
IGF-1. Pathologically, this results in cardiomyopathy, adrenal hyperplasia (especially aldosterone excess), intravascular volume expansion, and hyperadrenergic vasoconstriction. Hypertension is a prominent feature in one-third of
patients presenting with acromegaly.1 Hypertension is often multifactorial and driven by sodium and water retention, volume expansion, angiotensin II vasoconstriction, increased sympathetic tone, and increased cardiac output.
These conditions promote hypertension by the combined increase in stroke volume and peripheral resistance.
Other complications of GH excess such as obstructive sleep apnea, diastolic dysfunction, and insulin resistance
also contribute to the secondary hypertension of acromegaly.
The diagnosis of acromegaly can be made by measuring IGF-1 levels especially in patients with acral and
facial features. It is very reasonable to screen with IGF-1 levels in the setting of known complications of acromegaly including hypertension, cardiomyopathy, sleep apnea, hyperhidrosis, and polyosteoarthritis. Confirmation
can be made by the lack of suppression of GH to less than 1 µg/L following an oral glucose load. Radiographic
studies, especially magnetic resonance imaging, can identify a pituitary tumor. Multidisciplinary care involving
cardiology and endocrinology is essential for these patients to ensure proper evaluation, treatment, and prevention
of cardiovascular complications.
2. When should testosterone excess be suspected as a cause of hypertension?
Common clinical signs and symptoms that should raise suspicion of androgen excess or anabolic steroid abuse
are listed in Table 11.1. Virilizing or defeminizing symptoms in women often prompt an evaluation. Androgen
excess is more difficult to detect in men and may only be manifest by testicular atrophy and infertility due to
decreased spermatogenesis. Testosterone is directly synthesized in the testes in men and in much lesser amounts
in the ovaries in women. Testosterone is also derived from the adrenal precursors dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate (DHEAS), and androstenedione, which are converted in peripheral tissues (adipose,
skin) to testosterone. Testosterone may be converted to the more potent androgen dihydrotestosterone by 5-alpha
reductase in peripheral tissues where it activates local androgen receptors, amplifying its local effects.
Endogenous androgen excess can be seen in prolactinoma or polycystic ovarian syndrome (PCOS) or by
secretion from a functional adrenal, testicular, or ovarian tumor. Glucocorticoid resistance or congenital adrenal
hyperplasia can also cause androgen excess due to overproduction of adrenal androgens. The rapid development of androgen excess signs and symptoms should prompt the evaluation for an androgen secreting tumor.
Adrenocortical carcinomas often secrete multiple steroids including DHEA, DHEAS, and cortisol more often than
they are produced by adrenal adenomas. Ovarian or testicular tumors may also secrete androgens. Although total
serum testosterone is usually elevated in all of these conditions, increased DHEA and DHEAS suggest an adrenal
cause of androgen excess.
Although synthetic anabolic androgens are often used to enhance athletic performance, supraphysiological
doses of transdermal or intramuscular testosterone are increasingly used for low libido, impotence, anorexia, or
muscle wasting. When used appropriately to treat true hypoandrogenism, testosterone replacement is associated
with little risk and may be associated with reduced blood pressure and cardiovascular risk.
Anabolic androgen steroids (AAS) derived from testosterone are used by young men (typically aged 20–30)
to increase muscle mass or enhance athletic performance, with the vast majority of use by recreational bodybuild-
2,3
ers.
Other anabolic agents (e.g., human growth hormone, insulin like growth factor (IGF-1), and insulin) are often
used cyclically with AAS and other drugs to increase pain tolerance (e.g., opiates or nonsteroidal antiinflammatory drugs), promote fat loss (e.g., thyroxine), or prevent adverse effects of testosterone excess (e.g., aromatase
inhibitor or estrogen receptor antagonist). Opiates are frequently used with AAS to augment strength training,
therefore opiate dependence is more common in AAS users.3 Additional concern for human immunodeficiency
virus, hepatitis C, and hepatitis B is also warranted in users of injectable AAS. Various androgens are available in
CHAPTER 11
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