Endocrine EmergenciesEndocrine Emergencies

Adrenal InsufficiencyAdrenal Insufficiency

Adrenal physiologyAdrenal physiology

Cortisol functions at target tissues to maintain Cortisol functions at target tissues to maintain vascular resistance, cardiac output, hepatic glucose vascular resistance, cardiac output, hepatic glucose production and free water excretionproduction and free water excretion

Cortisol concentration normally demonstrates Cortisol concentration normally demonstrates diurnal variation and increases during times of diurnal variation and increases during times of medical stressmedical stress

Adrenal physiologyAdrenal physiology

The hypothalamus secretes CRH which in turn The hypothalamus secretes CRH which in turn stimulates ACTH production from the pituitarystimulates ACTH production from the pituitary

ACTH stimlates cortisol production from the adrenal ACTH stimlates cortisol production from the adrenal glandsglands

The hypothalamus and pituitary are influenced by The hypothalamus and pituitary are influenced by negative feedback from cortisolnegative feedback from cortisol

Adrenal physiologyAdrenal physiology

Aldosterone is controlled primarily by angiotensin II Aldosterone is controlled primarily by angiotensin II and circulating potassium levels; ACTH stimulates and circulating potassium levels; ACTH stimulates aldosterone secretion only transientlyaldosterone secretion only transiently

Aldosterone stimulates sodium exchange for Aldosterone stimulates sodium exchange for potassium in the distal nephronpotassium in the distal nephron

Autoimmune Adrenal InsufficiencyAutoimmune Adrenal Insufficiency

The most common cause of adrenal insufficiency in The most common cause of adrenal insufficiency in industrialized countriesindustrialized countries

May occur alone or associated with other autoimmune May occur alone or associated with other autoimmune disordersdisorders– Schmidt’s syndrome or type II autoimmune polyglandular Schmidt’s syndrome or type II autoimmune polyglandular

syndrome. Type I diabetes and autoimmune thyroid syndrome. Type I diabetes and autoimmune thyroid diseasedisease

– Type I autoimmune polyglandular syndrome or APECED Type I autoimmune polyglandular syndrome or APECED (autoimmune polyendocrinopathy-candidiasis-ectomdermal (autoimmune polyendocrinopathy-candidiasis-ectomdermal dystrophy) with chronic mucocutaneous candidiasis and dystrophy) with chronic mucocutaneous candidiasis and hypoparathyroidism.hypoparathyroidism.

Adrenal HemorrhageAdrenal Hemorrhage

Increasingly recognized as a cause of adrenal Increasingly recognized as a cause of adrenal insufficiencyinsufficiency

Meningococcemia (Waterhouse-Friderichsen Meningococcemia (Waterhouse-Friderichsen syndrome) and other forms of sepsissyndrome) and other forms of sepsis

Anticoagulation therapy and coagulation disorders Anticoagulation therapy and coagulation disorders including antiphospholipid antibody syndromeincluding antiphospholipid antibody syndrome

Severe illness and stress; ACTH-induced increases Severe illness and stress; ACTH-induced increases in adrenal blood flow that exceeds the capacity for in adrenal blood flow that exceeds the capacity for venous drainagevenous drainage

InfectionsInfections

TuberculosisTuberculosis HistoplasmosisHistoplasmosis CryptococcusCryptococcus BlastomycosisBlastomycosis ParacocciciomycosisParacocciciomycosis Cytomegalovirus associated with HIVCytomegalovirus associated with HIV

Adrenoleukodystrophy and Adrenoleukodystrophy and AdrenomyeloneuropathyAdrenomyeloneuropathy

X-linked peroxisomal disorders of imparied very long chain fatty X-linked peroxisomal disorders of imparied very long chain fatty acid oxidationacid oxidation

In adrenoleukodystropy the neurological features begin in In adrenoleukodystropy the neurological features begin in childhood and progress to coma and deathchildhood and progress to coma and death

Adrenomyeloneuropathy neurological features (central Adrenomyeloneuropathy neurological features (central demyelination, cortical blindness, neuropathies) begin in demyelination, cortical blindness, neuropathies) begin in adolescence or young adulthood, progress more slowly and adolescence or young adulthood, progress more slowly and involve peripheral nervesinvolve peripheral nerves

Diagnosis made by measuring high concentrations of VLCFADiagnosis made by measuring high concentrations of VLCFA Young men with adrenal insufficiency should be screened for Young men with adrenal insufficiency should be screened for

this disorderthis disorder

Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

A family of autosomal recessive disorders caused by A family of autosomal recessive disorders caused by deficiency of one of the multiple enzymes in the cortisol deficiency of one of the multiple enzymes in the cortisol synthesis pathwaysynthesis pathway

The enzyme deficiency causes inadequate cortisol The enzyme deficiency causes inadequate cortisol production and a compensatory increase in ACTHproduction and a compensatory increase in ACTH

ACTH stimulates adrenal hyperplasia and increased ACTH stimulates adrenal hyperplasia and increased production of precursors proximal to the block in cortisol production of precursors proximal to the block in cortisol synthesissynthesis

Bilateral Adrenal MetastasesBilateral Adrenal Metastases

Metastases to the adrenal are commonMetastases to the adrenal are common Breast 54%Breast 54% Bronchogenic 44%Bronchogenic 44% Renal 31%Renal 31% Adrenal insufficiency from metastases is very rareAdrenal insufficiency from metastases is very rare

MedicationsMedications

Accelerate metabolism Accelerate metabolism of cortisolof cortisol

Thyroid hormoneThyroid hormone RifampinRifampin PhenytoinPhenytoin PhenobarbitalPhenobarbital MitotaneMitotane

Inhibit cortisol synthesisInhibit cortisol synthesis Ketoconazole (but not Ketoconazole (but not

fluconazole or itraconazole)fluconazole or itraconazole) EtomidateEtomidate MetyraponeMetyrapone MitotaneMitotane AminoglutethimideAminoglutethimide

Secondary Adrenal InsufficiencySecondary Adrenal Insufficiency

Pituitary tumors due to mass or treatment of tumorPituitary tumors due to mass or treatment of tumor Metastases to pituitaryMetastases to pituitary CraniopharyngiomaCraniopharyngioma MeningiomaMeningioma Infiltrative disorders (histiocytosis X, lymphocytic Infiltrative disorders (histiocytosis X, lymphocytic

hypophysitis,sarcoidosis, hemochromatosis)hypophysitis,sarcoidosis, hemochromatosis) Postpartum pituitary necrosis (Sheehan’s syndrome)Postpartum pituitary necrosis (Sheehan’s syndrome) Iatrogenic from exogenous steroidsIatrogenic from exogenous steroids High doses of megestrol acetateHigh doses of megestrol acetate

Clinical PresentationClinical Presentation

FindingFinding PrimaryPrimary SecondarySecondary

Anorexia and weight lossAnorexia and weight loss Yes (100%)Yes (100%) Yes (100%)Yes (100%)

Fatigue and weaknessFatigue and weakness Yes (100%)Yes (100%) Yes (100%)Yes (100%)

Nausea/diarrheaNausea/diarrhea Yes (50%)Yes (50%) Yes (50%)Yes (50%)

Muscle,joint,abdominal painMuscle,joint,abdominal pain Yes (10%)Yes (10%) Yes (10%)Yes (10%)

Orthostatic hypotensionOrthostatic hypotension YesYes YesYes

HyponatremiaHyponatremia Yes (80%)Yes (80%) Yes (60%)Yes (60%)

HyperkalemiaHyperkalemia Yes (60%)Yes (60%) NoNo

HyperpigmentationHyperpigmentation yesyes NoNo

Secondary deficiencies of Secondary deficiencies of testosterone, GH, thyroid, ADHtestosterone, GH, thyroid, ADH

NoNo YesYes

Associated autoimmune diseasesAssociated autoimmune diseases YesYes NoNo

Adrenal CrisisAdrenal Crisis

Dehydration, hypotenstion, shock out of proportion to severity Dehydration, hypotenstion, shock out of proportion to severity of current illness, nausea, vomiting with anorexia, weight loss, of current illness, nausea, vomiting with anorexia, weight loss, unexplained fever, hyponatremia, hyperkalemia, azotemia, unexplained fever, hyponatremia, hyperkalemia, azotemia, hypercalcemia, eosinophilia, and hypoglycemiahypercalcemia, eosinophilia, and hypoglycemia

Often precipitated by intercurrent illness in patient with Often precipitated by intercurrent illness in patient with unrecognized adrenal insufficiency or in a patient with known unrecognized adrenal insufficiency or in a patient with known disease who did not increase cortisol replacement disease who did not increase cortisol replacement appropriately or patient who recently had glucocorticoid therapy appropriately or patient who recently had glucocorticoid therapy withdrawn, or in patient with bilateral adrenal hemorrhagewithdrawn, or in patient with bilateral adrenal hemorrhage

Laboratory TestingLaboratory Testing

In acute emergencies “treat first, test later”In acute emergencies “treat first, test later” In the acutely ill patient draw serum cortisol In the acutely ill patient draw serum cortisol

and ACTH then treat with dexamethasone 2-and ACTH then treat with dexamethasone 2-4 mg IV q12 hours or hydrocortisone 100 mg 4 mg IV q12 hours or hydrocortisone 100 mg q6 hours then switch to dexamethasone for q6 hours then switch to dexamethasone for testingtesting

Laboratory TestingLaboratory Testing

Static testing not very useful Static testing not very useful If cortisol between 8-9 am if less than or If cortisol between 8-9 am if less than or

equal to 3 ug/dl adrenal insufficiency likelyequal to 3 ug/dl adrenal insufficiency likely If cortisol greater than 19 adrenal If cortisol greater than 19 adrenal

insufficiency ruled outinsufficiency ruled out

Dynamic Testing: CortrosynDynamic Testing: Cortrosyn

A serum cortisol of 20 ug/dl or more 1 hour following 250 ug of A serum cortisol of 20 ug/dl or more 1 hour following 250 ug of cortrosyn IM or IV excludes primary adrenal insufficiencycortrosyn IM or IV excludes primary adrenal insufficiency

Some have suggested a value of 18 is an adequate responeSome have suggested a value of 18 is an adequate respone Difference between baseline and stimulated cortisol no longer Difference between baseline and stimulated cortisol no longer

usedused Does not exclude the presence of secondary adrenal Does not exclude the presence of secondary adrenal

insufficiencyinsufficiency

Dynamic Testing: CortrosynDynamic Testing: Cortrosyn

Low dose cortrosyn 1 ug IV followed by cortisol Low dose cortrosyn 1 ug IV followed by cortisol measurement in one half hour.measurement in one half hour.

There is evidence for and against the utility of this There is evidence for and against the utility of this testtest

ACTH MeasurementsACTH Measurements

In untreated primary adrenal insufficiency In untreated primary adrenal insufficiency ACTH is greater than 100 pg/mlACTH is greater than 100 pg/ml

Not useful for judging adequacy of therapyNot useful for judging adequacy of therapy

Insulin Tolerance TestInsulin Tolerance Test

Performed fasting in morningPerformed fasting in morning IV administration of 0.1-0.15 units regular insulin/kgIV administration of 0.1-0.15 units regular insulin/kg Cortisol >18 to 20 during hypoglycemia is normalCortisol >18 to 20 during hypoglycemia is normal Contraindicated in patients with severe illness, coronary artery Contraindicated in patients with severe illness, coronary artery

disease, seizures, psychiatric diseasedisease, seizures, psychiatric disease In patients with pituitary disease growth hormone is measured In patients with pituitary disease growth hormone is measured

simultaneouslysimultaneously

Metyrapone TestMetyrapone Test

Metyrapone activates the HPA axis by blocking cortiosl Metyrapone activates the HPA axis by blocking cortiosl production at the 11-hydroxylase step, the last step in cortisol production at the 11-hydroxylase step, the last step in cortisol synthesissynthesis

This leads to cortisol deficiency which should activate ACTH This leads to cortisol deficiency which should activate ACTH production and production of precursors proximal to the blockproduction and production of precursors proximal to the block

Metyrapone is given at midnight with a light snackMetyrapone is given at midnight with a light snack Cortisol and 11-deoxycortisol are measured at 8 am. The test Cortisol and 11-deoxycortisol are measured at 8 am. The test

is considered normal if cortisol is less than 5 and 11-is considered normal if cortisol is less than 5 and 11-deoxycortisol is at least 7 ung/dl.deoxycortisol is at least 7 ung/dl.

Once the diagnosis is made a search for the Once the diagnosis is made a search for the underlying cause is indicated if not immediately underlying cause is indicated if not immediately obviousobvious

For primary adrenal insufficiency adrenal imaging For primary adrenal insufficiency adrenal imaging is indicatedis indicated

For secondary disease MRI imaging of For secondary disease MRI imaging of pituitary/hypothalamus may be needed.pituitary/hypothalamus may be needed.

TreatmentTreatment

For primary adrenal crisis: hydrocortisone 100 mg For primary adrenal crisis: hydrocortisone 100 mg q6 hours if diagnosis established or dexamethasone q6 hours if diagnosis established or dexamethasone 2-4 mg q12 hours if diagnostic testing needed 2-4 mg q12 hours if diagnostic testing needed

For secondary adrenal crisis: dexamethasone may For secondary adrenal crisis: dexamethasone may be preferred to avoid fluid retention and be preferred to avoid fluid retention and hypokalemiahypokalemia

Intravenous saline to support volume and treat Intravenous saline to support volume and treat hyperkalemiahyperkalemia

Specific mineralocorticoid is usually not necessary Specific mineralocorticoid is usually not necessary while using high dose hydrocortisonewhile using high dose hydrocortisone

Maintenance TherapyMaintenance Therapy

Hydrocortisone 10-20 mg in am, 5-10 mg in early pmHydrocortisone 10-20 mg in am, 5-10 mg in early pm Prednisone 5 mg in am, 0-2.5 mg in pmPrednisone 5 mg in am, 0-2.5 mg in pm Florinef 0-0.1 mg per day Florinef 0-0.1 mg per day Adequacy of glucocorticoid judged by patient well-being, Adequacy of glucocorticoid judged by patient well-being,

decrease in pigmentation, electrolytes, blood pressuredecrease in pigmentation, electrolytes, blood pressure Adequacy of mineralocorticoid judged by blood pressure, Adequacy of mineralocorticoid judged by blood pressure,

edema, potassium and plasma renin activityedema, potassium and plasma renin activity All patients with adrenal insufficiency should have MedicAlert All patients with adrenal insufficiency should have MedicAlert

bracelet or carry documentation of this disorderbracelet or carry documentation of this disorder

Acute Illness CoverageAcute Illness Coverage

Mild to moderate illness: double or triple usual glucocorticoid Mild to moderate illness: double or triple usual glucocorticoid dosagedosage

Severe illness or vomiting: dexamethasone or solucortef IM Severe illness or vomiting: dexamethasone or solucortef IM self-administered by patient then seek prompt medical helpself-administered by patient then seek prompt medical help

Moderately stressful procedures such as endoscopy: Moderately stressful procedures such as endoscopy: hydrocortisone 100 mg one hour before procedurehydrocortisone 100 mg one hour before procedure

Major surgery: hydrocortisone 100 mg IV before induction of Major surgery: hydrocortisone 100 mg IV before induction of anesthesia and repeated q6 hours. Dose then tapered anesthesia and repeated q6 hours. Dose then tapered depending on patient’s rate of recovery, usually 50% decrease depending on patient’s rate of recovery, usually 50% decrease per day until maintenance dose achievedper day until maintenance dose achieved

Thyroid StormThyroid Storm

Thyroid StormThyroid Storm

Severe and life-threatening thyrotoxicosisSevere and life-threatening thyrotoxicosis Exaggeration of the typical symptoms of hyperthyroidismExaggeration of the typical symptoms of hyperthyroidism Tachycardia with rate often>140Tachycardia with rate often>140 CHFCHF FeverFever Change in mental status: delirium, psychosis, stupor, comaChange in mental status: delirium, psychosis, stupor, coma Nausea, vomiting, diarrhea, abdominal painNausea, vomiting, diarrhea, abdominal pain Hepatic failure, jaundice, abnormal liver function testsHepatic failure, jaundice, abnormal liver function tests

PrecipitantsPrecipitants

Usually precipitated by an acute event in a patient with untreated Usually precipitated by an acute event in a patient with untreated hyperthyroidismhyperthyroidism

Thyroid or nonthyroidal surgeryThyroid or nonthyroidal surgery TraumaTrauma InfectionInfection Acute iodine load or radioactive iodineAcute iodine load or radioactive iodine Poor compliance with specific therapyPoor compliance with specific therapy Low socioeconomic statusLow socioeconomic status

Preoperative preparation of patients undergoing thyroidectomy for Preoperative preparation of patients undergoing thyroidectomy for hyperthyroidism has led to dramatic reduction in prevalence of hyperthyroidism has led to dramatic reduction in prevalence of surgically-induced thyroid stormsurgically-induced thyroid storm

TreatmentTreatment

IV FluidIV Fluid AcetominophenAcetominophen Beta blockade to control adrenergic symptomsBeta blockade to control adrenergic symptoms Thionamide - methimazole or PTUThionamide - methimazole or PTU Iodine solution to block release of thyroid hormoneIodine solution to block release of thyroid hormone Iodinated contrast agent to inhibit the peripheral Iodinated contrast agent to inhibit the peripheral

conversion of T4 to T3conversion of T4 to T3 Glucocorticoids to reduce T4 to T3 conversion and Glucocorticoids to reduce T4 to T3 conversion and

to treat potential coexistent adrenal insufficiencyto treat potential coexistent adrenal insufficiency

Beta BlockersBeta Blockers

Use with caution in patients with CHF or other Use with caution in patients with CHF or other contraindication contraindication

Propranolol is frequently selected as it can be given Propranolol is frequently selected as it can be given intravenously and reduces the conversion of T4 to intravenously and reduces the conversion of T4 to T3T3

Esmolol - loading dose of 250-500 ug/kg IV followed Esmolol - loading dose of 250-500 ug/kg IV followed by infusion of 50-100 ug/kg/min. This permits rapid by infusion of 50-100 ug/kg/min. This permits rapid titration of drug and minimizes adverse reactionstitration of drug and minimizes adverse reactions

ThionamidesThionamides

Block de novo thyroid hormone synthesis within 1-2 hours of Block de novo thyroid hormone synthesis within 1-2 hours of administration but have no effect on preformed thyroid administration but have no effect on preformed thyroid hormone stored in the glandhormone stored in the gland

PTU blocks conversion of T4 to T3 but since other drugs PTU blocks conversion of T4 to T3 but since other drugs given in storm are usually coadministered it is okay to use given in storm are usually coadministered it is okay to use methimazole which has a longer duration of actionmethimazole which has a longer duration of action

High doses needed: Methimazole 30 mg q6 or PTU 200 mg High doses needed: Methimazole 30 mg q6 or PTU 200 mg q4 hoursq4 hours

Both drugs can be suspected in liquid for rectal Both drugs can be suspected in liquid for rectal administrationadministration

IodineIodine

Iodine blocks release of T4 and T3 from the glandIodine blocks release of T4 and T3 from the gland SSKI 5 drops every 6 hours or Lugol’s solution 10 SSKI 5 drops every 6 hours or Lugol’s solution 10

drops tiddrops tid Delay administration of at least one hour after Delay administration of at least one hour after

thionamide administration to prevent iodine being thionamide administration to prevent iodine being used as a substrate for new hormone synthesisused as a substrate for new hormone synthesis

If iodine allergic, lithium has been used for the same If iodine allergic, lithium has been used for the same purposepurpose

Iodinated Radiocontrast AgentsIodinated Radiocontrast Agents

Iopanoic acid used for oral cholecystography Iopanoic acid used for oral cholecystography Potent inhibitors of T4 to T3 conversionPotent inhibitors of T4 to T3 conversion Dose 0.5 to 1 gm qdDose 0.5 to 1 gm qd Give at least one hour after thionamide to prevent Give at least one hour after thionamide to prevent

iodine from being used as a substrate for new iodine from being used as a substrate for new hormone synthesishormone synthesis

GlucocorticoidsGlucocorticoids

Reduce T4 to T3 conversionReduce T4 to T3 conversion May have a direct effect on underlying autoimmune May have a direct effect on underlying autoimmune

process if storm is due to Graves diseaseprocess if storm is due to Graves disease Use of glucocorticoids has improved outcome in Use of glucocorticoids has improved outcome in

one series one series Hydrocortisone 100 mg IV q8 hoursHydrocortisone 100 mg IV q8 hours

Myxedema ComaMyxedema Coma

Myxedema ComaMyxedema Coma

Severe hypothyroidism due to severe long-standing Severe hypothyroidism due to severe long-standing untreated hypothyroidismuntreated hypothyroidism

Precipitating acute event almost always present: infection, Precipitating acute event almost always present: infection, myocardial infarction, cold exposure, sedative drugsmyocardial infarction, cold exposure, sedative drugs

Older women affected most frequentlyOlder women affected most frequently May result from any of the usual causes of hypothyroidismMay result from any of the usual causes of hypothyroidism Important clues in a poorly responsive patient include Important clues in a poorly responsive patient include

presence of thyroidectomy scar or history of radioiodine presence of thyroidectomy scar or history of radioiodine treatment or known hypothyroidismtreatment or known hypothyroidism

Mortality rate is high 30-40%Mortality rate is high 30-40%

Clinical PresentationClinical Presentation

HypothermiaHypothermia Decreased mental statusDecreased mental status HypotensionHypotension BradycardiaBradycardia HyponatremiaHyponatremia HypoglycemiaHypoglycemia HypoventilationHypoventilation

DiagnosisDiagnosis

History, physical exam, and exclusion of other causes of History, physical exam, and exclusion of other causes of comacoma

Treat before waiting for lab confirmation but draw TSH, free Treat before waiting for lab confirmation but draw TSH, free T4, cortisol before treatmentT4, cortisol before treatment

Most patients will have primary hypothyroidism with high Most patients will have primary hypothyroidism with high TSH and low free T4; rare patients have low free T4 and low TSH and low free T4; rare patients have low free T4 and low TSH consistent with secondary hypothyroidism due to TSH consistent with secondary hypothyroidism due to hypothalamic or pituitary diseasehypothalamic or pituitary disease

Cortisol measurement will help exclude coexistent adrenal Cortisol measurement will help exclude coexistent adrenal insufficiencyinsufficiency

Treatment: Thyroid HormoneTreatment: Thyroid Hormone

Optimal mode of thyroid hormone therapy is controversialOptimal mode of thyroid hormone therapy is controversial Increasing serum thyroid hormones rapidly carries some risk Increasing serum thyroid hormones rapidly carries some risk

of precipitating MI or atrial arrhythmia but this risk must be of precipitating MI or atrial arrhythmia but this risk must be accepted given high mortality rate of myxedema comaaccepted given high mortality rate of myxedema coma

Levothyroxine 0.2-0.4 mg IV initial doseLevothyroxine 0.2-0.4 mg IV initial dose .05 to 0.1 mg IV qd thereafter.05 to 0.1 mg IV qd thereafter Switch to oral when feasibleSwitch to oral when feasible T3 can be given 5-20 ug initially, then 2.5-10 ug q8 hoursT3 can be given 5-20 ug initially, then 2.5-10 ug q8 hours Stop T3 when clinical improvement occursStop T3 when clinical improvement occurs

Supportive MeasuresSupportive Measures

Avoid dilute fluidsAvoid dilute fluids Severe hypotension that does not respond to fluids Severe hypotension that does not respond to fluids

should be treated with vasopressors until T4 has should be treated with vasopressors until T4 has had time to acthad time to act

Passive rewarming with heating blanket (active Passive rewarming with heating blanket (active rewarming carries risk of vasodilatation)rewarming carries risk of vasodilatation)

Empiric antibiotics until appropriate cultures are Empiric antibiotics until appropriate cultures are proven negativeproven negative

PheochromocytomaPheochromocytoma

Catecholamine -Secreting Tumors: Catecholamine -Secreting Tumors: Pheochromocytoma and ParagangliomasPheochromocytoma and Paragangliomas

Arise from chromaffin cells of adrenal medulla and Arise from chromaffin cells of adrenal medulla and sympathetic ganglia sympathetic ganglia

Rare: incidence 2-8 cases per million; prevalence Rare: incidence 2-8 cases per million; prevalence estimates 0.01% to 0.1% of hypertensive population estimates 0.01% to 0.1% of hypertensive population

Occurs equally in men and women, primarily in 3rd Occurs equally in men and women, primarily in 3rd through 5th decadesthrough 5th decades

Curable with surgical removal of tumorCurable with surgical removal of tumor Potential for lethal paroxysmPotential for lethal paroxysm

SymptomsSymptoms

Usually present and are due to pharmacologic Usually present and are due to pharmacologic effects of excess circulating catecholamineseffects of excess circulating catecholamines

The five P’s:The five P’s:

Pressure- sudden major increase in BPPressure- sudden major increase in BP Pain- abrupt onset of throbbing headache, chest and/or Pain- abrupt onset of throbbing headache, chest and/or

abdominal painabdominal pain Perspiration- profuse generalized diaphoresis Perspiration- profuse generalized diaphoresis PalpitationsPalpitations PallorPallor

SpellsSpells

Extremely variable in presentationExtremely variable in presentation SpontaneousSpontaneous Precipitated by diagnostic procedures, postural Precipitated by diagnostic procedures, postural

changes, anxiety, exercise, or maneuvers that changes, anxiety, exercise, or maneuvers that increase intra-abdominal pressureincrease intra-abdominal pressure

Duration 10-60 minutes and may occur daily to Duration 10-60 minutes and may occur daily to monthlymonthly

Additional symptoms: constipation, attacks of Additional symptoms: constipation, attacks of hypotension and shock, tremor, anxiety, epigastric hypotension and shock, tremor, anxiety, epigastric and chest painand chest pain

Clinical SignsClinical Signs

Hypertension - paroxysmal in half, may be severe and resistant Hypertension - paroxysmal in half, may be severe and resistant to conventional therapyto conventional therapy

Orthostatic hypotensionOrthostatic hypotension PallorPallor Grade II-IV retinopathyGrade II-IV retinopathy TremorTremor Weight lossWeight loss FeverFever Café au lait spots in neurofibromatosisCafé au lait spots in neurofibromatosis Painless hematuria and paroxysmal attacks induced by Painless hematuria and paroxysmal attacks induced by

micturition in pheo of bladdermicturition in pheo of bladder HyperglycemiaHyperglycemia HypercalcemiaHypercalcemia ErythrocytosisErythrocytosis

Rule of 10Rule of 10

10% are extradrenal10% are extradrenal 10% occur in children10% occur in children 10% are multiple or bilateral10% are multiple or bilateral 10% recur after surgical removal10% recur after surgical removal 10% are malignant10% are malignant 10% are familial10% are familial

Differential DiagnosisDifferential Diagnosis

EndocrineEndocrine ThyrotoxicosisThyrotoxicosis Menopausal syndromeMenopausal syndrome HypoglycemiaHypoglycemia MastocytosisMastocytosis

CardiacCardiac Essential hypertensionEssential hypertension Cardiovascular deconditioningCardiovascular deconditioning Paroxysmal arrhythmiaParoxysmal arrhythmia Withdrawal of adrenergic inhibiting medications (clonidine)Withdrawal of adrenergic inhibiting medications (clonidine) MAO-inhibitor treatment and ingestion of tyramine or MAO-inhibitor treatment and ingestion of tyramine or

decongestantdecongestant AnginaAngina

Differential DiagnosisDifferential Diagnosis

PsychoneurologicPsychoneurologic Anxiety and panic attacksAnxiety and panic attacks HyperventilationHyperventilation Migraine headachesMigraine headaches Amphetamine, phenylpropanolamine, or cocaine useAmphetamine, phenylpropanolamine, or cocaine use Diencephalic epilepsyDiencephalic epilepsy

FactitiousFactitious Sympathomimetic ingestionSympathomimetic ingestion

Familial SyndromesFamilial Syndromes Familial pheochromocytomaFamilial pheochromocytoma

MENII aMENII a PheochromocytomaPheochromocytoma Medullary thyroid carcinomaMedullary thyroid carcinoma HyperparathyroidismHyperparathyroidism

MENII bMENII b Pheochromocytoma (bilateral in >70%)Pheochromocytoma (bilateral in >70%) Medullary thyroid carcinomaMedullary thyroid carcinoma Mucosal neuromasMucosal neuromas Thickened corneal nervesThickened corneal nerves Intestinal ganglioneuromatosisIntestinal ganglioneuromatosis Marfanoid body habitusMarfanoid body habitus

Familial SyndromesFamilial Syndromes

Neurofibromatosis (von Recklinghausen’s disease)Neurofibromatosis (von Recklinghausen’s disease) 1% develop pheochromocytoma1% develop pheochromocytoma

Von Hippel-Lindau (retinal angiomatosis and cerebellar Von Hippel-Lindau (retinal angiomatosis and cerebellar hemangioblastoma)hemangioblastoma)

Additional pheochromocytoma-related neurocutaneous syndromes:Additional pheochromocytoma-related neurocutaneous syndromes: Ataxia telangiectasiaAtaxia telangiectasia Tuberous sclerosisTuberous sclerosis Sturge-WeberSturge-Weber

Other known associations without familial basisOther known associations without familial basis Carney’s triadCarney’s triad Gastric leiomyosarcomaGastric leiomyosarcoma Pulmonary chondromaPulmonary chondroma Extra-adrenal pheochromocytomaExtra-adrenal pheochromocytoma

CholelithiasisCholelithiasis Renal artery stenosisRenal artery stenosis

ParagangliomasParagangliomas

Para-aortic sympathetic chainPara-aortic sympathetic chain Organs of Zuckerkandl at origin of inferior Organs of Zuckerkandl at origin of inferior

mesenteric arterymesenteric artery Wall of urinary bladderWall of urinary bladder Sympathetic chain in the neck or mediastinumSympathetic chain in the neck or mediastinum

Other Endocrine Manifestations of Other Endocrine Manifestations of PheochromocytomaPheochromocytoma

GHRH- acromegalyGHRH- acromegaly ACTH/CRH - Cushing’s syndromeACTH/CRH - Cushing’s syndrome VIP- watery diarrheaVIP- watery diarrhea PTH-RP- hypercalcemiaPTH-RP- hypercalcemia

Diagnostic EvaluationDiagnostic Evaluation

Biochemical documentation should precede any imaging Biochemical documentation should precede any imaging studiesstudies

24 hour urine collection for catecholamines, metanephrine and 24 hour urine collection for catecholamines, metanephrine and VMA VMA

24 hour urine collection should start with the onset of a spell in 24 hour urine collection should start with the onset of a spell in pateints with episodic hypertensionpateints with episodic hypertension

Usually more than 2 fold increase above the upper normal limitUsually more than 2 fold increase above the upper normal limit No role for provocative testing with histamine or glucagonNo role for provocative testing with histamine or glucagon

Medications Interfering with AssessmentMedications Interfering with Assessment

Increase valuesIncrease values Tricyclic antidepressantsTricyclic antidepressants LabetololLabetolol LevodopaLevodopa DecongestantsDecongestants Amphetamines, busipirone and most psychoactive medicationsAmphetamines, busipirone and most psychoactive medications SotalolSotalol MethyldopaMethyldopa EthanolEthanol BenzodiazepinesBenzodiazepines

Decrease valuesDecrease values MetyrosineMetyrosine MethylglucamineMethylglucamine

Plasma CatecholaminesPlasma CatecholaminesPlasma catecholamines Plasma catecholamines must be obtained from fasting supine patient with indwelling must be obtained from fasting supine patient with indwelling

catheter in place for 20 minutescatheter in place for 20 minutes affected by diuretics, smoking, renal insufficiencyaffected by diuretics, smoking, renal insufficiencyPlasma metanephrinesPlasma metanephrines Recent report shows accuracy for diagnosisRecent report shows accuracy for diagnosisChromogranin AChromogranin A Costored and secreted with catecholamines and increased in Costored and secreted with catecholamines and increased in

80-90% of patients with catecholamine secreting tumors80-90% of patients with catecholamine secreting tumorsNeuropeptide Y increased in 87%Neuropeptide Y increased in 87%Measurements of urinary catecholamines and metabolites, Measurements of urinary catecholamines and metabolites,

chromogranin A, plasma norepi and dopamine are invalid In chromogranin A, plasma norepi and dopamine are invalid In advanced renal insufficiency. Plasma epi levels more reliableadvanced renal insufficiency. Plasma epi levels more reliable

Localization StudiesLocalization Studies

90% of tumors are found in the adrenal and 98% are in the 90% of tumors are found in the adrenal and 98% are in the abdomenabdomen

Pheo’s have a characteristic T2-weighted appearance on MRIPheo’s have a characteristic T2-weighted appearance on MRI Common locations of extradrenal paragangliomas are superior Common locations of extradrenal paragangliomas are superior

para-aortic region in 46%, inferior para-aortic in 29%, urinary para-aortic region in 46%, inferior para-aortic in 29%, urinary bladder in 10%, thorax in 10%, head and neck 3%, pelvis 2%bladder in 10%, thorax in 10%, head and neck 3%, pelvis 2%

If results of imaging studies are negative an MIBG scan can be If results of imaging studies are negative an MIBG scan can be performed. Sensitivity 88%, specificity 99%performed. Sensitivity 88%, specificity 99%

Treatment of PheochromocytomaTreatment of Pheochromocytoma

Surgical resection after careful pre-op alpha and Surgical resection after careful pre-op alpha and beta adrenergic blockadebeta adrenergic blockade

Controls blood pressure and prevents intraoperative Controls blood pressure and prevents intraoperative hypertensive crisishypertensive crisis

Alpha blockade started at least 10 days preop to Alpha blockade started at least 10 days preop to allow for contracted blood volumeallow for contracted blood volume

Encourage high salt intake during this timeEncourage high salt intake during this time

Alpha blockadeAlpha blockade

Phenoxybenzamine 10 mg bid and increased 10-20 Phenoxybenzamine 10 mg bid and increased 10-20 mg every 2 days until BP and spells controlledmg every 2 days until BP and spells controlled

Average dosage 0.5-1.0 mg/kg dailyAverage dosage 0.5-1.0 mg/kg daily Orthostatic hypotension increased, tachycardia, Orthostatic hypotension increased, tachycardia,

miosis, nasal congestion, diarrhea, fatiguemiosis, nasal congestion, diarrhea, fatigue

Beta blockadeBeta blockade

Administer only after alpha inhibition is effective because beta Administer only after alpha inhibition is effective because beta blockade alone may result in more severe hypertension due to blockade alone may result in more severe hypertension due to unopposed alpha adrenergic stimulationunopposed alpha adrenergic stimulation

Indicated to control tachycardia associated with high circulating Indicated to control tachycardia associated with high circulating catecholamines and alpha blockadecatecholamines and alpha blockade

Use cautiously and at low dose as chronic circulating Use cautiously and at low dose as chronic circulating catecholamines may cause a cardiomyopathy and beta catecholamines may cause a cardiomyopathy and beta blockers can result in pulmonary edemablockers can result in pulmonary edema

Labetolol is a combined beta blocker and alpha blocker but Labetolol is a combined beta blocker and alpha blocker but instances of paradoxic hypertensive crisis (due to incomplete instances of paradoxic hypertensive crisis (due to incomplete alpha blockade) have been reported; safety as primary agent is alpha blockade) have been reported; safety as primary agent is controversialcontroversial

Catecholamine Synthesis Inhibitor: Catecholamine Synthesis Inhibitor: Metyrosine Metyrosine

Useful in patients with persistent catecholamine Useful in patients with persistent catecholamine producing tumors that cannot be treated with producing tumors that cannot be treated with combined alpha and beta blockadecombined alpha and beta blockade

Inhibits tyrosine hydroxylaseInhibits tyrosine hydroxylase Side effects: diarrhea, sedation, anxiety, Side effects: diarrhea, sedation, anxiety,

nightmares, urolithiasis, galactorrhea, nightmares, urolithiasis, galactorrhea, extrapyramidal manifestationsextrapyramidal manifestations

Acute Hypertensive Crises Acute Hypertensive Crises

Phentolamine test dose of 1 mg followed by repeat Phentolamine test dose of 1 mg followed by repeat 5 mg IV boluses5 mg IV boluses

Response maximal in 2-3 minutes and lasts 10-15 Response maximal in 2-3 minutes and lasts 10-15 minutesminutes

100mg/500 cc 5% dextrose can be infused IV and 100mg/500 cc 5% dextrose can be infused IV and titrated to BP controltitrated to BP control

Postoperative CoursePostoperative Course

Hypotension may occur after surgery: treat with fluids and Hypotension may occur after surgery: treat with fluids and colloidcolloid

Less frequent in patients who have had adequate alpha Less frequent in patients who have had adequate alpha blockade preoperativelyblockade preoperatively

HypoglycemiaHypoglycemia BP usually normal prior to dischargeBP usually normal prior to discharge Some patients remain hypertensive for up to 4-8 weeksSome patients remain hypertensive for up to 4-8 weeks 2 weeks after surgery 24 hour urine obtained to insure cure 2 weeks after surgery 24 hour urine obtained to insure cure

then every 5 yearsthen every 5 years