Endocrine CPC
Tim Miller, MD
1/22/2008
Case
 CC: I have been having headaches
 HPI: Pt is a 33 year old Hispanic male
seen for routine yearly follow up
 Reports headaches for 3 months
 Seen at walk-in clinic and diagnosed with
migraines
 Midrin and Maxalt were not effective
Case
 Headaches start behind both eyes and
encompass his entire head
 Recently (past 2 weeks) headaches
occur on a daily basis and are more
severe
 Headaches mainly occur at night
 Seem to be worse with exertion
Case
 Associated Signs/Symptoms
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Nausea
Photophobia
Phonophobia
Roommate says he “looks pale” with attacks
Sweats will accompany headaches, mainly
at night
 Experiences “fluttering” in his chest and
notes that his pulse is around 120
Case
 Pertinent Negatives
 No lacrimation
 No vision changes
 Location does not change
Case
 PMHx:
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Seasonal allergies
Eczema
Positive PPD – currently on INH therapy
NAFLD with elevated LFT’s (discovered
prior to initiation of INH)
 Hypertriglyceridemia
Case
 PSHx:
 None
 FH:
 Not given
 Meds:
 INH
 All:
 NKDA
 SocHx:
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Nonsmoker
Occasional EtOH
No drugs
Entomology graduate
student at Texas A&M
 Born in Cuba and
moved to Texas to
study
 Traveled to Peruvian
rainforest for research
within the last year
Case
 Review of Systems:
 General: no weight loss
 HEENT: no vision/hearing changes, no
odynophagia/dysphagia
 Pulmonary: no SOB, no cough
 Cardiovascular: no chest pain, (+) palpitations
 GI: no jaundice, no abd pain, no changes in bowel
habits
 GU: no changes in bladder habits
Case
 Physical Exam:
 BP 144/84 P 110 T 98.4 BMI 26
 General: well nourished, healthy appearing male
 HEENT: NCAT, PERRLA, EOMI, no icterus, mm
moist, conjunctiva pink
 Fundoscopic: no papilledema
 Neck: supple, no LAD, no bruits, no supraclavicular
fat pad
 CV: tachycardic (110) and regular, no murmurs,
gallops, or rubs
Case
 Physical Exam cont:
 Resp: clear bilaterally, good resp effort
 Abd: mild TTP with deep palpation on the right,
lateral to umbilicus, (+) BS, no HSM, no
rebound/guarding
 Ext: no C/C/E
 Neuro: CN 2-12 intact, strength 5/5 x 4, no gait
abnormalities
 Psych: normal mood and affect
 Skin: eczematous changes to palms and bilateral
antecubital fossae
Case
 Labs & Studies:
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CBC normal
CMP normal other than ALT 131
Hepatitis Panel negative
Ferritin normal
Thyroid function tests normal
2-view CXR normal
CT head w/wo contrast negative
Problem List
 ACUTE
 Headache x 3 months
 Progressively worsening






Looks pale with attacks
Sweats with headaches
Palpitations
Hypertension
Tachycardia
Travel to Peruvian
Rainforest

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




CHRONIC
Positive PPD
INH Therapy
Seasonal Allergies
Eczema
NAFLD Elevated LFT’s
Hypertriglyceridemia
Differential Diagnosis
 Chronic Headache
 Migraine
 Cluster
 Tension
 TB Meningitis
 CNS Neoplasm
 Hypertensive
Headache
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
Headache - Epidemiology
 Among the most common medical
complaints
 Overall prevalence 12-16%; accounts for
1-2% of ER visits and up to 4% of outpatient
office visits
 90% of headaches fall into categories of
migraine, cluster, and tension
Headache - Classification
 Acute
 New onset or clearly different than previous
headaches
 Often are a sign of serious illness
 Subarachnoid hemorrhage
 Meningitis
 Acute glaucoma
 Hypertensive encephalopathy
Headache - Classification
 Subacute
 Occurs over a period of weeks to months
 May or may not be related to underlying
systemic illness
 Recent subdural hematoma
 Subacute meningitis
 Primary or metastatic tumor
 Giant cell arteritis
 Optic Neuritis
Headache - Classification
 Chronic
 Continues
intermittently for years
 Usually has a benign
cause
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Migraine
Cluster
Tension
Sinusitis
Dental Disease
Headache – Approach to
Diagnosis
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Age of onset
Timing of pain
Precipitating factors
Characteristics of pain
Location of pain
Associated symptoms
History of prior
headaches and course
of this type of headache
 Physical Exam
Migraine Headache
 Unilateral and usually
pulsatile
 Often associated with
nausea, photo- and
phonophobia
 Moderate to severe intensity
 55% occur initially prior to
age 20
 Usually familial
 Auras occur in 10% of
patients
 Most often occur in women
Migraine Headache
 Clinical Presentation
 Classic Migraine (preceded by aura)
 Visual, noxious, or sensory alterations followed
by intense unilateral throbbing headache Usually
do not occur more frequently than weekly
 Last between 4 and 72 hours
 Common Migraine (lacks aura)
 Usually unilateral and throbbing
Cluster Headache
 Clinical Presentation
 Brief, severe, constant, nonthrobbing
headache
 Lasts 15-180 minutes without treatment
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Always unilateral
Much more common in men
Mean age of onset is 25
Episodes are separated by months or even
years
Cluster Headache
 Begins with
sensation by the
nose or behind the
eye
 Ipsilateral
lacrimation,
conjuntival injection,
or ptosis may occur
 Key to diagnosis is
brevity of symptoms
Tension Headache
 Clinical Presentation
 Lacks features of migraine or cluster
 Frequent (possibly daily), bilateral occipital,
nonthrobbing
 Often a band distribution
 Rarely nausea, vomiting, or visual prodrome,
although may occasionally have features of
migraine
Tension Headache?
 Women more
common then men
 Secondary gain?
Headache - Imaging
 Danger signs that indicate need for imaging
 Sudden onset of worst headache ever or headache
that reaches full intensity in minutes
 Absence of similar terrible headaches in past
 Worsening pattern
 Focal neurologic signs or papilledema
 Fever
 Change in mental status or personality
 Rapid onset with strenuous exercise
 Presentation to any ER with headache
Differential Diagnosis
 Chronic Headache
 Migraine
 Cluster
 Tension
 TB Meningitis
 CNS Neoplasm
 Hypertensive
Headache
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
CNS Tuberculosis
 3 Categories
 TB Meningitis
 Intracranial Tuberculoma
 Spinal tuberculous arachnoiditis
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Account for 1% of all TB cases
Quite rare in United States
Fatal in 15-40% of cases, usually within 5-8 weeks
Active TB outside the CNS is not necessary to make
diagnosis
 Send CSF for acid fast smear, TB culture, and TB PCR
Differential Diagnosis
 Chronic Headache
 Migraine
 TB Meningitis
 CNS Neoplasm
 Hypertensive
Headache
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
CNS Neoplasm
 Headache is a common symptom in
patients with brain malignancies
 Worst symptom in half of patients
 Usually described as dull and constant,
occasionally throbbing
 Typically tension-type (77%); can be
migraine-type (9%), or other (14%)*
 Severe headaches are infrequent
*Forsyth, PA, Posner, JB. Headaches in patients with brain tumors. Neurology 1993; 43:1678.
CNS Neoplasm
 Other clues to malignant headaches
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40% have nausea and vomiting
Change in prior headache pattern
Abnormal neurologic exam
May worsen with maneuvers that increase the ICP (bending
over, sneezing, coughing)
 Tend to be worse at night (vasodilatation from transient
increase in PCO2)
 Typical location is bifrontal but may be generalized if ICP is
increased
 Headache, nausea, papilledema ( ICP)
 Other signs of CNS malignancy include seizures, syncope,
cognitive dysfunction, focal neurologic deficits
Differential Diagnosis
 Chronic Headache
 Migraine
 CNS Neoplasm
 Hypertensive
Headache
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
Hypertensive Headache
 Routine essential hypertension has not been
shown to directly cause headaches*
 Can lead to conditions that cause headaches
 Intracerebral or subarachnoid bleeding
 Sudden onset of severe headaches
 Hypertensive encephalopathy
 Insidious onset of headache, N/V, followed by
restlessness and confusion, and eventually seizure
and coma if not treated
*Strovmer LJ, Vatten L, et al. Blood pressure and risk of headache. J Neurol Neurosurg Psychiatry 2002;72:463–6.
Hypertensive Headache
 Law, et al studied whether blood pressure meds
lowered headaches in a meta-analysis
 94 randomized placebo-controlled trials using 4 major types of
BP meds (thiazides, b-blockers, ACE-I, and ARB)
 Separated into treatment and placebo groups
 Average SBP fell by 9.4 and DBP fell by 5.5 in treatment
groups
 8% reported headaches in treatment groups and 12.4%
reported headaches in placebo groups
 RRR 33% (P<.001)
 However, many observational studies do not support
hypertension as a cause of headaches
Law M, Morris JK, Jordan R, Wald N. Headaches and the treatment of blood pressure. Circulation. 2005; 112: 2301–
2306.
Differential Diagnosis
 Chronic Headache
 Migraine
 Hypertensive
Headache
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
Cushing’s Disease
 Chronic excess of glucocorticoid
 Clinical features:
 Progressive obesity including moon facies,
supraclavicular fat pad and buffalo hump
 Skin changes of easy bruisability and striae
 Osteoporosis
 Proximal muscle weakness
 Hypertension
 Headache in up to 47% of patients
Pituitary Adenoma
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Microadenoma < 1 cm
Macroadenoma > 1 cm
Arise from anterior pituitary
Secrete hormones depending on type of tumor
(Prolactin, ACTH, GH)
 Clinical Presentation
 Visual defects are most common presenting symptom of
nonfunctioning adenomas
 Bitemporal hemianopsia
 Headaches are common and nonspecific
 Pituitary apoplexy causes severe headache and diplopia and
cranial nerve deficits
Differential Diagnosis
 Chronic Headache
 Migraine
 Endocrine Headache
 Pheochromocytoma
 Cushing’s Disease
 Pituitary Adenoma
Pheochromocytoma General
 Catecholamine secreting tumors of chromaffin
cells arising from the adrenal medulla
 Epinephrine and norepinephinre; rarely dopamine
 Stimulate alpha and beta adrenergic receptors
 Approximately 0.2% of patients diagnosed with
hypertension will have a pheochromocytoma
 Equal incidence in men and women
 Peak incidence between 3rd and 5th decade
Catecholamines
 Epinephrine, Norepineprhine, and
Dopamine secreted from the adrenal
medulla
 Act on α1 (peripheral vasoconstriction)
and α 2 receptors and β1 (heart rate and
inotropy), β2 (muscle and liver
vasodilatation)
Effects of Catecholamines
 Increase force of cardiac
contractility
 Increases heart rate (epi >
norepi)
 Peripheral vasoconstriction
 Dilates bronchioles
 Glycogynolysis (mobilizing
glucose)
 Increased metabolic rate
 Dilates pupils
 Inhibits non-essential
processes such as GI motility
Norepinephrine and epinephrine levels in human venous
blood in various physiologic and pathologic states
Cryer PE: Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436.
Pheochromocytoma Clinical Presentation
 Clinical Triad
 Episodic Headaches
 Sweating
 Tachycardia
(or palpitations)
 Frequency ranges from multiple times per day to
monthly
 Worsens with time and becomes more frequent
 Half will have paroxysmal hypertension and a third
appear to have essential hypertension
 5-15% present with normal blood pressure
Pheochromocytoma –
Clinical Presentation
 Headaches occur in 90% of symptomatic
patients
 May be mild or severe and are variable in duration
 Sweating occurs in 60-70% of patients
 Other signs and symptoms
 Dyspnea
 Generalized Weakness
 Panic Attack
Pheochromocytoma –
Presentation
 May often be unmasked during routine
procedure or drug administration
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Anesthesia induction
Cold Medications
Opiates
Dopamine Antagonists
Cocaine or TCA’s which inhibit catecholamine
reuptake
 Childbirth
 Trauma
Pheochromocytoma –
Rule of 10’s
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10% Bilateral
10% Malignant
10% Extra-adrenal
10% Calcify
10% Familial
10% Children
Pheochromocytoma –
Familial Conditions
 MEN 2a
 Pheochromocytoma
 Medullary Thyroid
Cancers
 Parathyroid Tumors
 MEN 2b
 Pheochromocytoma
 Medullary Thyroid
Cancers
 Neuromas
 Von Hippel-Lindau
 Cerebellar
Hemangioblastomas
 Retinal Angiomas
 Renal Cell Carcinoma
 Pheochromocytoma
 Neurofibromatosis
 Café-au-lait spots
 Neurofibromas
 Pheochromocytoma
Pheochromocytoma –
Evaluation
 Which patients should be evaluated for
pheochromocytoma?
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Patients with difficult to control hypertension
Patients receiving more than 4 BP meds
Patients with onset of htn before age 35
Patients with onset of htn after age 60
Patients with signs or symptoms of
pheochromocytoma as mentioned before
 Patients with familial history of predisposing
disorders
 Severe pressor response during anesthesia
Pheochromocytoma –
Lab Diagnosis
 Free plasma metanephrine level
 Screening Test for at risk patients
 96% sensitive but 85% specific (better if
drawn during an attack)
 Standard venipuncture test
Pheochromocytoma –
Lab Diagnosis
 Urinary catecholamines and metanephrines
 Confirmatory test
 87% sensitive and up to 99% specific
 Must be collected in a 24-hour urine specimen
 Order metanephrines (best test), catecholamines,
and vanillylmandelic acid (worst test)
 Ensure creatinine is measured to ensure adequacy
 Collect during or immediately after an attack if
possible
 2-3x increase in levels is diagnostic
Pheochromocytoma –
Lab Diagnosis
 Other diagnostic tests
 Clonidine Suppression Test
 Confirmatory test; 90% accurate
 Clonidine normally suppresses release of catecholamines
centrally, but not from a pheo
 Administer Clonidine and measure plasma metanephrines
before, and 3 hours after
 Levels will decrease in essential hypertension
 Levels remain increased in pheochromocytoma
 Chromogranin A level
 Increased in 80% of patients with pheochromocytoma
 Not specific for pheochromocytoma
Pheochromocytoma –
Imaging
 Imaging should only be
obtained after biochemical
diagnosis has been confirmed
 MRI has reported sensitivity
of 100% for adrenal pheos
 Better than CT for picking up
extra-adrenal tumors as well
 MRI can distinguish between
incidentilomas on T2weighted images
 CT may miss tumors smaller
than 1 cm
Pheochromocytoma –
Imaging
 MIBG Nuclear Medicine
Scan is reserved for
biochemically proven
cases with negative MRI
or CT
 MIBG structure
resembles norepi and
concentrates in adrenal
or extra-adrenal pheos
 Used in familial
syndromes, recurrent
pheo, or malignant pheo
Malignant
Pheochromocytoma
 10 % of pheochromocytomas are
malignant
 Direct invasion into surrounding tissue
 Distant metastasis
 Clinical, biochemical, or histological features
cannot predict malignancy
 Common metastatic sites include bone, liver,
and lymph nodes
Extra-adrenal
Pheochromocytoma
 90% of pheochromocytomas
are located in the adrenal
glands
 98% located in the abdomen
 Extra-adrenal
pheochromocytomas arise in
paraganglion chromaffin
tissue of the sympathetic CNS
 Anywhere from the base of
the brain to the bladder
Pheochromocytoma –
After Diagnosis
 Rule out familial pheochromocytoma
syndromes
 PTH level and Calcium level (MEN 2a)
 Ophtho consult to rule out retinal angiomas
and MRI head to rule out cerebellar
hemangioblastomas (VHL)
 CT pancreas and kidneys
 Consider genetic testing for family
Pheochromocytoma –
Treatment
 Block alpha receptors first with pure alpha
blocker Phenoxybenzamine
 After alpha blockade is achieved, begin
nonselective beta-blockers
 Administer last doses the morning of surgery
 Hydrate well and expand volume with isotonic
saline
 Surgically resect tumor; give stress-dose
steroids if bilateral adrenalectomy is planned
Pheochromocytoma –
Long term follow up
 Test plasma free metanephrines 2 weeks
post-operatively, then every 5 years
thereafter
 Ensure resolution of hypertension and
associated complications
Problem List
 ACUTE
 Headache x 3 months
 Progressively worsening






Looks pale with attacks
Sweats with headaches
Palpitations
Hypertension
Tachycardia
Travel to Peruvian
Rainforest







CHRONIC
Positive PPD
INH Therapy
Seasonal Allergies
Eczema
NAFLD Elevated LFT’s
Hypertriglyceridemia
Differential Diagnosis
 Chronic Headache
 Migraine
 Endocrine Headache
 Pheochromocytoma
 Final Diagnosis:
Pheochromocytoma
 Test of Choice:
24-hour urine
catecholamines,
metanephrines, and VMA
References
1.
2.
3.
4.
5.
6.
7.
Forsyth, PA, Posner, JB. Headaches in patients with brain tumors: a study of
111 patients. Neurology 1993; 43:1678.
Cryer PE: Physiology and pathophysiology of the human sympathoadrenal
neuroendocrine system. N Engl J Med 1980;303:436.
Headache classification committee of international headache society.
Classification and diagnostic criteria for headache disorders, cranial neuralgias,
and facial pain. Cephalalgia 1988; 9 Suppl 7:1.
Headache Classification Committee of the International Headache Society. The
International Classification of Headache Disorders. Cephalalgia 2004; 24:1.
Strovmer LJ, Vatten L, et al. Blood pressure and risk of headache: a prospective
study of 22 685 adults in Norway. J Neurol Neurosurg Psychiatry 2002;72:463–
6.
Law M, Morris JK, Jordan R, Wald N. Headaches and the treatment of blood
pressure: results from a meta-analysis of 94 randomized placebo-controlled
trials with 24 000 participants. Circulation. 2005; 112: 2301–2306.
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