ADDISONS DISEASE

KRISIS ADRENAL

Cross section through the adrenal

gland cortex and medulla

salt
sugar

sex

Hypothalamus-Pituitary-Adrenal axis
Circadian regulation
+

CRH

Stress:
Physical stress
Emotional stress
Hypoglycemia
Cold exposure
Pain

Cortisol

Adrenal cortex

+ ACTH
ACTH

Anterior lobe
of pituitary gland

CRH=corticothropin releasing hormone; ACTH=adrenocorticothropin hormone. Kirk LF. Am Fam Physician 2000

Production of
catecholamin
es

COMT = Catecholamine Ortho Methyl Transferase)

ADRENAL DISORDERS

ADRENOCORTICAL
DISORDERS
ACUTE ADRENOCORTICAL
INSUFFICIENCY (ADRENAL CRISIS)
CHRONIC ADRENOCORTICAL
INCUFFICIENCY (ADDISONS
DISEASE)
CUSHINGS SYNDROME
(HYPERCORTISOLISM)
HIRSUTISM & VIRILIZATION
PRIMARY HYPERALDOSTERONISM

ADRENOMEDULLA
DISORDERS
PHAEOCHROMOCYTOMA

ADDISONS
DISEASE

 BACKGROUND:
o Thomas Addison first described the clinical
presentation of primary adrenocortical
insufficiency (Addison disease) in 1855 in his
classic paper, On the Constitutional and Local
Effects of Disease of the Supra-Renal Capsules.

PATHOPHYSIOLOGY:
o Addison disease is adrenocortical
insufficiency due to the destruction or
dysfunction of the entire adrenal cortex.
o It affects both glucocorticoid and
mineralocorticoid Function
o The onset of disease usually occurs when
90% or more of both adrenal cortices are
dysfunctional or destroyed.

o An adrenal cortical hypofunction

o Deficiency of all steroid hormones
Glucocorticoid deficiency: hypoglycemia
Mineralocorticoid deficiency: low blood
volume and low blood pressure
Hyperpigmentation: from increased
ACTH due to loss of feedback inhibition
o Autoimmune disorder
Treatment: administration of
corticosteroids

Cortisol
Abdominal pain
Anorexia
Vomiting
Diarhea
Fluid intake

Gluconeogenesis
Glucose uptake

Renal K Secretion
Renal Na secretion

Hyperpigmentation
Hypoglycemia

Hyperkalemia
Hyponatremia

dehydration
Hypotension
Hypovolemia
Renal perfusion
BUN

ACTH

Decreased Body Weight

General Weakness

 Primary adrenal insufficiency

Causes
o Infectious
TB most common cause in 3rd world
countries
HIV, histoplasmosis, blastomycosis,
coccidiomycosis
o Autoimmune disorders anti-adrenal
antibodies (most cause common)
o Medications ketoconazole,
aminoglutethamide, etomidate
o Adrenal hemorrhage
o Lymphoma, bilateral adrenal metastasis,
Kaposis sarcoma
o Infiltrative amylodosis, sarcoidosis,
adrenoleukodystrophy

 Secondary adrenal insufficiency

Pituitary failure panhypopitutarism,
Sheehans syndrome (post-partum pituitary
injury)

Tertiary adrenal insufficiency

Adrenal suppression due to glucocorticoid
use
Chronic suppression
Sudden cessation of replacement glucocorticoids
Inadequate increase during stress, trauma,
surgery

Primary Adrenal
Insufficiency
Symptoms and sign
Weakness and fatigue
Hyperpigmentation
Unexplained weight loss
Anorexia, nausea, and vomiting
Hypotension (BP < 110/70 mmHg)
Hyponatremia
Hyperkalemia

Percent of
Patients
99
98
97
90
88
88
64

Appearance of hand (right side of photograph) of patient

with Addisons disease compared with hand of normal
subject.

Primary Adrenal
Insufficiency
A triphasic pattern :
Phase 1 : few/no symptoms, non spesific
malaise, pigmentation
Phase 2 : gradually worsening simptoms ;
lethargy, weight loss, increased
pigmentation over exposed areas,
hypotension, anorexia, nausea, diarhoea,
loss axillary, pubic and body hair
Phase 3 : decompentation ; adrenal crisis,

Primary versus secondary

adrenal insufficiency
Manifestations
Hyperpigmentation
Pallor
Low Na
High K
Hypotension
Cortisol level
ACTH level

Primary
Yes
No
Yes
Yes
Yes
Low
High

Secondary
No
Yes
No
No
No
Low
Low

TREATMENT
Replacement therapy combination
Glucocorticoids and
Mineralocorticoid
Hydrocortisone,
Fludocortisone asetate
Dehydroepiandrosterone (DHEA)

PROGNOSIS
Patient ADDISONS DISEASE can
expect a life normal expectancy if
their adrenalin insufficiency is
diagnos and treated with
appropriatre replacement doses of
glucocorticoid and mineralocirticoid

ADDISONS CRISIS
Acute adrenal insufficiency
o Similar causes
Adrenal hemorrhage
Chronic steroid use and
trauma/stress/surgery

o Hypotension, volume depletion, fever,

nausea and vomiting, tachycardia,
weakness, hypoglycemia
o Premed prior to interventions

Addisons Crisis
Treatment acut of adrenal crisis
The five Ss management are salt, sugar, steroid,
support, and search for presipitating illness.
General and supportive measure
o Correct volume depletion, dehydration, and
hypoglycemia with IV 0.9% saline with 5% dextrose
o Evaluate and correct infection and other precipitating
factors

Glucocorticoid replacement
o Administer hydrocortisone 100 mg every 6 hours for
24 hours
o When the patient is stable, reduce the dosage to 50
mg every 6 hours
o Taper to maintenance theraphy by day 4 or 5 and add
mineralocorticoid theraphy as required
o Maintain or increase the dose to 200-400 mg/d if
complications persist or occur

Addisons Crisis
Maintenance therapy
Glucocorticoid and mineralocorticoid
o Oral dose hydrocortisone : 10-20 mg in the
morning and 5-10 mg later in day.
o Fludrocortisone : 0,05-0,2 mg/d orally in the
morning.

Response to theraphy
o General clinical sign, good appetite and sense
of well being.
o Signs of Cushings syndrome indicate
overtreatment

Adrenocortical
disorders

Cushings Syndrome
Supraphysiologic glucocoticoid
exposure (excess cortisol)
o Protein catabolic state
o Liberation of amino acids by muscle
o AA are transformed into glucose and
glycogen and then transformed into fat

The source of excess glucocorticoids

may be exogenous or endogenous

Causes of Cushings
Syndrome
Dependent (80%)
Cushings Disease (85%)
Primary excretion of ACTH from pituitary
Microadenoma, macroadenoma or corticotrophic
hyperplasia
Basophilic or chromophobe

F>M (3:1)

Ectopic source (15%)

Produce ACTH or CRH
Small cell lung CA (most common), carcinoid
tumors, medullary thyroid, pancreas,
ovarian, pheochromocytoma, small-cell CA
of prostate

Causes of Cushings
Syndrome

ACTH Independent

Exogenous steroid use (common)

o PO or topical
o Most common cause (overall)

Adrenal adenomas (10%)

Adrenal carcinoma (5%)
o Most common cause in children

Cause of Cushings
Syndrome
Pseudo-Cushings disease
o Mimic clinical signs and symptoms
o Non-endocrine causes

Alcoholism
Major depression
Morbid obesity
Acute illness

Cushings Syndrome
Symptoms and Sign

Weight gain, round facies and

truncal obesity
Weakness
Hypertension
Hirsutism (in women)
Amenorrhea
Cutaneous striae
Ecchymoses
Osteoporosis
Hyperglycemia

Percent of Patients
97
87
82
80
77
67
65
Common
Common

Diagnosis of Cushings
Syndrome

Clinical assesment
Screening tests :

o Baseline glucocorticoids (a.m. and p.m. serum cortisol

levels, 24-hr urinary free cortisol excretion; 11 p.m.
Salivary cortisol)
o Low dose dexamethasone suppression test or combined
low-dose dexamethasone-oCRH

Subtype diagnosis
o Plasma ACTH concentration
o Dynamic testing (oCRH stimulation test, metyrapon
stimulation test, high dose dexamethasone supression test)
all with limited utility or prescision
o Directed computerized imaging (pituitary, adrenals, lungs,
etc)
o Pituitary venous sampling for ACTH with CRH stimualtion

Diagnosis of Cushings
Syndrome
Screening tests
o 24 hour urinary cortisol (UFC)
RIA : 80-108g (221-298nmol)
Baseline 24-hour UFC measurements may be high :
Carbamazepin, high urine volume, severe illness, CS,
alcoholism, depression, sleep apnea.
o Late night plasma or salivary cortisol
A midnight sleeping serum cortisol concentration > 1.8g/dl
(>50nmol/L) is 100% sensitive in patients with Cushings
syndrome.
o Overnight 1-mg dexamethasone supression test (DST)
A failure to supress serum cortisol with 1-mg DST is positive
screen and should lead to confirmatory evaluations.
Causes for cortisol non-supression with the overnight 1-mg
DST incl : CS, patient error in taking, estrogen therapy,
pregnancy, renal failure, stress, drugs (anticonvulsants,
rifampisin), obesity, psychiatric disorder (depression, panic
attacks)

Diagnosis of Cushings
Syndrome

Confirmatory tests for CS

o When baseline 24-hour UFC is >300g (828 nmol)

and the clinical and the clinical picture is
consisten with CS : no additional confirmatory
studies are needed.
o 2-day low dose DST
24-hour UFC < 300g : should confirmed with the low
dose DST (dexamethasone 0.5 mg, orally every 6 hours
for 48 hours); 24-hour urinary cortisol excretion > 20 g
(55nmol) confirm diagnosis.
The low dose DST works best for those patients that carry
of low index of suspicion for CS.

o Dexamethasone oCRH test

To correct false negative supression with DST (pituitary
dependent CS)

Clinical Suspicion of
Cushings Syndrome
24 hour UFC

1 mg DST
No supression
Confirm with 24 hr UFC
Normal
supression

Elevated
(>300g/d)

Intermediate
(90-300g/d)

Normal
(<90g/d)
Repeat, if normal

Cushings Syndrome
unlikely

Diurnal variation
And/or Dex-CRH test

Cushing Syndrome

Continue Evaluation

Cushing syndrome doubful

PsudoCushings
Treat underlying illness
Follow clinical examination
Repeat evaluation

Differential Subtype
Evaluation Tests

Plasma ACTH concentration

o ACTH dependent (normal to high levels of ACTH or ACTH

independent (low/undetectable ACTH)
o IRMA assay : normal 10-60 pg/ml, plasma ACTH values are
<5 pg/ml in adrenal dependent disease, 10 to 200 pg/ml in
pituitary-dependent disease, and 50 to >200 pg/ml in
ectopic ACTH syndrome

ACTH Dependent Disease

o Pituitary MRI
o Inferior petrosal venous sampling (IPSS) with CRH
stimulation
Measure petrosal venous sinus ACTH level and correlate
to plasma levels
The most important advanced in the past 2 decades for
subtype evaluation of CS
IPSS does not diagnose Cushings syndrome
o CRH stimulation test
o High dose DST
o Positron emission scanning: occult neuroendocrine and
ather ACTH-secreting tumors
No test is perfect for subtype evaluation of Cushings syndrome!

Cushings Syndrome
Treatment program :
o The resolution of hypercorticolism
o The parellel treatmet of the complications of CS (e.g.
hypertension, osteoporosis, diabetes mellitus, mucle
rehabilitation)
o Management of glucocorticoid withdrawal and
hypothalamic pituitary-adrenal (HPA) axis recov ery

Treatment: Surgical
o Cushings disease
Transphenoidal surgery (TSS)
The treatment choice
The longterm surgical cure rate for ACTH
secreting microadenomas is 80-90%.
Transient post-op diabetes insipidus, adrenal
insufficiency, CSF rhinorrhea, meningitis
Tansphenoidal irradiation
If TSS is not curative.
High success rate in kids (80%)
Low success in adults (20%)

Cushings Syndrome
Treatment: Surgical
o Cushings disease
o Bilateral adrenalectomy
If failed pituitary surgery
Life-long steroid replacement

o Adrenal lesions/carcinoma
o Removal of primary lesion
o Survival based on underlying disease

o Ectopic ACTH lesions

o Remove lesion
o Survival based on primary disease
o May need bilateral adrenalectomy to control
symptoms if primary tumor unresectable

Cushings Syndrome
Treatment: Medical
Used as prep for surgery or poor operative candidate
o Metyrapone- inhibits conversion of deoxycortisol to
cortisol
o Aminoglutethimide-inhibits desmolase
Cholesterol to pregnenolone
Blocks synthesis of all 3 corticosteroids
Side effects: N/V, anorexia, lethargy
o Ketoconazole- an imidazole that blocks cholesterol
synthesis
o Mitotane (O-P-DDD)-inhibits conversion to pregnenolone
Inhibits final step in cortisol synthesis
Destroys adrenocortical cells (spares glomerulosa
cells)

42

MULTIPLE ENDOCRINE
NEOPLASIA

outline

Definition
Classification
MEN1/ MEN2
epidemiology
Clinical manifestations
Diagnosis
Treatment
conclusion

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Definition
Multiple endocrine neoplasia syndrome
is defined as a disorder with neoplasms
in two or more different hormonal tissues
in several members of a family.
Usually at an earlier age.
Currently three well-defined MEN
syndromes MEN 1, MEN 2a, MEN 2b.
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Disease Associations in the Multiple Endocrine

Neoplasia (MEN) Syndromes.
MEN1
MEN2
MIXED SYNDROMES
Parathyroid hyperplasia or
adenoma
Islet cell hyperplasia,
adenoma, or carcinoma
Pituitary hyperplasia or
adenoma
Other less common
manifestations: foregut
carcinoid,
pheochromocytoma,
subcutaneous or visceral
lipomas

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MEN2A
MTC
Pheochromocytoma
Parathyroid
hyperplasia or
adenoma
MEN2A with
cutaneous lichen
amyloidosis
MEN2A with
Hirschsprung disease
Familial MTC MEN2B
MTC
Pheochromocytoma
Mucosal and
gastrointestinal
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neuromas

Von HippelLindau
syndrome
Pheochromocytoma
Islet cell tumor
Renal cell carcinoma
Hemangioblastoma
of central nervous
system
Retinal angiomas
Neurofibromatosis
with features of MEN1
or 2 Carney complex,
Myxomas of heart,
skin, and breast
Spotty cutaneous
pigmentation
Testicular, adrenal,
and GH-producing
pituitary tumors
Peripheral nerve

. MEN1 (Wermer's
syndrome)
It is inherited as an autosomal
dominant trait.
Although the mechanism of tumor
genesis at the cellular level is recessive.
Clinical manifestations vary
Generally manifest by the 3rd or 4th
decade
Although rare, MEN1 is the most
common MEN syndrome with
prevalence of 220 per 100,000 .
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The syndrome is Characterized by:

1. neoplasia of the parathyroid

glands-90%
2. enteropancreatic tumors-80%,
3. anterior pituitary adenomas-55%,
4. adrenal adenomas-30%
5.Thyroid nodules -10%

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.
Race
No racial predilection is known.
Sex
The incidence is equal for men and
women.

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Pathphysiology
This syndrome is caused by
inactivating mutations of the tumorsuppressor gene MEN1 located at
chromosome 11q13.
The MEN1 gene codes for a nuclear
protein called Menin

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 Normally ,Menin interacts with JunD,

.
suppressing the JunD-dependent
transcriptional activation.
JunD is associated with inhibition of cell
growth.
When Mutant menin interacts with JunD it
no longer inhibits cell growth hence the
neoplasia.
Each child born to an affected parent has
a 50% probability of inheriting the gene.
The variable penetrance of the several
neoplastic components can make the
differential diagnosis and treatment
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challenging.

Mortality/Morbidity
Benign endocrine and cutaneous
tumors cause morbidity, and
malignancies cause most mortality in
multiple endocrine neoplasia type 1
(MEN1).

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Primary
hyperparathyroidism
The most common manifestation of MEN1
(95100%).
Hypercalcemia may develop during the
teenage years,(hyperplasia of parathyroid
glands)
most individuals are affected by age 40
(adenoma of parathyroid gland).
One of the cardinal features of endocrine
tumors in MEN1multicentricity.
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.
The neoplastic changes inevitably
affect multiple parathyroid glands,
making surgical cure difficult.
Diagnosis :
1.demonstrating elevated levels of
serum calcium
2.intact parathyroid hormone.

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Clinical Manifestations:

Hyperparathyroidism of MEN1 do
not differ substantially from those in
sporadic hyperparathyroidism and
include:
1. calcium-containing kidney stones,
2. kidney failure,
3. nephrocalcinosis,
4. bone abnormalities (i.e.,
osteoporosis, osteitis fibrosa cystica),
5. gastrointestinal and musculoskeletal
complaints

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. Management of .MEN1 is
challenging because of;
1.early onset,
2. significant recurrence rates,
3. multiplicity of parathyroid gland
involvement.
4.Ectopic/ occult glands.
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.
The neoplastic changes inevitably
affect multiple parathyroid glands,
making surgical cure difficult.
Diagnosis :
1.demonstrating elevated levels of
serum calcium
2.intact parathyroid hormone.

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CinicalManifestations:

Hyperparathyroidism of MEN1 do
not differ substantially from those in
sporadic hyperparathyroidism and
include:
1. calcium-containing kidney stones,
2. kidney failure,
3. nephrocalcinosis,
4. bone abnormalities (i.e.,
osteoporosis, osteitis fibrosa cystica),
5. gastrointestinal and musculoskeletal
complaints

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 Hyperparathyroidism of MEN1 can be

.
differentiated from other forms of familial
primary hyperparathyroidism based on;
1. family history,
2. histology of resected parathyroid tissue,
3. presence of a MEN1 mutation and,
4. long-term observation to determine
whether other manifestations of MEN1
develop.
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Treatment
Criteria for surgery
1.Individuals with serum calcium levels
>3.0 mmol/L (12 mg/dL),
2.evidence of calcium nephrolithiasis or
renal dysfunction,
3. neuropathic or muscular symptoms, or
4.bone involvement (including osteopenia)
or
5. individuals <50 years of age .
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 When surgery is indicated , there are

two approaches. .
I. All parathyroid tissue are identified and
removed and parathyroid tissue is
implanted in the nondominant forearm.
+ Thymectomy because of
development of malignant carcinoid
tumors.

2. Remove 33.5 parathyroid glands from

the neck (leaving ~50 mg of parathyroid
tissue),
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Enteropancreatic tumors

Second most common manifestation

of MEN1,
30% are malignant
estimated penetrance of 50%.
They tend to occur in parallel with
hyperparathyroidism.
tumors secrete peptide hormones
that cause specific clinical
syndromes.
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1. Gastrinomas

most common enteropancreatic tumors in

MEN1 patients
result in the Zollinger-Ellison syndrome
(ZES).
ZES is caused by excessive gastrin
production
Occurs in > of MEN1 pts with small
carcinoid-like tumors in the duodenal wall
or, less often, by pancreatic islet cell
tumors.
There may be > one gastrin-producing
tumor, making localization
difficult.
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manifestation
The robust acid production may cause;
1. esophagitis,
2.duodenal ulcers throughout the duodenum,
3. ulcers involving the proximal jejunum, and
4. diarrhea.
The ulcer diathesis is commonly refractory
to conservative therapy such as antacids.
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diagnosis

Increased gastric acid secretion,

elevated basal gastrin levels in the
serum [generally >115 pmol/L
an exaggerated response of serum
gastrin to either secretin or calcium.
NB:Approximately one-fourth of all ZES
occurs in the context of MEN1

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Other causes of elevated serum gastrin

levels should be excluded , such as :

1. achlorhydria,
2. treatment with H2 receptor antagonists
or proton pump inhibitors,
3. retained gastric antrum,
4. small-bowel resection,
5. gastric outlet obstruction, and
6. hypercalcemia,

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2 . Insulinomas
second most common
enteropancreatic tumors in MEN1.
Unlike gastrinomas, most insulinomas
originate in the pancreas bed,
becoming the most common
pancreatic tumor in MEN1.
The tumors may be benign or
malignant (25%).
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diagnosis
hypoglycemia during a short fast
inappropriate elevation of serum
insulin and C-peptide levels.
Large insulinomas may be identified
by CT or MRI scanning.
Intraoperative ultrasonography.
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3 . Glucagonoma

seen occasionally in MEN1,

manifestations :
causes a syndrome of,
hyperglycemia,
skin rash (necrolytic migratory erythema),
anorexia,
glossitis,
anemia,
depression,
diarrhea, and venous thrombosis.

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4. VIPomas (1%) secrete

VIP and cause
.
profuse watery diarrhea,
hypokalemia, and achlorhydria
(WDHA, VernerMorrison syndrome).

5. Somatostatinomas (0.7%) can cause

diabetes mellitus, steatorrhea, and
cholelithiasis.
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.
The pancreatic neoplasms differ from
the other components of MEN1 in
that approximately one-third of the
tumors display malignant features,
including hepatic metastases

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Tx of Pancreatic Islet Cell Tumors

Two features complicate the

management.
1. the pancreatic islet cell tumors are
multicentric, malignant about a third of
the time, and cause death in 1020% of
patients.

2. performance of a total pancreatectomy

to prevent malignancy causes diabetes
mellitus, a disease with significant longterm complications that include
neuropathy, retinopathy, and
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nephropathy.

general concepts in tx;

(1) Islet cell tumors should be resected
because medical therapy for the hormonal
effects are generally ineffective.
(2) Gastrin-producing islet cell tumors that
cause ZES are frequently multicentric.
Caused by duodenal wall carcinoid tumors
and that resection of these tumors improves
the cure rate.
(3) In families in which there is a high
incidence of malignant islet cell tumors that
cause death, total pancreatectomy at an
early age may be considered to prevent
malignancy.
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 Mgt of metastatic islet

. cell carcinoma is
unsatisfactory.
Hormonal abnormalities can sometimes
be controlled. eg ZES can be treated
with H2 receptor antagonists or proton
pump inhibitors;
somatostatin analogues eg octreotide or
lanreotide, are useful in the management
of carcinoid, glucagonoma, and the
watery diarrhea syndrome.
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 Bilateral adrenalectomy for ectopic ACTH

syndrome .

Islet cell carcinomas frequently metastasize

to the liver but may grow slowly.
Hepatic artery embolization,
radiofrequency ablation, or chemotherapy
may reduce tumor mass, control symptoms
of hormone excess, and prolong life;
however, these treatments are never
curative.
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Pituitary tumors
occur in 2030% of patients
These tumors can exhibit aggressive behavior
and local invasiveness that makes them difficult
to resect.
1 Prolactinomas are most common
Diagnosis:
serum prolactin levels >200 g/L, with or without
a pituitary mass evident by MRI.
Values <200 g/L may be due to a prolactinsecreting neoplasm or to compression of the
pituitary stalk by a different type of pituitary
tumor.
2 Acromegaly due to excessive GH production is the
second most common syndrome caused by
pituitary tumors in MEN1.
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3. Cushing's disease: .
caused by ACTH-producing pituitary
tumors or by ectopic production of ACTH or
CRH by other components of MEN1
syndrome including islet cell or carcinoid
tumors or adrenal adenomas.
Diagnosis:
pituitary Cushing's disease is generally
best accomplished by a high-dose
dexamethasone suppression test or by
petrosal venous sinus sampling for ACTH
after IV injection of CRH.
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Adrenal adenomas
/hyperplasia
:
occurs in about 37% of patients with MEN 1

50% are bilateral.

They are generally benign and nonfunctional.
In one series, one out of 12 patients
developed a feminizing adrenal carcinoma.
These adrenal lesions are pituitary
independent
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Tx of Pituitary Tumors
Treatment of prolactinomas is with
dopamine agonists (bromocriptine,
cabergoline, or quinagolide) which
usually returns the serum prolactin
level to normal and prevents further
tumor growth.
Surgical resection of a prolactinoma
not curative but may relieve mass
effects.

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 Octreotide reduces tumor mass in

.
one-third of GH-secreting
tumors and
reduces GH and insulin-like growth
factor I levels in >75% of patients.

Pegvisomant, a GH antagonist,
rapidly lowers insulin-like growth factor
levels in patients with acromegaly .

Radiation therapy in large or recurrent

tumors.
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Nonendocrine tumors
Small facial angiofibromas
subcutaneous lipomas .
Collagenomas can present as firm
dermal nodules.
Malignant melanomas have been
reported
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MEN 2

Sipple 1st described an ass btw

thyroid cancer and
pheochromocytoma in 1961.
The thyroid ca was discovered to be
a medullary ca in 1965.
This familial constellation of
pathology in conjunction with
parathyroid hyperplasia was
recognized as MEN 2 in 1968.

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 Although pts with mucosal neuromas were

identified at this time, the distinction btw
MEN 2A and MEN 2B was not made until
1975.

MEN 2A pts do not have mucosal neuromas

and marfanoid habitus found in MEN 2B pts.
MEN 2A patients also have a less virulent
form of medullary thyroid ca (MTC) than MEN
2B pts.
MEN 2A pts may have parathyroid
hyperplasia, which is jcarare in MEN 2B pts.
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MEN 2A (Sipple's
Syndrome)
MEN 2A is a rare familial
multiglandular syndrome that is
inherited as an autosomal dominant
trait.

Pts have ret protooncogene (RET)

mutation.
Their first-degree relatives may have
specific RET mutation.
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Patients may present with:

1. medullary thyroid carcinoma (> 90%);
2. hyperparathyroidism (2050%), due to
hyperplasia or multiple adenomas in over
70% of cases;
3. pheochromocytomas (2035%), which
are often bilateral; or
4. Hirschsprung's disease.
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Laboratory Studies
Screening for medullary thyroid
carcinoma is done with the pentagastrin
stimulation test,
Urinary catecholamines and
metanephrines screen for
pheochromocytomas.
Serum calcium level and PTH levels
screen for hyperparathyroidism.
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Imaging Studies
Perform CT scanning or MRI for
imaging of the adrenals.
If calcitonin levels are elevated at
either baseline or with provocative
testing, evaluate the chest and
abdomen for metastatic disease.

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Tx
MTC : Total thyroidectomy has been
recommended for pts as young as
age 3 years for MEN 2A if they
contain the genetic mutation.
Thyroid hormones
For supplemental therapy in
hypothyroidism
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Imaging Studies
Perform CT scanning or MRI for
imaging of the adrenals.
If calcitonin levels are elevated at
either baseline or with provocative
testing, evaluate the chest and
abdomen for metastatic disease.

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Parathyroid disease
Hyperparathyroidism usually manifests in
patients older than 30 years.
Histologically, consist of a chief-cell
hyperplasia.
If all parathyroid glands are enlarged, a
subtotal parathyroidectomy is advocated,
leaving an approximately 60-mg remnant.
Cervical thymectomy because of the increased
risk of supernumerary parathyroid glands.
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Parathyroid disease
Hyperparathyroidism usually manifests in
patients older than 30 years.
Histologically, consist of a chief-cell
hyperplasia.
If all parathyroid glands are enlarged, a
subtotal parathyroidectomy is advocated,
leaving an approximately 60-mg remnant.
Cervical thymectomy because of the increased
risk of supernumerary parathyroid glands.
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.
Vitamin D supplements
May increase serum calcium levels
by improving calcium absorption.

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Tx Pheochromocytoma
Unilateral adrenalectomy avoids the risk of
Addisonian crisis and improves the quality
of life by not requiring replacement therapy.
Some investigators have advocated
bilateral adrenalectomy in all patients
because of risk of malignancy (rare) and
the operative complications from
subsequent surgeries.
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 Mineralocorticoids
.
Partial replacement therapy for
primary and secondary
adrenocortical insufficiency
Corticosteroids
Cause profound and varied
metabolic effects. Corticosteroids
modify the body's immune
response to diverse stimuli.

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MEN 2B
familial, autosomal dominant
multiglandular syndrome that is
caused by a mutation of the ret
protooncogene (RET) on
chromosome 10.

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MEN 2B is characterized by;

1. mucosal neuromas (>90%) with bumpy and
enlarged lips and tongue,
2. Marfan-like habitus (75%),
3. adrenal pheochromocytomas (60%) that are
rarely malignant and often bilateral,
4. medullary thyroid carcinoma (80%).
5. intestinal ganglioneuromas,
6. skeletal abnormalities (87%), and
7. delayed puberty (43%).

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.
Medullary thyroid carcinoma is
aggressive and presents early in life.
Therefore, infants having a parent
with MEN 2B receive genetic
screening; those carrying the RET
mutation undergo a prophylactic
total thyroidectomy by age 6
months.
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Follow up
Monitor pts for recurrence ofmedullary thyroid
carcinomawith calcitonin, CEA, and +/provocative calcitonin testing.
Perform annual screening for
hyperparathyroidism with serum calcium and PTH
levels in MEN 2A patients.
Obtain urinary catecholamine levels on an annual
basis to assess for pheochromocytoma.
Carefully monitor medication dosage and adverse
effects
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Nonendocrine Tumors
Ectopic hormones: hormones secreted by
nonendocrine tumors that are identical with or
mimic action of true hormones
Usual origin: produced by malignant tumors
Lung, pancreas, kidneys, connective tissue

conclusion
MEN is rare
Inheritance is by autosomal dorminance
effective management requires an understanding
of endocrine neoplasia
Early genetic testing help decisions for
prophylactic surgeries for individuals at risk
Early treatment ofmedullary thyroid carcinoma
prevents death.
Careful monitoring for pheochromocytomas can
decrease the chance of hypertensive episodes

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101