Endocrine Path Flashcards
(130 cards)
1
Q
A number of pathologies can disturb the
normal activity of the endocrine system.
A
¡ abnormal synthesis or release of hormones from endocrine (and sometimes non-endocrine) tissues ¡ abnormal responses to hormones by their target tissues and organs
2
Q
Causes of hormone overproduction
hyperfunction
A
¡ Adenoma (most common)
¡ Acute inflammation
¡ Hyperplasia
¡ Cancer
3
Q
Causes of hormone underproduction
hypofunction
A
¡ Autoimmune destruction (most common) ¡ Any process that destroys endocrine tissue l infarction, surgery, radiation, infection, etc. ¡ Decreased stimulation by neuroendocrine messengers ¡ Enzyme deficiency ¡ Neoplasia ¡ Congenital disorder
4
Q
lactotrophs
A
prolactin
5
Q
mammosomatotrophs
A
prolactin
GH
6
Q
somatotroph
A
GH
7
Q
lactotroph regulators
A
TRH
dopamine
8
Q
mamosomatotrophs regulators
A
dopamine
GHRH
somatostatin
9
Q
somatotroph regulators
A
GHRH
somatostatin
10
Q
Hyperpituitarism
A
l adenoma (most common) l hyperplasia l cancer l non-pituitary tumors l hypothalamic disorders
11
Q
Hypopituitarism
A
l destructive processes: ischemia, surgery,
radiation, inflammation
l nonfunctional adenomas that compress and
destroy functional pituitary tissue -most common
adult cause
hypothalamic disorders
-most common cause in children (craniopharyngioma)
12
Q
Local mass effects
A
l expanding lesions near the sella turcica compress
the optic chiasm → visual field disturbances
-classically affect lateral (temporal) vision =
bitemporal hemianopsia
l signs and symptoms of elevated cranial pressure
-headache, nausea, vomiting
13
Q
pituitary apoplexy
A
l acute hemorrhage into adenoma with rapid
lesion enlargement
l causes sudden onset of excruciating
headache, diplopia (due to pressure on
oculomotor nerves), and hypopituitarism
l surgical emergency (can lead to sudden
death)
14
Q
Molecular features of pituitary
adenomas
A
¡ monoclonal in origin ¡ features of aggressive tumors l RAS-activating mutations l c-Myc overexpression ¡ MEN1 mutations uncommon in sporadic cases ¡ best characterized genetic abnormality = G-protein gene mutations
15
Q
Prolactinoma
A
¡ produce increased serum levels of prolactin (hyperprolactinemia) ¡ most common hyperfunctioning pituitary tumor (~40%) -most (90%) are small, intrasellar tumors that rarely increase in size *efficient producers of prolactin
16
Q
Prolactinoma:
Clinical Features
A
¡ most common in premenopausal women: amenorrhea and infertility -most commonly detected after discontinuation of oral contraceptives -less common: galactorrhea (80%), oligomenorrhea ¡ most tumors small at diagnosis ¡ most common in men: headaches and neurologic disturbances -less common: impotence, infertility, decreased libido -uncommon: galactorrhea and gynecomastia ¡ large size at diagnosis
17
Q
Other causes of hyperprolactinemia…
A
¡ any process that interferes with dopamine secretion or delivery to the portal vessels of the anterior pituitary -nonfunctioning pituitary tumors that compress the pituitary stalk (known as “the stalk effect”) -hypothalamic neoplasms (e.g., craniopharyngiomas) -head trauma -medications ¡ pregnancy and breast-feeding ¡ renal failure -decreased clearance ¡ primary hypothyroidism -mild hyperprolactinemia may develop due to increased synthesis of thyrotropin-releasing hormone
18
Q
Other causes of hyperprolactinemia…
A
¡ any process that interferes with dopamine secretion or delivery to the portal vessels of the anterior pituitary -nonfunctioning pituitary tumors that compress the pituitary stalk (known as “the stalk effect”) -hypothalamic neoplasms (e.g., craniopharyngiomas) -head trauma -medications ¡ pregnancy and breast-feeding ¡ renal failure -decreased clearance ¡ primary hypothyroidism -mild hyperprolactinemia may develop due to increased synthesis of thyrotropin-releasing hormone
19
Q
Prolactinoma:
Diagnostic Features
A
¡ obtain serum prolactin level -because levels are pulsatile or can be affected by stress, repeat tests that show mild elevations ¡ rule out other causes using the -H&P -pregnancy test -assessments of thyroid and renal function ¡ confirm diagnosis with MRI
20
Q
Prolactinoma biopsy
A
although biopsy is not necessary to diagnose prolactinomas, you should know that excised lesions show a tendency to undergo dystrophic calcification -psammoma bodies (microscopic calcifications) -pituitary stones (gross calcification of tumor mass)
21
Q
Growth Hormone (Somatotroph) Adenomas
A
cause elevated levels of serum growth hormone (GH) -because the manifestations of excessive GH are subtle, these adenomas are usually quite large by the time they are diagnosed second most common type of hyperfunctioning pituitary adenoma
22
Q
Growth Hormone (Somatotroph) Adenomas: Clinical Features
A
In adults, Acromegaly -Acro = tip, extremity, end In children and teenagers, gigantism
23
Q
Growth Hormone (Somatotroph) Adenomas: Diagnostic Features
A
¡ elevated IGF-I levels
¡ autonomous secretion of growth hormone
-failure to suppress GH production in response to an
oral glucose load is one of the most sensitive tests
for acromegaly
¡ use H&P, etc. to exclude other causes of elevated
growth hormone
¡ Pituitary MRI with contrast material is the most
sensitive imaging study for determining the
source of excess growth hormone… usually
(>90% of cases) an adenoma is the cause.
24
Q
Corticotroph Adenomas
A
Causes excess production of ACTH, leading to
adrenal hypersecretion of cortisol and the
development of hypercortisolism (Cushing disease)
Nelson Syndrome
25
Nelson Syndrome
```
a pre-existing corticotroph tumor
grows rapidly after surgical removal
of the adrenal glands
hypercortisolism doesn’t develop,
but mass effects occur
hyperpigmentation common
```
26
Gonadotroph (LH- or FSH-producing)
| Adenomas
```
difficult to recognize because they
do not cause a recognizable clinical
syndrome and hormone production
varies considerably
most common presentation:
neurologic symptoms due to mass
effects
different effect than most
adenomas: these usually cause
hypofunction rather than
hyperfunction (clonal cell population
is non-functioning, and compresses
normal functioning tissue)
-men: reduced testosterone à
decreased energy and libido
-premenopausal women: amenorrhea
```
27
```
Sheehan syndrome (post-partum
necrosis of the anterior pituitary)
```
¡ most common form of clinically
significant ischemic necrosis of the
pituitary
¡ know pathogenesis
28
Rathke’s Cyst
```
¡ reminder: anterior
pituitary is
embryologically
derived from the
Rathke pouch
¡ cysts accumulate
proteinaceous fluid
and expand,
compromising the
normal gland
```
29
Primary Empty Sella Syndrome
```
¡ due to defect in the
diaphragma sella
-allows arachnoid
matter and CSF to
herniate into the sella,
compressing the
pituitary
¡ risk groups: obese
women with multiple
pregnancies
```
30
Secondary Empty Sella Syndrome
a mass enlarges the sella, but it is
either surgically removed or
undergoes spontaneous necrosis,
leading to loss of pituitary function
31
Hypothalamic Disorders
```
¡ in contrast to diseases that
involve the pituitary
directly, these also
diminish the secretion of
ADH, resulting in diabetes
insipidus
¡ in addition to tumors,
inflammatory disorders and
infections can also
compromise the
hypothalamus (e.g.,
sarcoidosis and tuberculous
meningitis)
```
32
Hypopituitarism
```
the clinical manifestations of
anterior pituitary hypofunction are
determined by the specific
hormones that are lacking…
-GH deficiency: pituitary dwarfism
*whereas achondroplastic dwarfism
primarily affects the long bones, pituitary
dwarfism is proportional
```
33
Diabetes Insipidus
```
condition characterized by excessive
urination (polyuria)
-kidneys cannot resorb water properly
from urine
*produce large volumes of dilute urine with
low specific gravity
results in excessive thirst and
polydipsia
```
34
Central Diabetes Insipidus
```
originating from
ADH deficiency
causes:
-head trauma
-tumors
-inflammatory
disorders of the
hypothalamus and
pituitary
surgery
```
35
Nephrogenic Diabetes Insipidus
results from tubular unresponsiveness to
| circulating ADH
36
Syndrome of Inappropriate ADH
| (SIADH) Secretion
```
ADH excess causes resorption of
excessive amounts of free water,
resulting in hyponatremia
-leads to cerebral edema and neurologic
dysfunction
```
37
Thyroid Function Tests
Serum TSH
-most valuable
Total serum T4
-represents T4 bound to TBG and free T4 (FT4)
*Interpret with caution: any change in TBG will
affect total serum T4, but not free T4 (which
is active form)
*↑TBG: estrogen
~pregnancy, oral contraceptives, HR
*↓TBG: anabolic steroids, nephrotic syndrome
Free serum T4 or T3
Radioactive iodine uptake
- 131I, 123I, or 99mTc
38
Thyroid Function Tests
Serum TSH
-most valuable
Total serum T4
-represents T4 bound to TBG and free T4 (FT4)
*Interpret with caution: any change in TBG will
affect total serum T4, but not free T4 (which
is active form)
*↑TBG: estrogen
~pregnancy, oral contraceptives, HR
*↓TBG: anabolic steroids, nephrotic syndrome
Free serum T4 or T3
Radioactive iodine uptake
- 131I, 123I, or 99mTc
39
Hypothyroidism
```
inadequate levels of thyroid
hormone
l primary hypothyroidism
-intrinsic thyroid abnormality
l secondary hypothyroidism
-pituitary abnormality (↓TSH)
l tertiary hypothyroidism (rare)
-hypothalamic abnormality (↓TRH)
```
40
Causes of primary hypothyroidism
thyroprivic
| goitrous
41
thyroprivic
(absence or loss of thyroid
parenchyma)
radiation
surgery (thyroidectomy)
42
goitrous
(enlargement of the thyroid due to
↑TSH)
iodine-deficiency
autoimmune (most common in iodine-sufficient
areas)
-Hashimoto thyroiditis most common (see below)
drugs
-intentional (e.g., methimazole, propylthiouracil)
-unintentional (e.g., lithium, p-aminosalicylic acid)
inborn errors of thyroid metabolism (uncommon)
43
Clinical Manifestations of
| Hypothyroidism: Cretinism
```
¡ limited to neonates and children
¡ formerly most common in areas of
endemic iodine-deficiency… now
fairly restricted to inborn errors of
thyroid metabolism and maternal
hypothyroidism (before fetal thyroid
develops)
```
44
Cretinism clinical features
```
l severe mental retardation
-from the French chrétien
(Christ-like), as afflicted
individuals believed to
be too mentally
retarded to commit sin
l short stature
l coarse facial features,
protruding tongue
l umbilical hernia
```
45
Clinical Manifestations of
| Hypothyroidism: Myxedema
clinical manifestations more severe
in younger patients, whereas they
develop insidiously in adults
```
Clinical Features:
-initially: generalized fatigue, apathy,
mental sluggishness
*may mimic depression in early stages
edema, broadening of facial
features, enlarged tongue,
voice deepens
-due to accumulation of
matrix substances (e.g.,
GAGs, hyaluronic acid) in
skin, subcutaneous tissue,
and visceral sites
cold-intolerance; cool, pale
skin
slowed metabolism →
overweight
reduced cardiac output:
breathlessness, ↓exercise
capacity
decreased sympathetic
activity: constipation,
↓sweating
```
46
Hashimoto Thyroiditis
| Chronic Lymphocytic Thyroiditis
¡ presented here as the prototype of
hypothyroid disorders
¡ autoimmune destruction of the thyroid
gland
¡ most common cause of hypothyroidism in
areas of the world where iodine levels are
sufficient
-most prevalent in 45-65 y.o. women (female
predominance 10-20:1), but also a major
cause of nonendemic goiter in children
47
Hashimoto Thyroiditis info
l genetic component to susceptibility
-concordance rate in monozygotic twins =
30-60%
-50% of asymptomatic 1st-degree relatives
have circulating antithyroid antibodies
l associated with chromosomal abnormalities
-Turner syndrome
*circulating antithyroid antibodies common
*~20% develop hypothyroidism that is clinically
indistinguishable from Hashimoto thyroiditis
-Down syndrome
*increased risk for Hashimoto thyroiditis and
hypothyroidism
48
Hashimoto Thyroiditis
| Pathogenesis
immune system reacts against thyroid antigens
-anti-TSH receptor antibodies, antithyroglobulin,
antithyroid peroxidase
49
Hashimoto Thyroiditis Morphology
l diffuse enlargement of the thyroid
l fine-needle aspiration biopsies typified by Hürthle cells and heterogeneous population of
lymphocytes
-Hürthle cells = metaplastic response of
follicular epithelium to injury
*distinguished by eosinophilic, granular cytoplasm
50
Hashimoto Thyroiditis
| Clinical Features
```
typical presentation: painless diffuse
enlargement of the thyroid in middleaged
woman demonstrating some
degree of hypothyroidism
-hypothyroidism develops gradually
*in some cases, death of thyroid follicles
releases thyroid hormone, causing transient
thyrotoxicosis (“hashitoxicosis”)
```
51
Hyperthyroidism
```
¡ usually synonymous with
thyrotoxicosis, a hypermetabolic
state caused by elevated circulating
levels of free T3 and T4
-primary hyperthyroidism
*intrinsic thyroid abnormality
-secondary hyperthyroidism
*pituitary abnormality (↑TSH)
-tertiary hyperthyroidism
*hypothalamic abnormality (↑TRH)
```
52
Causes of primary hyperthyroidism
```
¡ diffuse hyperplasia of the thyroid
associated with Graves disease
- ~85% of cases… note that this “breaks
the rule” for most common causes of
endocrine hyperfunction
¡ hyperfunctional multinodular goiter
¡ hyperfunctional adenoma of the
thyroid
```
53
Causes of primary hyperthyroidism
```
¡ diffuse hyperplasia of the thyroid
associated with Graves disease
- ~85% of cases… note that this “breaks
the rule” for most common causes of
endocrine hyperfunction
¡ hyperfunctional multinodular goiter
¡ hyperfunctional adenoma of the
thyroid
```
54
Hyperthyroidism
| Clinical Features
```
related to hypermetabolic state and
overactivity of sympathetic nervous
system
-↑basal metabolic rate
*weight loss despite increased appetite
* skin warm and flushed due to ↑peripheral
vasodilation to dissipate heat to heat
intolerance
cardiac manifestations (most consistent
feature)
-↑cardiac contractility and ↑peripheral O2
requirements
-tachycardia, palpitations, cardiomegaly
- arrhythmias (esp. atrial fibrillation) more
common in older patients
tremor, hyperactivity, emotional
lability, anxiety, insomnia
thyroid myopathy (decreased
muscle mass)
GI: hypermotility, malabsorption,
and diarrhea
bone resorption stimulated to
osteoporosis, fractures
ocular changes: staring gaze, lid lag
-differs from exophthalmos of Graves
disease
```
55
Graves Disease
¡ presented here as the prototype of hyperthyroid
disorders
¡ also an autoimmune disorder of the thyroid, but
TSH receptor autoantibodies stimulate thyroid
hyperfunction
¡ most common cause of endogenous
hyperthyroidism
-most prevalent in women 20-40 y.o. (female
predominance ~7:1)
-genetic component to susceptibility
*increased incidence among family members of
affected patients
*concordance rate in monozygotic twins ~60%
*associated with HLA-B8 and HLA-DR4, and
polymorphisms in cytotoxic T-lymphocyteassociated-
4 (CTLA-4) gene
56
Graves Disease
```
similar to Hashimoto disease, a
variety of antibodies are present in
the serum, but the net effect is
stimulation of thyroid gland growth
and release of hormone
-Thyroid-stimulating immunoglobulin (TSI)
-Thyroid growth-stimulating
immunoglobulins (TGI)
-TSH-binding inhibitor immunoglobulins
(TBII)
```
57
Thyroid-stimulating
| immunoglobulin (TSI)
```
most important
antibody to
pathogenesis and
diagnosis
-TSI is specific to
Graves disease, in
contrast to other
antibodies
IgG antibody that
mimics TSH by binding
the TSH receptor and
stimulating adenyl
cyclase à thyroid
hormone release
```
58
Graves Disease
| Morphology
diffuse hypertrophy and hyperplasia
| of thyroid follicular epithelium
59
Graves Disease typical presentation
painless diffuse
enlargement of the thyroid gland in a young
woman demonstrating some degree of
hyperthyroidism
“characterized by a triad of clinical
findings” (but not found in all patients)
-diffuse hyperplasia of the thyroid, producing
hyperthyroidism
-infiltrative ophthalmopathy with resultant
exophthalmos
a localized, infiltrative dermopathy most
common over the shins (pretibial myxedema)
60
Graves Disease:
| Exophthalmos
```
orbital preadipocyte
fibroblasts express
TSH receptor, so
they are also
targets of
autoimmune attack
```
61
Graves Disease:
| Pretibial myxedema
```
¡ a localized,
infiltrative
dermopathy
most common
over the shins
¡ least common
feature in the
triad
```
62
thyroid storm occurs most commonly in
| patients with underlying Graves disease
```
l term for abrupt onset of severe
hyperthyroidism
l TH increases target cell response to
catecholamines, so any form of stress
(surgery, infection, trauma) can precipitate
onset
l a medical emergency: death by cardiac
arrhythmias possible
```
63
Diffuse and Multinodular Goiter
```
¡ goiter = enlargement of the
thyroid
-as you've seen so far, the
most common manifestation
of thyroid disease
¡ unless autoimmune, most
common cause is iodine
deficiency
-impaired synthesis of thyroid
hormone causes
compensatory rise in serum
TSH, causing hypertrophy
and hyperplasia of thyroid
follicular cells
```
64
Diffuse Nontoxic Goiter
```
¡ diffuse involvement of the entire
gland; no nodularity
-enlarged follicles filled with colloid, so
aka "colloid goiter“
¡ Two distributions
-Endemic goiter
-Sporadic goiter
```
65
Multinodular Goiter
```
result from unresolved simple goiter:
recurrent episodes of hyperplasia
and involution combine to produce
irregular, nodular enlargement
may be nontoxic (majority of
patients) or produce thyrotoxicosis
-Toxic multinodular goiter
*aka, Plummer syndrome
*classic signs and symptoms of
hyperthyroidism
*hyperfunctioning nodules concentrate
radioiodine and appear "hot"
```
66
Multinodular Goiter
```
¡ mistaken for neoplasms
¡ mass effects
-airway obstruction
-dysphagia
¡ compression of large vessels in neck and
upper thorax
```
67
Thyroid Neoplasms
almost all present as solitary thyroid
nodules (palpably discrete swellings)
within an apparently normal thyroid gland
-clinical significance of thyroid nodules
-incidence of 1-10% of U.S. population; 4x
more common in women
*higher in endemic goitrous regions
-overwhelming majority are not neoplastic, and
of those that are, most are benign
(outnumber carcinomas by 10:1)
*most thyroid carcinomas are indolent (90%
survival at 20 years)
68
Clues that a thyroid nodule has a
| higher likelihood of being neoplastic:
¡ it is solitary
¡ the patient is young
¡ the patient is male
¡ the patient has a history of radiation
treatment to the head and neck
¡ “hot” nodules (take up radioactive iodine
in imaging studies) are more likely to be
non-neoplastic or benign than malignant
- ~10% of cold nodules eventually prove to be
malignant, whereas hot nodules are rarely
malignant
69
Thyroid Adenomas
```
¡ with rare exception, they are all
derived from follicular epithelium
(follicular adenomas)
¡ most are nonfunctional, but a small
number produce thyroid hormone
and can cause thryotoxicosis (toxic
adenomas)
This one breaks general rule about
“most common cause” of endocrine
hyperfunction
```
70
Thyroid Adenomas
```
¡ with rare exception, they are all
derived from follicular epithelium
(follicular adenomas)
¡ most are nonfunctional, but a small
number produce thyroid hormone
and can cause thryotoxicosis (toxic
adenomas)
This one breaks general rule about
“most common cause” of endocrine
hyperfunction
```
71
Thyroid Adenomas path
```
activating mutations
in TSH receptor or Gprotein
α-subunit to
↑cAMP to follicular
cell proliferation and
hormone release
-only represent
~10-75% of
adenomas, so
other mutations
remain undefined
```
72
Thyroid Adenomas clinical features
```
l typical: solitary
painless mass
discovered during
routine physical exam
l most appear as cold
nodules
¡ some may
degenerate into cysts
filled with blood,
hemosiderin pigment,
and cell debris (also
true for multinodular
goiters)
```
73
Papillary Thyroid Carcinoma
```
¡ most common form
-75-85% of thyroid cancers
¡ most often in 20-40 y.o. females
exposed to ionizing radiation
¡ solitary or multifocal
¡ encapsulated or with ill-defined margins
```
74
Papillary Thyroid Carcinoma hallmarks
l contain papillae (fibrovascular stalk covered by
cuboidal epithelium)
l nuclei contain finely dispersed chromatin,
imparting a clear or empty appearance
(“ground glass”, “Orphan Annie eye nuclei”)
l psammoma bodies common
75
Papillary Thyroid Carcinoma
| Pathogenesis
```
l RET or NTRK1
(neurotrophic tyrosine
kinase receptor 1)
rearrangements
-receptor tyrosine
kinases that transduce
extracellular signals for
growth and
differentiation via MAP
kinase pathway
l BRAF oncogene activating
mutations
-intermediary in MAP
kinase pathway
l RAS mutations
Paps are due to mutations affecting MAPs
```
76
Papillary Thyroid Carcinoma
usually asymptomatic, freely-moving nodule
-first manifestation is often a cervical lymph
node mass
-hoarseness, dysphagia, cough, or dyspnea
(signals advanced disease)
-hematogenous metastases (lung) uncommon at
time of diagnosis
usually cold mass on scintiscans
excellent prognosis: 10-year survival rate
>95%
-dependent on age (worse >40 yoa), local
invasion, and presence of distant metastases
77
Follicular Thyroid Carcinoma
```
accounts for 10-20% of all thyroid
cancers
most common in 40-60 y.o.
women; increased in areas of iodine
deficiency
```
78
Follicular Thyroid Carcinoma clinical features
```
l usually slowly enlarging painless
nodules
l usually cold on scintiscans
l little propensity for invading
lymphatics, but hematogenous
dissemination is common (bone, lungs,
liver)
l prognosis poor for widely invasive
form: 10-year survival ~50%
```
79
Medullary Thyroid Carcinoma
in contrast to other thyroid carcinomas,
this type is derived from the parafollicular
cells (C cells)
-cells secrete calcitonin (no hypocalcemia, but
used as serum tumor marker)
-cells may also secrete other polypeptide
hormones (somatostatin, serotonin, and
vasoactive intestinal peptide)
*may cause paraneoplastic syndromes (e.g.,
diarrhea due to VIP)
80
Medullary Thyroid Carcinoma incidence
```
¡ peak incidence: 40-60 y.o.a.
¡ most are sporadic (~80%), but can
arise in context of MEN syndrome
2A or 2B, or familial medullary
thyroid carcinoma (FMTC)
-Pathogenesis: activating RET mutations
```
81
Medullary Thyroid Carcinoma morphology
l sporadic cases usually solitary nodules, whereas
familial have multiple lesions
l stroma may contain amyloid deposits, derived
from altered calcitonin
l C-cell hyperplasia in a tumor should raise
suspicion of familial cancer syndrome
82
Medullary Thyroid Carcinoma clincial features
```
l comes to attention as either a mass in
the neck (may produce dysphagia or
hoarseness), or a paraneoplastic
syndrome
l major risk factor for poor outcome in
patients with MEN-2 RET mutations (so
prophylactic thyroidectomy is offered to
these patients)
```
83
Anaplastic Thyroid Carcinoma
```
¡ aggressive tumors (mortality rate almost
100% because no effective therapy)
¡ 65 y.o.a.; half have
history of multinodular goiter; many have
history of other thyroid cancer
¡ Clinical Features
-rapidly enlarging bulky neck mass
(compression and invasion symptoms)
```
84
Hyperparathyroidism
```
¡ special note: hypercalcemia is NOT
universal to hyperparathyroidism
¡ hyperparathyroidism occurs in two
major forms: primary and
secondary
```
85
Primary Hyperparathyroidism
```
¡ autonomous overproduction of PTH
by the parathyroid gland
¡ one of the most common endocrine
disorders
¡ generally a disease of adults (most
cases >50 yoa); more common in
women (3:1)
```
86
Primary Hyperparathyroidism
| Presents in one of two ways:
```
asymptomatic hyperparathyroidism
-elevated serum calcium is detected by
routine work-up for unrelated conditions
-most common cause of asymptomatic
hypercalcemia
symptomatic hyperparathyroidism
```
87
Primary Hyperparathyroidism causes
```
l parathyroid adenomas: 75-80%
l primary hyperplasia of the parathyroid
(diffuse or nodular): 10-15%
l parathyroid carcinoma: very rare
(
```
88
Primary Hyperparathyroidism path
l MEN-1 mutations (familial and sporadic forms)
l RET activating mutations (familial and sporadic
forms)
l CASR mutations (familial only)
-CASR is a calcium-sensing receptor
*mutations cause decreased sensitivity to
extracellular calcium à parathyroid hyperplasia
and enhanced PTH secretion
l Parathyroid adenoma 1 (PRAD1)
-sporadic only
-encodes cyclin D1
89
Primary Hyperparathyroidism must be
| distinguished from FHH
```
CASR mutations cause familial
hypocalciuric hypercalcemia (FHH)
-hypercalcemia should be obvious, but
why low urinary calcium?
*calcium receptors also deficient in kidney
to perceived low calcium
*PTH stimulates resorption of Ca++ by
kidney, so less makes it into the urine
-typically asymptomatic
-autosomal dominant or recessive?
```
90
Primary Hyperparathyroidism must be
| distinguished from FHH
```
CASR mutations cause familial
hypocalciuric hypercalcemia (FHH)
-hypercalcemia should be obvious, but
why low urinary calcium?
*calcium receptors also deficient in kidney
to perceived low calcium
*PTH stimulates resorption of Ca++ by
kidney, so less makes it into the urine
-typically asymptomatic
-autosomal dominant or recessive?
```
91
Primary Hyperparathyroidism morphology
```
l adenomas typically involve 1 gland,
whereas hyperplasia classically affects
all 4 (even though sometimes a gland
or two is spared)
l parathyroid carcinomas cannot be
distinguished from parathyroid
adenomas based on cytology à only
reliable criteria of malignancy is
presence of metastases or local
invasion
```
92
Secondary Hyperparathyroidism
```
caused by any condition associated with
chronic depression in serum calcium level
-renal failure (most common cause)
*mechanisms not fully understood
*↓phosphate excretion to hyperphosphatemia
to calcium/phosphate uptake by bone
*decreased α-1-hydroxylase for vitamin D
activation
-dietary calcium deficiency
-steatorrhea
-Vitamin D deficiency
```
93
Secondary Hyperparathyroidism clinical presentation
```
l bone abnormalities (renal
osteodystrophy)
-but less severe than those seen in
primary hyperparathyroidism
l calciphylaxis = vascular calcifications à
ischemic damage to skin, other organs
l may lead to autonomous and excessive
parathyroid hormone production à
tertiary hyperparathyroidism
```
94
Other causes of hypercalcemia
```
¡ immobilization
¡ thiazide diuretics
¡ vitamin D toxicity
¡ sarcoidosis (and other
granulomatous diseases)
¡ thyrotoxicosis
-T3 stimulates osteoclast bone
resorption
-occurs in 1/5 of patients
```
95
Other causes of hypercalcemia
```
most common cause of symptomatic
hypercalcemia = malignancy
-osteolytic metastases
-paraneoplastic syndrome: production of PTHrelated
protein (PTHrP)
```
96
Hypoparathyroidism
```
much less common than
hyperparathyroidism
Causes:
-surgery
-congenital absence of parathyroid
-familial hypoparathyroidism
-autoimmune polyendocrine syndrome type 1
(APS1)
*discussed in adrenal notes
-idiopathic hypoparathyroidism
*most likely autoimmune (60% of patients
have autoantibodies against CASR)
```
97
Hypoparathyroidism
| Clinical Manifestations
l hallmark: tetany
l neuromuscular irritability
-numbness or paresthesias to laryngospasm and
seizures
-Chvostek sign: tap of cheek causes facial
muscle spasms
-Trousseau sign: BP cuff induces carpal spasms
98
Hypoparathyroidism clinical manifestation
l mental status changes
-emotional instability, anxiety and depression,
confusion, hallucinations, psychosis
l intracranial manifestations
-calcifications of the basal ganglia, parkinsonianlike
movement disorders, increased intracranial
pressure, papilledema
l cataracts (calcification of the lens)
l cardiovascular: conduction defect
(prolongation of QT interval)
l if hypocalcemia occurs in early development,
dental abnormalities
-dental hypoplasia, failure of eruption,
defective enamel and root defects, abraded
carious teeth
99
Pseudohypoparathyroidism
```
¡ hypoparathyroidism
occurs due to endorgan
resistance to
PTH activation
¡ Pathogenesis
-mutation prevents
signal relay
```
100
Pseudohypoparathyroidism
| pathogenesis
```
BUT IT’S REALLY MORE
COMPLICATED…
l GNAS1 is selectively imprinted in
different tissues
-in pituitary and kidneys, paternal allele is
silenced
*so mutations affecting mom’s allele are
expressed
-other tissues, no imprinting
*but still creates a 50% decrease in GSα
function
```
101
Pseudohypoparathyroidism Type 1A
mutation is inherited on maternal allele
¡ since maternal allele is the only one
expressed in pituitary and kidneys, results
in decreased stimulation by any hormones
(not just PTH) that transduce signals via
cAMP pathway
-TSH, GHRH, PTH
102
Pseudohypoparathyroidism Type 1A
mutation is inherited on maternal allele
¡ since maternal allele is the only one
expressed in pituitary and kidneys, results
in decreased stimulation by any hormones
(not just PTH) that transduce signals via
cAMP pathway
-TSH, GHRH, PTH
103
Pseudohypoparathyroidism Type 1A clinical features
```
l multihormone resistance
-short stature
(insensitive to GHRH)
-obesity and mental
deficits (insensitive to
TSH)
l Albright hereditary
osteodystrophy (AHO)
-syndrome characterized
by skeletal and
developmental defects
(insensitive to PTH)
```
104
Pseudopseudohypoparathyroidism
```
¡ mutation is inherited on the
paternal allele
-since mutation on paternal allele is
silenced in kidneys and pituitary, there
is no multihormone resistance
¡ Clinical features
-AHO only
```
105
Hyperaldosteronism
any condition that produces elevations in
aldosterone secretion
-primary = autonomous overproduction of hormone
-secondary = aldosterone released due to activation
of renin-angiotensin system
106
Adrenogenital Syndromes
```
¡ elevated sex steroid release by
adrenal cortex, producing disorders
of sexual differentiation
¡ caused by
-autonomous production by cells in the
zona reticularis
*neoplasms (particularly carcinomas)
*congenital adrenal hyperplasia
-as a component of Cushing disease
(stimulation by ↑ACTH)
```
107
Congenital Adrenal Hyperplasia (CAH)
inherited deficiencies in enzymes involved in
| cortical steroid biosynthesis, particularly cortisol
108
Congenital Adrenal Hyperplasia (CAH):
| 21-Hydroxylase deficiency as prototype
```
due to recombination of gene with a
neighboring non-functional
pseudogene
Hispanics and Ashkenazi Jewish
populations have highest carrier
frequencies
Degree of replacement of CYP21 with nonfunctioning pseudogene
sequence determines severity
```
109
Congenital Adrenal Hyperplasia (CAH):
21-Hydroxylase deficiency
Salt-wasting (classic) adrenogenitalism
```
absence of any hydroxylase activity
-aldosterone and cortisol synthesis
blocked
*soon after birth, salt wasting,
hyponatremia, and hyperkalemia
develop, followed by hypotension,
cardiovascular collapse, and possible
death
-reduced catecholamine secretion
*medulla requires glucocorticoids to
facilitate catecholamine synthesis
*predisposes to hypotension and
circulatory collapse
```
110
Congenital Adrenal Hyperplasia (CAH):
| 21-Hydroxylase deficiency block
```
block in pathway
shunts to androgen
production
-leads to virilization
-easily recognized in
female infants, but
unrecognized in
male infants until
salt-losing crisis
~5-15 days after
birth
```
111
```
Adrenocortical Hypofunction
(Insufficiency)
```
```
caused by:
primary hypoadrenalism
-primary adrenal disease
secondary hypoadrenalism
-decreased stimulation of the adrenals due
to ACTH deficiency
*no hyperpigmentation
*no hyperkalemia or hyponatremia
```
112
Primary Acute Adrenocortical
| Insufficiency
¡ An adrenal crisis
¡ Clinical features
-intractable vomiting, abdominal pain, hypotension,
coma, vascular collapse
¡ Causes
-rapid withdrawal of steroids
-stress in patients with chronic adrenocortical
insufficiency (glands incapable of responding)
-massive adrenal hemorrhage
*in newborns following difficult delivery with trauma
and hypoxia
*anticoagulant therapy
*DIC with subsequent adrenal infarction
*Waterhouse-Friderichsen Syndrome
113
Primary Acute Adrenocortical
| Insufficiency
¡ An adrenal crisis
¡ Clinical features
-intractable vomiting, abdominal pain, hypotension,
coma, vascular collapse
¡ Causes
-rapid withdrawal of steroids
-stress in patients with chronic adrenocortical
insufficiency (glands incapable of responding)
-massive adrenal hemorrhage
*in newborns following difficult delivery with trauma
and hypoxia
*anticoagulant therapy
*DIC with subsequent adrenal infarction
*Waterhouse-Friderichsen Syndrome
114
Waterhouse-Friderichsen Syndrome
```
bacterial infection complicated
by massive adrenal hemorrhage
-classically associated with
Neisseria meningitides
septicemia
*also Pseudomonas,
Haemophilus influenzae,
staphylococci
-characterized by rapidly
progressive hypotension leading
to shock, DIC with widespread
purpura, and (of course)
adrenocortical insufficiency
-most common in children
-death follows within days if not
recognized and treated promptly
```
115
Primary Chronic Adrenocortical
| Insufficiency (Addison Disease)
```
¡ adrenocortical insufficiency resulting from
progressive destruction of adrenal cortex
¡ Causes:
l autoimmune adrenalitis
l tuberculosis
l AIDS
l metastatic cancers
l lymphoma
l amyloidosis
l sarcoidosis
l hemochromatosis
l fungal infection
l adrenal hemorrhage
```
116
Addison Disease:
| Autoimmune adrenalitis
```
autoimmune destruction of
steroidogenic cells
-antibodies to several key steroidogenic
enzymes (e.g., 21-hydroxylase)
-occurs in 1 of 3 clinical settings:
*Autoimmune polyendocrine syndrome
type 1 (APS1)
*Autoimmune polyendocrine syndrome
type 2 (APS2)
*isolated autoimmune Addison disease
```
117
Addison Disease:
| Tuberculous adrenalitis
```
¡ once accounted for ~90% of
Addison disease; less common
now, but keep in mind
¡ usually associated with
infection at other sites (lung,
genitourinary tract)
¡ other causes of infectioninduced
Addison disease:
-Histoplasma capsulatum
-Coccidioides immitis
-cytomegalovirus
-Mycobacterium aviumintercellulare
```
118
Addison Disease clinical features
```
l insidious development; not apparent clinically
until >90% of gland is destroyed
l progressive weakness, easy fatigability
l gastrointestinal disturbances
-anorexia, nausea, vomiting, weight loss
l hyperpigmentation of skin (why?)
l potassium and sodium disturbances
-hyperkalemia, hyponatremia, volume
depletion, hypotension
l hypoglycemia
```
119
Adrenocortical adenomas
```
usually clinically silent and found at
autopsy (other cause of death) or
during unrelated abdominal imaging
functional adenomas are usually
associated with atrophy of the
neighboring cortex (and in the opposite
adrenal gland) due to suppression of
ACTH by tumor products
```
120
Adrenocortical carcinomas
```
if the neoplasm is virilizing, it is more
likely to be a carcinoma
adrenocortical carcinomas are
associated with Li-Fraumeni syndrome
and Beckwith-Wiedemann syndrome
adrenal cancers have a strong tendency
to invade the adrenal vein, vena cava,
and lymphatics
```
121
Pheochromocytoma
```
uncommon neoplasms derived
from chromaffin cells
-elaborate catecholamines
*classically produce hypertension
~although only 0.1-0.3% of
hypertensive patients have
pheochromocytoma, it’s
important to recognize it… can
develop into malignant
hypertension and be fatal if
tumor not removed
*may elaborate peptide
hormones or steroids
~can produce paraneoplastic
Cushing syndrome or other
endocrinopathy
```
122
Pheochromocytoma rule of 10s
```
10% arise in association with familial
syndromes
-MEN-2A and MEN-2B
-von Recklinghausen syndrome(type I
neurofibromatosis)
-von Hippel-Lindau syndrome
-Sturge-Weber syndrome
10% are extra-adrenal
-called paragangliomas to
distinguish from
pheochromocytomas
```
123
Pheochromocytoma masses
¡ range from small lesions (~1 g) to large masses
weighing >4 kg!
¡ incubation of fresh tissue with potassium dichromate
solution turns the tumor dark brown due to oxidation of
stored catecholamines (thus, chromaffin)
¡ cytology cannot predict malignancy; based on presence
of mets
124
Pheochromocytoma clinical features
classically produces acute hypertension
| (but in reality, affects
125
Multiple Endocrine Neoplasia
¡ group of genetically inherited diseases resulting in
proliferative lesions of multiple endocrine organs
¡ like any familial cancer syndrome, have features
that set them apart from sporadic counterparts:
-occur at a younger age
-arise in multiple endocrine organs, sometimes
synchronously
-often multifocal tumors in a single organ
-tumors are usually preceded by asymptomatic stage
of hyperplasia
¡ tumors are usually more aggressive and recur
126
Multiple Endocrine Neoplasia:
| Type 1
¡ remember 3 P’s: characterized by abnormalities in
parathyroid, pancreas, and pituitary
-parathyroid
*produces primary hyperparathyroidism
~ most common MEN-1 manifestation (~95% of patients) and is
usually initial sign of disorder
-pancreas
*often multifocal and functional
~usually aggressive and present w/metastatic disease
~ leading cause of morbidity and mortality in MEN-1 patients
-pituitary
*most frequent anterior pituitary tumor = prolactinoma
§ most common extraendocrine change: duodenal
gastrinoma (exceeds pancreatic gastrinomas in
frequency)
127
Multiple Endocrine Neoplasia:
| Type 1 path
germ-line mutations in MEN1 gene
- encodes menin, a tumor suppressor gene
* helps regulate the cell cycle and transcription
128
Multiple Endocrine Neoplasia
| Type 2
¡ subclassified into MEN-2A and MEN-2B
¡ Pathogenesis in both is activating
mutations of RET protooncogene (just
occur in different locations of the gene)
-recall that RET is a receptor tyrosine kinase
that transmits growth and differentiation
signals
-diagnosis via genetic screening of at-risk
family members is important: prophylactic
thyroidectomy to prevent life-threatening
medullary carcinoma
129
Multiple Endocrine Neoplasia:
| Type 2A characterized by
medullary carcinoma
-100% of patients
-usually multifocal and aggressive
-variant of MEN-2A has predisposition only to
medullary carcinoma: Familial medullary thyroid
cancer
pheochromocytoma
-40-50% of patients
-usually bilateral and more likely to occur in extraadrenal
sites
parathyroid hyperplasia
-10-20% of patients
-evidence of hypercalcemia or nephrolithiasis
130
Multiple Endocrine Neoplasia:
| Type 2B characterized by
```
l medullary carcinoma
-more aggressive than
in MEN-2A
l pheochromocytoma
l extraendocrine changes
-neuromas involving
skin, oral mucosa,
eyes, respiratory
tract, GI tract
-marfanoid habitus
(long axial skeletal
features,
hyperextensible joints)
l note that
hyperparathyroidism is
NOT present
```
