Endocrine Path Flashcards
A number of pathologies can disturb the
normal activity of the endocrine system.
¡ abnormal synthesis or release of hormones from endocrine (and sometimes non-endocrine) tissues ¡ abnormal responses to hormones by their target tissues and organs
Causes of hormone overproduction
hyperfunction
¡ Adenoma (most common)
¡ Acute inflammation
¡ Hyperplasia
¡ Cancer
Causes of hormone underproduction
hypofunction
¡ 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
lactotrophs
prolactin
mammosomatotrophs
prolactin
GH
somatotroph
GH
lactotroph regulators
TRH
dopamine
mamosomatotrophs regulators
dopamine
GHRH
somatostatin
somatotroph regulators
GHRH
somatostatin
Hyperpituitarism
l adenoma (most common) l hyperplasia l cancer l non-pituitary tumors l hypothalamic disorders
Hypopituitarism
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)
Local mass effects
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
pituitary apoplexy
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)
Molecular features of pituitary
adenomas
¡ 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
Prolactinoma
¡ 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
Prolactinoma:
Clinical Features
¡ 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
Other causes of hyperprolactinemia…
¡ 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
Other causes of hyperprolactinemia…
¡ 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
Prolactinoma:
Diagnostic Features
¡ 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
Prolactinoma biopsy
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)
Growth Hormone (Somatotroph) Adenomas
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
Growth Hormone (Somatotroph) Adenomas: Clinical Features
In adults, Acromegaly -Acro = tip, extremity, end In children and teenagers, gigantism
Growth Hormone (Somatotroph) Adenomas: Diagnostic Features
¡ 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.
Corticotroph Adenomas
Causes excess production of ACTH, leading to
adrenal hypersecretion of cortisol and the
development of hypercortisolism (Cushing disease)
Nelson Syndrome
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
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
Sheehan syndrome (post-partum necrosis of the anterior pituitary)
¡ most common form of clinically
significant ischemic necrosis of the
pituitary
¡ know pathogenesis
Rathke’s Cyst
¡ reminder: anterior pituitary is embryologically derived from the Rathke pouch ¡ cysts accumulate proteinaceous fluid and expand, compromising the normal gland
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
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
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)
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
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
Central Diabetes Insipidus
originating from ADH deficiency causes: -head trauma -tumors -inflammatory disorders of the hypothalamus and pituitary surgery
Nephrogenic Diabetes Insipidus
results from tubular unresponsiveness to
circulating ADH
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
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
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
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)
Causes of primary hypothyroidism
thyroprivic
goitrous
thyroprivic
(absence or loss of thyroid
parenchyma)
radiation
surgery (thyroidectomy)
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)
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)
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
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
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
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
Hashimoto Thyroiditis
Pathogenesis
immune system reacts against thyroid antigens
-anti-TSH receptor antibodies, antithyroglobulin,
antithyroid peroxidase
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
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”)
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)
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
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
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
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
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)
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
Graves Disease
Morphology
diffuse hypertrophy and hyperplasia
of thyroid follicular epithelium
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)
Graves Disease:
Exophthalmos
orbital preadipocyte fibroblasts express TSH receptor, so they are also targets of autoimmune attack
Graves Disease:
Pretibial myxedema
¡ a localized, infiltrative dermopathy most common over the shins ¡ least common feature in the triad
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
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
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
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"
Multinodular Goiter
¡ mistaken for neoplasms ¡ mass effects -airway obstruction -dysphagia ¡ compression of large vessels in neck and upper thorax
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)
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
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
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
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
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)
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
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
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
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
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
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%
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)
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
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
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)
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)
Hyperparathyroidism
¡ special note: hypercalcemia is NOT universal to hyperparathyroidism ¡ hyperparathyroidism occurs in two major forms: primary and secondary
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)
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
Primary Hyperparathyroidism causes
l parathyroid adenomas: 75-80% l primary hyperplasia of the parathyroid (diffuse or nodular): 10-15% l parathyroid carcinoma: very rare (
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
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?
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?
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
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
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
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
Other causes of hypercalcemia
most common cause of symptomatic hypercalcemia = malignancy -osteolytic metastases -paraneoplastic syndrome: production of PTHrelated protein (PTHrP)
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)
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
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
Pseudohypoparathyroidism
¡ hypoparathyroidism occurs due to endorgan resistance to PTH activation ¡ Pathogenesis -mutation prevents signal relay
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
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
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
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)
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
Hyperaldosteronism
any condition that produces elevations in
aldosterone secretion
-primary = autonomous overproduction of hormone
-secondary = aldosterone released due to activation
of renin-angiotensin system
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)
Congenital Adrenal Hyperplasia (CAH)
inherited deficiencies in enzymes involved in
cortical steroid biosynthesis, particularly cortisol
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Pheochromocytoma clinical features
classically produces acute hypertension
(but in reality, affects
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
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)
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
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
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
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
