Chapter 24 Flashcards
What are the three types of signaling
Autocrine
Paracrine
Endocrine
Endocrine signaling
Hormones
What are endocrine hormones carried by
Blood
Feedback inhibition
Target tissue of hormones often secretes factors that down regulate the activity of the gland that produces the stimulating hormone, a process
What are the endocrine disorders
- Underproduction or overproduction of hormones and their resulting biochemical and clinical consequences
- Diseases associated with the development of mass lesions
- nonfunction, overproduction, underproduction
What are the components of the pituitary
Anterior pituitary constitutes 80%
Posterior pituitary 20%
Anterior pituitary gets + and - acting factors from the hypothalamus from the
Portal vascular system
What hormones are released from the anterior pituitary
GnRH—-FSH LH + CRH—- ACTH+ TRH—TSH+ PIF(dopamine)—prolactin - GHRH+ GIH- —-GH
Histology anterior pituitary
Colorful array of cells is present that contain eosinophilic cytoplasm (acidophilus), basophils (basophils) or poorly staining cytoplasm (chromophobe) cells
What are the six terminally differentiated cell types in the anterior pituitary
Somatotrophys making GH
Mammosomatotrophs making GH and prolactin (PRL)
Lactotrophs making PRL
Corticotheophs making ACTH, POMC, MSH
Thyrotrophs making TSH
Gonadotropin, producing FSH and LH
Somatotrophs
GH
Mammosomatotrophs
GH and prolactin
Lactotrophs
Prolactin
Corticotrophs
ACTH, POMC, MSH
Thyrotrophs
TSH
Gonadotrophs
FSH, LH
FHS and LH
Stimulate the formation of Graafian follicles int he ovary, and LH indices ovulation and the formation of corpora lutes int he ovary. They also regulate spermatogenesis and testosterone production in males
___ ___ have been identified that regulate the differentiation of pluripotent stem cells in rather pouch into these terminally differentiated cell types. Like what
Transcription factors
Somatotrophs, mammosomatotrophs, and lactotrophs are derived from stem cells that express the pituitary transcription factor
PIT-1
What are factors that required for gonadotropin differentiation
Steroidogenic factor-1 and GATA-2
Posterior pituitary
Modified glial cells (pituicytes) and axonal processes extending from the hypothalamus through the pituitary stalk to the posterior lobe (axon terminals)
What is secreted by posterior pituitary
2 peptide hormones
Oxytocin and ADH(vasopressin)
Where are the posterior pituitary hormones made
Hypothalamus and stored in the axon terminals residing in the posterior pituitary.
How are posterior pituitary hormones released
In response to stimuli, the preformed hormones are released directly into the systemic circulation through the venous channels of the pituitary.
How is oxytocin released
Dilation of the cervix in pregnancy releases it leading to contraction of the uterine smooth muscle, facilitating parturition
Nipple stimulation -in postnatal period acts on the smooth muscles surrounding the lactiferous ducts of the mammary gland and facilitates lactation.
Synthetic oxytocin
Induce labor
ADH
Conserve water by restricting diuresis during periods of dehydration and hypovolemia.
What stimulates ADH release
Decreased bp sensed by baroreceptors in cardiac atria and carotids
Increase in plasma osmotic pressure detected by osmoreceptors also triggers ADH secretion.
What inhibits ADH secretion
Hypovolemia and increased atrial distention result in inhibition
What causes manifestations of pituitary disorders
Excess, defiency, mass effects
Hyperpituitarism
Arising form excess secretion of tropical hormones
What causes hyperpituitarism
Pituitary adenoma, hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by nonpituitary tumors and certain hypothalamic disorders
Hypopituiarism
Arising from defiency of tropical hormones.
What causes hypopituitarism
Destructive processes, including ischemic injury, surgery or radiation, inflammatory reactions, and nonfunctional pituitary adenomas
Local mass effects
Among the earliest changes referable to mass effects are radiographically abnormalities of the sella turcica, including stellar expansion, bony erosion, and disruption of diaphragma sella.
Expansion of the pituitary lesion may compress what
Decussating fibers int he optic chiasm ….visual field abnormalities, usually bitemporal hemianopsia (both lateral fields)
Can get other from asymmetrical growth of tumors
Like any expanding intracranial pressure, including, what
Elevated intracranial pressure, HA, nausea vomiting
Acute hemorrhage into a pituitary adenoma
Associated with clincial evidence of rapid enlargement of the lesion, a situation called pituitary apoplexy
NEUROSURGICAL EMERGENCY, can cause sudden death
Why do posterior pituitary diseases come to attention
Increase or decreased secretion of ADH
Most common cause of hyperpituitarism
Adenoma arising int he anterior lobe
Adenoma benign or malignant
Benign tumors are classified on the basis of the hormones that are produced by the neoplastic cells, which are detected by immunohistochemical stains
What do pituitary adenomas secrete
GH and prolactin most common combo
Functional pituitary adenomas
Hormone excess and clincial manifestations
Nonfunctioning hormone
Without clincial symtpoms of hormone excess
Less common causes of hyperpituitarism
Pituitary carcinomas and some hypothalamic disorders. Large pituitary adenomas, and particularly nonfunctioning ones, may cause hypopituitarism by encroaching on and destroying the adjacent pituitary parenchyma
Lactotroph
Prolactin
Lactotroph adenoma, silent lactotroph adenoma
Galactorrhea and amenorrhea ( in females) sexual dysfunction, infertility
Somatotrophs
GH
Densely granulated somatotroph adenoma, sparsely granulated somatotroph adenoma, silent somatotroph adenoma
Gigantism (children) acromegaly (adult)
Mammosomatotroph
Prolactin GH
Mammosomatotroph adenomas
Combined features of GH and prolactin excess
Corticotroph
ACTH and other POMC derived peptides
Densely granulated corticotroph adenoma, sparsely granulated corticotroph adenoma, silent corticotroph adenoma
Cushing syndrome, Nelson syndrome
Thyrotrophs
TSH
Thyrotroph adenomas
Silent thyrotroph
Adenomas
Hyperthyroidism
Gonadotropin
FSH LH
Gonadotroph adenomas
Silent gonadotroph
Adenomas (null cell)
Hypogonadism, mass effects, and hypopituitarism
Nonfunctional silent adenomas on histology and function
Express corresponding hormones within the neoplastic cells, as determined by special immunohistochemical staining on tissues. However do not produce the associated clinical syndrome, and present with mass effects accompanied by hypopituitarism due to destruction of normal pituitary parenchyma. These features are particularly common with gonadotroph adenomas
Epidemiology pituitary adenomas
35-60
Microadenoma
Less than 1 cm
Macroadenomas
Over 1 cm in diameter
14% of population most ae clinically silent macroadenomas (pituitary incidentaloma)
Non functional adenomas when come to light
Later stage than endocrine abnormalities and are more likely to be macroadenomas
Most common alterations in pituitary adenomas
G protein mutations
Which G protein that is in pituitary tumors
Gs , the a subunit is encoded by the GNAS gene, located on chromosome 20q13
What binds to Gs
GHRH, TSH, PTH,
Has a, b and y subunit
Activate AC increase cAMP to proliferate, synthesize hormones and secretion
Basal state Gs
Inactive with GDP bound to the guanine nucleotide binding site of Gsa
Gs with interaction with ligand boing cell surface receptor
GDP dissociates and GTP binds to Gsa, activating the G protein
Activation Gsa
Results in the generation of cAMP, which is a potent mitogen for a variety of endocrine cell types , promoting cellular proliferation and hormone synthesis and secretion
Why is Gsa activation transient
Bc an intrinsic GTPase activity in the a subunit, which hydrolyzes GTP into GDP
40% of ___ cell adenomas have GNAS mutations that abrogate the GTPase activity of Gsa, leading to constitutive activation of Gsa, a persistent generation of cAMP and unchecked cellular proliferation
Somatotroph
Why are GNAS mutations absent in thyrotroph, lactotroph and gonadotroph adenomas
Their respective hypothalamic release hormones do not act via cAMP dependent pathways
Most adenomas are ___
Sporadic
5% are inherited
Causative genes to pituitary adenomas in the genetic adenomas
MEN1, CDKN1B, PRKAR1A and AIP
-not in sporadic
Molecular abnormalities associated with aggressive behavior include aberrations in cell cycle checkpoint proteins
Overexpression of cyclin D1, mutations of TP53, and epigenetic silencing of the retinoblastoma gene (RB)
-HRAS activating in pituitary carcinomas
Morphology pituitary adenoma
Soft, well circumscribed
Small adenomas may be confined to the sella turcica, but with expansion they frequently erode the sella turcica and anterior Clinic processes. Larger extend superiorly through the diaphragm sella into the suprasellar region, where they often compress the optic chiasm and adjacent structures, such as some of the CN.
Invasive adenomas
Adenomas ae not grossly encapsulated and infiltrate neighboring tissues such as the cavernous and sphenoid sinuses, sure, and on occasion, the brain itself
Are micro or macroadenomas more likely to be invasive
Macro
What else is more common in larger adenomas
Foci of hemorrhage or necrosis
Histology pituitary adenoma
Uniform, polygonal cells arrayed in sheets or cords. Supporting CT, or reticulum is sparse, accounting for the soft gelatinous consistency of many of these tumors.
Little mitosis
Cytoplasm is acidophilus, basophils, or chromophobe depending not he type and amount of secretory product within the cells, but is generally uniform throughout the tumor
What distinguished pituitary adenoma from nonneoplastic anterior pituitary parenchyma
Cellular monomorphism and absence of a significant reticulin network
A subset of pituitary adenomas demonstrate elevated mitosis activity and nuclear p52 expression
Correlated with the presence of TP53 mutations. These tumors have a higher propensity for aggressive behavior including invasion and recurrence and are termed ATYPICAL ADENOMAS
GNAS
Encodes for alpha subunit of stimulators G protein, Gsa. Oncogene mutation of GNAS constitutively activates Gsa, leading to upregulation of intracellular cyclic AMP (cAMP) activity
Gain of function GNAS
Activating mutation most common in GN adenomas
Protein kinase a, regulatory subunit 1 (PRKAR1A)
Encodes for a negative regulator of protein kinase a (PKA), a downstream mediator of cAMP signaling. Loss of PKA regulation leads to inappropriate cAMP activity
Gain of function PRK!R1A
Germline inactivating mutations of PRKARIA are present in AD carney complex
GH and prolactin adenomas
Cyclin D1
Cell cycle regulatory protein promotes G1-A transition
Gain of function cyclin D1
Overexpression
Aggressive adenomas
HRAS
Ras regulates multiple concogenic pathways including proliferation, cell survival and metabolism
Gain of function HRAS
Activativating mutation
Pituitary carcinomas
MEN1
MEN1 encodes for menin, a protein with protean roles in tumor suppression, includingrepression of oncogenic transcription factor JunD, and in histone modification
Loss of function MEN1
Germline inactivating mutations of CDKN1B (MEN1 like syndrome)
ACTH adenomas
Arya hydrocarbon receptor interacting protein (AIP)
Receptor for Arya hydrocarbons and a ligand activated transcription factor
Loss of function Arya hydrocarbon receptor interacting protein AIP
Germline mutations of AIP cause pituitary adenoma predisposition (PAP) syndrome
GH adenomas (espicially in patients younger than 35 years old)
RB
Retinoblastoma protein is a negative regulator of the cell cycle
Loss of function RB
Methylation of RB gene promoter
Aggressive adenomas
Signs and symptoms of pituitary adenomas
Related to endocrine abnormalities and mass effects.
Local mass effects
Radiographically abnormalities of the sella turcica, visual field abnormalities, signs and symtpoms of elevated ICP, and hypopituitarism
Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy as noted earlier
Lactotroph adenoma
Prolactin secreting lactotroph adenomas are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized cases . These lesions range from small macroadenomas to large, expansive tumors associated with substantial mass effect
Morphology lactotroph adenoma
Chromophobe cells with juxtanuclear localization of transcription factor PIT-1; these are known as sparsely granulated lactotroph adenomas
Much rarer are the acidophilus densely granulated lactotroph adenomas, characterized by diffuse cytoplasmic PIT-1 expression localization
Prolactin can be seen with stain
Lactotroph adenomas have a propensity to undergo dystrophic calcification of virtually the entire tumor mass
Prolactin secretion by functioning adenomas is usually efficient and proportional in that serum prolactin concentrations tend to correlate with the size of the adenoma
What do serum prolactin concentrations tend to correlate with
Size of adenoma
Clincial prolactinemia
Amenorrhea, glactorrhea, loss of libido, infertility.
Diagnose adenoma
More readily in women espicially between 20-40, presumably bc of the sensitivity of messes to disruption o fhyperprolactinemia.
Lactotroph adenoma underlies almost a quarter of cases of amenorrhea.
In contrast, in men and older women, the hormonal manifestations may be subtle, allowing the tumors to reach considerable size before being detected CLINCIALLY
What things other than prolactin secreting pituitary adenomas can cause hyperprolactinemia
Physiologic hyperprolactinemia in pregnancy
Nipple stimulation, as occurs during suckling in lactating women and as a response to. Many types of stress
Lactotroph hyperplasia cause by loss of dopamine mediated inhibiton of prolactin secretion
-with damage of the dopaminergi neurons of the hypothalamus, damage of the pituitary stalk may disturb the normal inhibitors influence of the hypothalamus on prolactin secretion, resulting in hyperprolactinemia. Therefore, a mild elevation ins drum prolactin in a person with a pituitary adenoma does not necessarily indicate a prolactin secreting tumor.
Renal failure and hypothyroidism
Treat lactotroph adenomas
Surgery or bromocriptine, a dopamine receptor agonist that causes the lesions to diminish in size
Somatotroph adenomas
GH secreting somatotroph adenomas are the second most common type of functioning pituitary adenoma, and cause gigantism in children and acromegaly in adults
Why may somatotroph adenomas be quite large by the time they come to clinical attention
Manifestations of excessive GH may be subtle
Histology somatotroph adenomas
Densely granulated and sparsely granulated subtypes
Densely granulated adenomas
Monomorphic, acidophilus cells that have strong cytoplasmic GH reactivity on immunohistochemical you.
Sparsely granulated somatotroph
Composed of chromophobe cells with considerable nuclear and cytologic pleomorphism and focal, weak staining for GH
Bihormonla mammosomatroph
May synthesize both GH and prolactin are being increasingly recognized
-have reactivity for prolactin as well as GH
Clinical somatotroph adenomas
Persistently elevated GH stimulate the hepati secretion of insulin like growth factor 1 which causes many of the clincial manifestations
If somatotroph adenoma appears in children before the epiphysis have closed
The elevated levels of GH results in gigantism
-increase in body size with disproportionately long arms and legs
Somatotroph increased levels of GH after closure of epiphysis
Acromegaly
-growth is most conscious in skin and soft tissues, viscera, and the bones of the face, hands and feet
Bone density ma increase (hyperostosis) in both the spine and the hips
Enlargement of jaw results in its protrusion (prognathism) and broadening of the lower face
Feet and hand enlarge and fingers are sausage like
Acromegaly as well
Slowly over time allowing adenoma to reach big sister
GH excess is associated with what else
Gonadal dysfunction, DM, muscle weakness, HTN, arthritis, CHF, and increased risk of GI cancer
Diagnose GH pituitary tumor
Document elevated serum GH and IGF-1 levels
Failure to suppress GH production in response to an oral load of glucose is one of the most sensitive tests for acromegaly
Treat GH pituitary tumor
Surgery or treated via pharmacology (somatostatin which inhibits secretion of GH) or gh receptor antagonists
Do symptoms go away if GH stopped
Yup and metabolic abnormalities improve
Corticotroph adenomas
Excess production of ACTH by functioning corticotroph adenomas leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (Cushing)
Morphology corticotroph adenomas
Micro at diagnosis
Basophils (densely granulated) but occasionally chromophobe cells 9sparsely granulated). Both variants stain positively with PAS bc of carbohydrate in POMVC, the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivitiy for POMC and its derivatives, including ACHT and B endorphin
Clinical corticotroph adenomas
Cushing syndrome. (See adrenal)
-can be caused by lots of things in addition to pituitary tumor
Called Cushing when due to ACTH excess from pituitary
What surgery May spark Cushing
Large destructive pituitary adenomas can develop in patients after surgical removal of the adrenal glands for treatment of cushing
-NELSON SYNDROME
—-from loss of the inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma. Bc adrenals are absent , hypercortisolism does not develop, and patients present with mass effects due to the pituitary tumor and there can be hyperpigmentation bc of the stimulators effect of other products of the catch precursor molecule on melanocytes
Gonadotroph adenoma
LH and FS producing
Why gonadotroph adenomas difficult to recognize
Secrete hormones inefficiently and variably and the secretory products usually do not cause a recognizable clincial syndrome (nonfunctioning adenoma)
Who gest gonadotroph
Middle aged men and women when large enough to cause neurologic symptoms, such as impaired vision, HA, diploid or pituitary apoplexy
Or pituitary hormone defiencies (impaired LH)-decrease libido in men and amenorrhea in premenopausal women.
Genetics gonadotroph
Demonstrate immunoreactivity for the common gonadotropin a subunit and the specific b-fsh and b-lh subunits; fsh is usually the predominant secreted hormone. Gonadotroph adenomas usually express steroidogenic factor-1 (SF-1) and GATA-2, transcription factors associated with normal gonadotroph differentiation
Thyrotroph
TSH-producing) adenomas are uncommon, accounting for approximately 1% of all pituitary adenomas. Thyrotroph adenomas are a rare cause of hyperthyroidism
Nonfunctioning pituitary adenomas
s are a heterogeneous group that constitutes approximately 25% to 30% of all pituitary tumors. Their lineage can be established by immunohistochemical staining for hormones or by biochemical demonstration of cell type-specific transcription factors. In the past, many such tumors have been called silent variants or null-cell adenomas . Not surprisingly, nonfunctioning adenomas typically present with symptoms stemming from mass effects. These lesions may also compromise the residual anterior pituitary sufficiently to cause hypopituitarism, which may appear slowly due to gradual enlargement of the adenoma or abruptly because of acute intratumoral hemorrhage (pituitary apoplexy
Pituitary carcinoma
is rare, accounting for less than 1% of pituitary tumors. The presence of craniospinal or systemic metastases is a sine qua non of a pituitary carcinoma. Most pituitary carcinomas are functional, with prolactin and ACTH being the most common secreted products. Metastases usually appear late in the course, following multiple local recurrences
Most common cause of hyperpituitarism
Anterior lobe pituitary adenoma
Two distinctive morphological features of most adenomas
▪ The two distinctive morphologic features of most adenomas are their cellular monomorphism and absence of a reticulin network
Hypopituitarism
decreased secretion of pituitary hormones, which can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (see later) is almost always of hypothalamic origin .
Most cases of hypopituitarism arise from destructive processes directly involving the anterior pituitary. The causes include the following
Tumors and other mass lesions
Traumatic brain injury and subarachnoid hemorrhage
Pituitary surgery or radiation
Pituitary apoplexy
Ischemic necrosis of the pituitary and Sheehan syndrome
Rather cleft cyst
Empty sella syndrome
Hypothalamus lesions
Inflammatory disorders
Genetic defects
Tumors and other mass lesions
Pituitary adenomas, other benign tumors arising within the sella, primary and metastatic malignancies, and cysts can cause hypopituitarism. Any mass lesion in the sella can cause damage by exerting pressure on adjacent pituitary cells
Traumatic brain injury and subarachnoid hemorrhage
A re among the most common causes of pituitary hypofunction
Pituitary surgery or radiation
Surgical excision of a pituitary adenoma may inadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary, used to prevent regrowth of residual tumor after surgery, can damage the nonadenomatous pituitary
Pituitary apoplexy
As mentioned earlier, this is caused by a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma. In its most dramatic presentation, apoplexy causes the sudden onset of excruciating headache, diplopia due to pressure on the oculomotor nerves, and hypopituitarism. In severe cases, it can cause cardiovascular collapse, loss of consciousness, and even sudden death. The combination of mass effects from the hemorrhage and the acute hypopituitarism makes pituitary apoplexy a true neurosurgical emergency
Ischemic necrosis of the pituitary and Sheehan syndrome
Sheehan syndrome, also known as postpartum necrosis of the anterior pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary. During pregnancy the anterior pituitary enlarges to almost twice its normal size. This physiologic expansion of the gland is not accompanied by an increase in blood supply from the low-pressure venous system; hence, there is relative hypoxia. Any further reduction in blood supply caused by obstetric hemorrhage or shock may precipitate infarction of the anterior lobe. Because the posterior pituitary receives its blood directly from arterial branches, it is much less susceptible to ischemic injury and is therefore usually not affected. Pituitary necrosis may also be encountered in other conditions, such as disseminated intravascular coagulation and (more rarely) sickle cell anemia, elevated intracranial pressure, traumatic injury, and shock of any origin. Whatever the pathogenesis, the ischemic area is resorbed and replaced by a nubbin of fibrous tissue attached to the wall of an empty sella.
Rather cleft cyst
These cysts, lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland
Empty sella syndrome
Any condition or treatment that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation, can result in an empty sella and the empty sella syndrome . There are two types: (1) In a primary empty sella, a defect in the diaphragma sella allows the arachnoid mater and cerebrospinal fluid to herniate into the sella, expanding the sella and compressing the pituitary. Classically, this occurs in obese women with a history of multiple pregnancies. Affected individuals often present with visual field defects and occasionally with endocrine anomalies, such as hyperprolactinemia , due to interruption of inhibitory hypothalamic inputs. Sometimes the loss of functioning parenchyma is sufficient to produce hypopituitarism. (2) In secondary empty sella, a mass, such as a pituitary adenoma, enlarges the sella and is then either surgically removed or undergoes infarction, leading to loss of pituitary function
Hypothalamic lesions
: As mentioned earlier, hypothalamic lesions can also affect the pituitary by interfering with the delivery of pituitary hormone-releasing factors. In contrast to diseases that involve the pituitary directly, hypothalamic abnormalities can also diminish the secretion of ADH, resulting in diabetes insipidus (discussed later). Hypothalamic lesions that cause hypopituitarism include tumors , which may be benign (e.g., craniopharyngioma) or malignant; most of the latter are metastases from tumors such as breast and lung carcinoma. Hypothalamic insufficiency can also appear following irradiation of brain or nasopharyngeal tumors
Inflammatory disorders and infections
such as sarcoidosis or tuberculous meningitis, can involve the hypothalamus and cause deficiencies of anterior pituitary hormones and diabetes insipidus
Genetic defects
Congenital deficiency of transcription factors required for normal pituitary function is a rare cause of hypopituitarism. For example, mutation of the pituitary-specific gene PIT-1 results in combined pituitary hormone deficiency, characterized by deficiencies of GH, prolactin, and TSH
Clincial children with hypopituitarism
• Children can develop growth failure (pituitary dwarfism) due to growth hormone deficiency
Gonadotrophin LH and FSH defiency
onadotropin (LH and FSH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men
TSH and ACTH defiencies symtpoms
• TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter
Prolactin defiency
• Prolactin deficiency results in failure of postpartum lactation
MSH defiency
• The anterior pituitary is also a rich source of MSH, synthesized from the same precursor molecule that produces ACTH; therefore, one of the manifestations of hypopituitarism includes pallor due to a loss of stimulatory effects of MSH on melanocytes
Posterior pituitary syndome
The clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH
Diabetes insipidus. ADH deficiency causes diabetes insipidus , a condition characterized by excessive urination (polyuria) due to an inability of the kidney to resorb water properly from the urine
Diabetes insipidus can occur in a variety of conditions, including head trauma, tumors, inflammatory disorders of the hypothalamus and pituitary, and surgical complications. The condition can also arise spontaneously, in the absence of an identifiable underlying disorder. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of these two disorders are similar and include the excretion of large volumes of dilute urine with a lower than normal specific gravity. Serum sodium and osmolality are increased by the excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water generally compensate for the urinary losses, but patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration
• Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremia
The most frequent causes of SIADH are the secretion of ectopic ADH by malignant neoplasms (particularly small-cell carcinoma of the lung), drugs that increase ADH secretion, and a variety of central nervous system disorders, including infections and trauma. The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop.
Hypothalamus suprasellar tumors
Neoplasms in this location may induce hypofunction or hyperfunction of the anterior pituitary, diabetes insipidus, or combinations of these manifestations
Most common hypothalamic suprasellar tumors
Gliomas and craniopharyngiomas
Craniopharyngioma
The craniopharyngioma is thought to arise from vestigial remnants of Rathke pouch. These slow-growing tumors account for 1% to 5% of intracranial tumors. A small minority of these lesions occurs within the sella, but most are suprasellar, with or without intrasellar extension. A bimodal age distribution is observed, with one peak in childhood (5 to 15 years) and a second peak in adults 65 years or older. Patients usually come to attention because of headaches and visual disturbances, while children sometimes present with growth retardation due to pituitary hypofunction and GH deficiency.
Genetics craniopharyngiomas
A bnormalities of the WNT signaling pathway , including activating mutations of the gene encoding β-catenin, have been reported in craniopharyngiomas
Morphology craniopharyngiomas
Craniopharyngiomas average 3 to 4 cm in diameter; they may be encapsulated and solid, but more commonly they are cystic and sometimes multiloculated. They often encroach on the optic chiasm or cranial nerves, and not infrequently they bulge into the floor of the third ventricle and base of the brain
Histologic variants of craniopharyngiomas
Two distinct histologic variants are recognized: adamantinomatous craniopharyngioma (most often observed in children) and papillary craniopharyngioma (most often observed in adults). The adamantinomatous type frequently contains radiologically demonstrable calcifications; the papillary variant calcifies only rarely.
Adamant tomatoes craniopharyngioma
Adamantinomatous craniopharyngioma consists of nests or cords of stratified squamous epithelium embedded in a spongy “reticulum” that becomes more prominent in the internal layers. “Palisading” of the squamous epithelium is frequently observed at the periphery. Compact, lamellar keratin formation (“wet keratin”) is a diagnostic feature of this tumor ( Fig. 24-7 ). As mentioned earlier, dystrophic calcification is a frequent finding. Additional features include cyst formation, fibrosis, and chronic inflammation. The cysts of adamantinomatous craniopharyngiomas often contain a cholesterol-rich, thick brownish-yellow fluid that has been compared to “machine oil.” These tumors extend fingerlets of epithelium into adjacent brain, where they elicit a brisk glial reaction
Papillary craniopharyngiomas
Papillary craniopharyngiomas contain both solid sheets and papillae lined by well-differentiated squamous epithelium. These tumors usually lack keratin, calcification, and cysts. The squamous cells of the solid sections of the tumor lack the peripheral palisading and do not typically generate a spongy reticulum in the internal layers
Prognosis craniopharyngiomas
Patients with craniopharyngiomas, especially those less than 5 cm in diameter, have an excellent recurrence-free and overall survival. Larger lesions are more invasive but this does not impact on the prognosis. Malignant transformation of craniopharyngiomas into squamous carcinomas is exceptionally rare and usually occurs after irradiation
Thyroid gland
The thyroid gland, usually located below and anterior to the larynx, consists of two bulky lateral lobes connected by a relatively thin isthmus. The thyroid is divided by thin fibrous septae into lobules composed of about 20 to 40 evenly dispersed follicles, lined by a cuboidal to low columnar epithelium, and filled with PAS-positive thyroglobulin. In response to hypothalamic factors, TSH (thyrotropin) is released by thyrotrophs in the anterior pituitary into the circulation. The binding of TSH to its receptor on the thyroid follicular epithelium results in activation of the receptor, allowing it to associate with a G s protein ( Fig. 24-8 ). Activation of the G protein stimulates downstream events that result in an increase in intracellular cAMP levels, which stimulates thyroid growth and thyroid hormone synthesis and release via cAMP-dependent protein kinases
T4 T3
Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T 4 ) and lesser amounts of triiodothyronine (T 3 ) . T 4 and T 3 are released into the systemic circulation, where most of these peptides are reversibly bound to circulating plasma proteins, such as thyroxine-binding globulin and transthyretin. The binding proteins act as a buffer that maintains the serum unbound (“free”) T 3 and T 4 concentrations within narrow limits, while ensuring that the hormones are readily available to the tissues. In the periphery, the majority of free T 4 is deiodinated to T 3 ; the latter binds to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does T 4 and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor (TR) results in the assembly of a multiprotein hormone-receptor complex on thyroid hormone response elements (TREs) in target genes, up regulating their transcription ( Fig. 24-8 ). Thyroid hormone has diverse cellular effects, including the stimulation of carbohydrate and lipid catabolism and protein synthesis in a wide range of cells. The net result is an increase in the basal metabolic rate. In addition, thyroid hormone has a critical role in brain development in the fetus and neonate (see later
The function of the thyroid gland can be inhibited by a variety of chemical agents, collectively referred to as ____
Goitrogens
Goitrogens
Because they suppress T 3 and T 4 synthesis, the level of TSH increases, and subsequent hyperplastic enlargement of the gland ( goiter ) follows.
Propylthiouracil
The antithyroid agent propylthiouracil inhibits the oxidation of iodide and thus blocks the production of thyroid hormones; parenthetically, propylthiouracil also inhibits the peripheral deiodination of circulating T 4 into T 3 , thus ameliorating symptoms of thyroid hormone excess (see later). Iodide, when given in large doses to individuals with thyroid hyperfunction, also blocks the release of thyroid hormones by inhibiting the proteolysis of thyroglobulin. Thus, thyroid hormone is synthesized and incorporated into colloid, but it is not released into the blood.
Parafollicular cells
The thyroid gland follicles also contain a population of parafollicular cells , or C cells, which synthesize and secrete the hormone calcitonin . This hormone promotes the absorption of calcium by the skeletal system and inhibits the resorption of bone by osteoclasts
Diseases of the thyroid
Diseases of the thyroid include conditions associated with excessive release of thyroid hormones (hyperthyroidism), thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. We will first consider the clinical consequences of disturbed thyroid function, and then turn to the disorders that generate these problems
Hyperthyroidism
Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T 3 and T 4 . Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism . However, in certain conditions the oversupply is related to either excessive release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than hyperfunction of the gland ( Table 24-3 ). Thus, strictly speaking, hyperthyroidism is only one (albeit the most common) cause of thyrotoxicosis . The terms primary and secondary hyperthyroidism are sometimes used to designate hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such as a TSH-secreting pituitary tumor, respectively. With this caveat, we follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably
Hyperthyroidism/thyrotoxicosis most common causes
Diffuse hyperplasia of the thyroid associated with Graves disease (approximately 85% of cases)
• Hyperfunctional multinodular goiter
• Hyperfunctional thyroid adenoma
Primary causes of hyperthyroidism
Diffuse hyperplasia (graves)
Hyperfunctioning (toxic) multinodular goiter
Hyperfunctioning (toxic) adenoma
Iodine-induced hyperthyroidism
Neonatal thyrotoxicosis associated with maternal Graves’ disease
Secondary cause of hyperthyroidism
TSH secreting pituitary adenoma
Not associated with hyperthyroidism
Granulomatous (de Quervain) thyroiditis ( painful )
Subacute lymphocytic thyroiditis ( painless )
Struma ovarii (ovarian teratoma with ectopic thyroid)
Factitious thyrotoxicosis (exogenous thyroxine intake
Clincial course hyperthyroidism
The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone and to overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic “tone”
Clincial excessive thyroid hormone
Excessive levels of thyroid hormone result in an increase in the basal metabolic rate . The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation, adaptations that serve to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Heightened catabolic metabolism results in weight loss despite increased appetite
Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism
Individuals with hyperthyroidism can have elevated cardiac contractility and cardiac output, in response to increased peripheral oxygen requirements. Tachycardia, palpitations, and cardiomegaly are common. Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. Congestive heart failure may develop, especially in older patients with preexisting cardiac disease. Myocardial changes, such as focal lymphocytic and eosinophilic infiltrates, mild fibrosis, myofibril fatty change, and an increase in size and number of mitochondria, have been described. Some individuals with thyrotoxicosis develop reversible left ventricular dysfunction and “low-output” heart failure, so-called thyrotoxic or hyperthyroid cardiomyopathy
Overactivity of sympathetic nervous system hyperthyroidism
Overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle weakness and decreased muscle mass are common (thyroid myopathy) . In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, diarrhea, and malabsorption
Ocular changes hyperthyroidism
Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the superior tarsal muscle (also known as Müller’s muscle ), which functions alongside the levator palpebrae superioris muscle to raise the upper eyelid ( Fig. 24-9 ). However, true thyroid ophthalmopathy associated with proptosis occurs only in Graves disease (see later).
Person with hyperthyroidism
A person with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs, also adds to the protuberant appearance of the eyes
Skeletal system hyperthyroidism
Thyroid hormone stimulates bone resorption, increasing porosity of cortical bone and reducing the volume of trabecular bone. The net effect is osteoporosis and an increased risk of fractures in patients with chronic hyperthyroidism. Other findings include atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in the hepatocytes; and generalized lymphoid hyperplasia and lymphadenopathy in patients with Graves’ disease
Thyroid storm
Thyroid storm refers to the abrupt onset of severe hyperthyroidism. This condition occurs most commonly in patients with underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress. Patients are often febrile and present with tachycardia out of proportion to the fever. Thyroid storm is a medical emergency. A significant number of untreated patients die of cardiac arrhythmias
Apathetic hyperthyroidism
refers to thyrotoxicosis occurring in older adults, in whom advanced age and various co-morbidities may blunt the features of thyroid hormone excess that typically bring younger patients to attention. The diagnosis of thyrotoxicosis in these individuals is often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease
Diagnosis of hyperthyroidism
A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The measurement of serum TSH concentration is the most useful single screening test for hyperthyroidism, because its levels are decreased even at the earliest stages, when the disease may still be subclinical. A low TSH value is usually confirmed with measurement of free T 4 , which is predictably increased. In occasional patients, hyperthyroidism results predominantly from increased circulating levels of T 3 (“T 3 toxicosis”). In these cases, free T 4 levels may be decreased, and direct measurement of serum T 3 may be useful. In rare cases of pituitary-associated (secondary) hyperthyroidism, TSH levels are either normal or raised. Determining TSH levels after the injection of thyrotropin-releasing hormone (TRH stimulation test) is used in the evaluation of cases of suspected hyperthyroidism with equivocal changes in the baseline serum TSH level. A normal rise in TSH after administration of TRH excludes secondary hyperthyroidism. Once the diagnosis of thyrotoxicosis has been confirmed by a combination of TSH assays and free thyroid hormone levels, measurement of radioactive iodine uptake by the thyroid gland can help to determine the etiology. For example, there may be diffusely increased uptake in the whole gland (Graves disease), increased uptake in a solitary nodule (toxic adenoma), or decreased uptake (thyroiditis
Treat hyperthyroidism
The therapeutic options for hyperthyroidism include several medications, each with a different mechanism of action. Typically, these include a β-blocker to control symptoms induced by increased adrenergic tone, a thionamide to block new hormone synthesis, an iodine solution to block the release of thyroid hormone, and agents that inhibit peripheral conversion of T 4 to T 3 . Radioiodine, which is incorporated into thyroid tissues, resulting in ablation of thyroid function over a period of 6 to 18 weeks, may also be used
Hypothyroidism
Hypothyroidism is a condition caused by a structural or functional derangement that interferes with the production of thyroid hormone. Hypothyroidism is a fairly common disorder
Epidemiology hypothyroidism
Hypothyroidism is a fairly common disorder. By some estimates the population prevalence of overt hypothyroidism is 0.3%, while subclinical hypothyroidism can be found in greater than 4%. The prevalence increases with age, and it is nearly tenfold more common in women than in men
Cause of hypothyroidism
. It can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism, this disorder is divided into primary and secondary forms, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid itself, or occurs as a result of pituitary and hypothalamic disease ( Table 24-4 ). Primary hypothyroidism accounts for the vast majority of cases, and may be accompanied by an enlargement in the size of the thyroid gland (goiter
Primary hypothyroidism
Congenital, autoimmune, iatrogenic
Genetic defects in thyroid development ( PAX8, FOXE1 , TSH receptor mutations) (rare)
Thyroid hormone resistance syndrome ( THRB mutations) (rare)
Postablative
Surgery, radioiodine therapy, or external irradiation
Autoimmune hypothyroidism
Hashimoto thyroiditis *
Iodine deficiency *
Drugs (lithium, iodides, p -aminosalicylic acid) *
Congenital biosynthetic defect (dyshormonogenetic goiter) (rare)
Secondary causes hypothyroidism
Pituitary failure (rare) Hypothalamic failure (rare
Congenital hypothyroidism
Worldwide, congenital hypothyroidism is most often the result of endemic iodine deficiency in the diet (see later). Other rare forms of congenital hypothyroidism include inborn errors of thyroid metabolism (dyshormonogenetic goiter) , wherein any one of the multiple steps leading to thyroid hormone synthesis may be defective, such as (1) iodide transport into thyrocytes, (2) “organification” of iodine (binding of iodine to tyrosine residues of the storage protein, thyroglobulin), and (3) iodotyrosine coupling to form hormonally active T 3 and T 4 . In rare instances there may be complete absence of thyroid parenchyma (thyroid agenesis) , or the gland may be greatly reduced in size (thyroid hypoplasia) due to germline mutations in genes responsible for thyroid development
Autoimmune hypothyroidism
Autoimmune hypothyroidism is the most common cause of hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-microsomal , antithyroid peroxidase , and antithyroglobulin antibodies, are found in this disorder, and the thyroid is typically enlarged (goitrous). Autoimmune hypothyroidism can occur in isolation or in conjunction with autoimmune polyendocrine syndrome (APS), types 1 and 2 (see discussion in “Adrenal Glands
Iatrogenic hypothyroidism
This can be caused by either surgical or radiation-induced ablation . A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism or a primary neoplasm can lead to hypothyroidism. The gland may also be ablated by radiation, whether in the form of radioiodine administered for the treatment of hyperthyroidism, or exogenous irradiation, such as external radiation therapy to the neck. Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can also cause acquired hypothyroidism, as can agents used to treat nonthyroid conditions (e.g., lithium, p -aminosalicylic acid
Secondary hypothyroidism
Secondary (or central) hypothyroidism is caused by deficiencies of TSH or, far more uncommonly, TRH. Any of the causes of hypopituitarism (for example, pituitary tumor, postpartum pituitary necrosis, trauma, and nonpituitary tumors), or of hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases can cause central hypothyroidism.
Cretinism
Cretinism refers to hypothyroidism that develops in infancy or early childhood . The term cretin was derived from the French chrétien , meaning “Christian” or “Christlike,” and was applied to these unfortunates because they were considered to be so mentally retarded as to be incapable of sinning. In the past this disorder occurred fairly commonly in regions of the world where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. It is now much less prevalent as a result of the widespread supplementation of foods with iodine. On rare occasions, cretinism may also result from genetic defects that interfere with the biosynthesis of thyroid hormone (dyshormonogenetic goiter, see earlier
Clinical cretinism
Clinical features of cretinism include impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity of the mental impairment seems to be related to the time at which thyroid deficiency occurs in utero. Normally, maternal T 3 and T 4 cross the placenta and are critical for fetal brain development. If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. In contrast, maternal thyroid hormone deficiency later in pregnancy, after the fetal thyroid has become functional, does not affect normal brain development
Myxedema
The term myxedema is applied to hypothyroidism developing in the older child or adult . Myxedema was first linked with thyroid dysfunction in 1873 by Sir William Gull in an article addressing the development of a “cretinoid state” in adults. The clinical manifestations vary with the age of onset of the deficiency. Older children show signs and symptoms intermediate between those of the cretin and those of the adult with hypothyroidism. In the adult the condition appears insidiously and may take years before arousing clinical suspicion
Clinical myxedema
Myxedema is marked by a slowing of physical and mental activity . The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic depression. Speech and intellectual functions are slowed. Patients with myxedema are listless, cold intolerant , and frequently overweight. Decreased sympathetic activity results in constipation and decreased sweating. The skin is cool and pale because of decreased blood flow. Reduced cardiac output probably contributes to shortness of breath and decreased exercise capacity, two frequent complaints. Thyroid hormones regulate the transcription of several sarcolemmal genes, such as calcium ATPases and the β adrenergic receptor, and lowered expression of these genes results in a decrease in cardiac output. In addition, hypothyroidism promotes an atherogenic profile—an increase in total cholesterol and low-density lipoprotein (LDL) levels—that probably contributes to the increased cardiovascular mortality in this disease. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and a number of visceral sites. This results in nonpitting edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice
MYXEDEMA diagnosis
Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism because of the nonspecific nature of symptoms. Patients with unexplained increases in body weight or hypercholesterolemia should be assessed for potential hypothyroidism. Measurement of the serum TSH level is the most sensitive screening test for this disorder. The TSH level is increased in primary hypothyroidism as a result of a loss of feedback inhibition of TRH and TSH production by the hypothalamus and pituitary, respectively. The TSH level is not increased in persons with hypothyroidism due to primary hypothalamic or pituitary disease. T 4 levels are decreased in individuals with hypothyroidism of any origin.
Thyroiditis
Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation
Most common causes of thyroiditis
Although multiple entities exist under the diagnostic umbrella of “thyroiditis,” this discussion focuses on the three most common and clinically significant subtypes: (1) Hashimoto thyroiditis, (2) granulomatous (de Quervain) thyroiditis, and (3) subacute lymphocytic thyroiditis
Hashimoto thyroiditis
Hashimoto thyroiditis is an autoimmune disease that results in destruction of the thyroid gland and gradual and progressive thyroid failure. It is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. The name is derived from the 1912 report by Hashimoto describing patients with goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa) . It is most prevalent between 45 and 65 years of age and is more common in women than in men, with a female predominance of 10 : 1 to 20 : 1. It can also occur in children and is a major cause of nonendemic goiter in the pediatric population
Pathogenesis hashimoto
Hashimoto thyroiditis is caused by a breakdown in self-tolerance to thyroid autoantigens. This is exemplified by the presence of circulating autoantibodies against thyroglobulin and thyroid peroxidase in the vast majority of Hashimoto patients. The inciting events have not been elucidated, but possibilities include abnormalities of regulatory T cells (Tregs), or exposure of normally sequestered thyroid antigens ( Chapter 6 ). Similar to other autoimmune diseases, Hashimoto thyroiditis has a strong genetic component. Increased susceptibility to Hashimoto thyroiditis is associated with polymorphisms in immune regulation-associated genes, including cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase-22 (PTPN22) , both of which code for regulators of T-cell responses. Susceptibility to other autoimmune diseases, such as type 1 diabetes (see later), is also associated with polymorphisms in both CTLA4 and PTPN22
Induction of thyroid autoimmunity is accompanied by a progressive depletion of thyroid epithelial cells by apoptosis and replacement of the thyroid parenchyma by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to thyroid cell death, including
- CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may destroy thyroid follicular cells.
- Cytokine-mediated cell death: Activation of CD4+ T cells leads to the production of inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles.
- A less likely mechanism involves binding of antithyroid antibodies (antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity
Morphology hashimoto
The thyroid is often diffusely enlarged, although more localized enlargement may be seen in some cases. The capsule is intact, and the gland is well demarcated from adjacent structures. The cut surface is pale, yellow-tan, firm, and somewhat nodular. There is extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers ( Fig. 24-11 ). The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthle cells . This is a metaplastic response of the normally low cuboidal follicular epithelium to ongoing injury. In fine-needle aspiration biopsy samples, the presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes is characteristic of Hashimoto thyroiditis. In “classic” Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant. Unlike Reidel thyroiditis (see later), the fibrosis does not extend beyond the capsule of the gland
Histo hashimoto
Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells are also seen
Clincial hashimoto
Hashimoto thyroiditis most often comes to clinical attention as painless enlargement of the thyroid, usually associated with some degree of hypothyroidism, in a middle-aged woman. The enlargement of the gland is usually symmetric and diffuse, but in some cases it may be sufficiently localized to raise the suspicion of a neoplasm. In the usual case, hypothyroidism develops gradually. In some patients, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, leading to release of thyroid hormones (“ hashitoxicosis ”). During this phase, free T 4 and T 3 levels are elevated, TSH is diminished, and radioactive iodine uptake is decreased. As hypothyroidism supervenes, T 4 and T 3 levels fall, accompanied by a compensatory increase in TSH
What are people with hashimoto at increased risk for
Individuals with Hashimoto thyroiditis are at increased risk for developing other autoimmune diseases, both endocrine (type 1 diabetes, autoimmune adrenalitis) and nonendocrine (systemic lupus erythematosus, myasthenia gravis, and Sjögren syndrome; Chapter 6 ). They are also at increased risk for the development of extranodal marginal zone B-cell lymphomas within the thyroid gland ( Chapter 13 ). The relationship between Hashimoto disease and thyroid epithelial cancers remains controversial, with some morphologic and molecular studies suggesting a predisposition to papillary carcinomas
Subacute lymphocytic (painless) thyroiditis
Subacute lymphocytic thyroiditis , which is also referred to as painless thyroiditis , usually comes to clinical attention because of mild hyperthyroidism, goitrous enlargement of the gland, or both. Although it can occur at any age, it is most often seen in middle-aged adults and is more common in women. A disease process resembling painless thyroiditis can occur during the postpartum period in up to 5% of women (postpartum thyroiditis) . Painless and postpartum thyroiditides are variants of autoimmune thyroiditis. Most of the patients have circulating antithyroid peroxidase antibodies or a family history of other autoimmune disorders. As many as a third of cases can evolve into overt hypothyroidism over time, and the thyroid histology may resemble Hashimoto thyroiditis
Morphology subacute lymphocytic thyroitidis
Except for possible mild symmetric enlargement, the thyroid appears grossly normal. Microscopic examination reveals lymphocytic infiltration with large germinal centers within the thyroid parenchyma and patchy disruption and collapse of thyroid follicles. Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell metaplasia are not prominent
Clincial subacute lymphocytic (painless) thyroiditis
Affected individuals may present with a painless goiter, transient overt hyperthyroidism, or both. Some patients transition from hyperthyroidism to hypothyroidism before recovery. As stated, as many as a third of affected individuals eventually progress to overt hypothyroidism over a 10-year period
Granulomatous thyroiditis
Granulomatous thyroiditis (also called De Quervain thyroiditis ) occurs much less frequently than does Hashimoto disease. The disorder is most common between the ages of 40 and 50 and, like other forms of thyroiditis, affects women considerably more often than men (4 : 1
Pathogenesis granulomatous thyroiditis
Granulomatous thyroiditis is believed to be triggered by a viral infection. The majority of patients have a history of an upper respiratory infection just before the onset of thyroiditis. The disease has a seasonal incidence, with occurrences peaking in the summer, and clusters of cases have been reported in association with coxsackievirus, mumps, measles, adenovirus, and other viral infections. Although the pathogenesis of the disease is unclear, one model suggests that it results from a viral infection that leads to exposure to a viral or thyroid antigen secondary to virus-induced host tissue damage. This antigen stimulates cytotoxic T lymphocytes, which then damage thyroid follicular cells. In contrast to autoimmune thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the process is limited
Morphology granulomatous thyroiditis
The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule that may adhere to surrounding structures. On cut section, the involved areas are firm and yellow-white and stand out from the more rubbery, normal brown thyroid substance. Histologic changes are patchy and depend on the stage of the disease. Early in the active inflammatory phase, scattered follicles may be disrupted and replaced by neutrophils forming microabscesses. Later, more characteristic features appear in the form of aggregates of lymphocytes, activated macrophages, and plasma cells associated with collapsed and damaged thyroid follicles. Multinucleate giant cells enclose naked pools or fragments of colloid ( Fig. 24-12 ), hence the designation granulomatous thyroiditis . In later stages of the disease a chronic inflammatory infiltrate and fibrosis may replace the foci of injury. Different histologic stages are sometimes found in the same gland, suggesting waves of destruction over a period of time
Histology granulomatous thyroiditis
Granulomatous thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right
Clinical granulomatous thyroiditis
Granulomatous thyroiditis is the most common cause of thyroid pain . There is a variable enlargement of the thyroid. Inflammation of the thyroid and hyperthyroidism are transient, usually diminishing in 2 to 6 weeks, even if the patient is not treated. Nearly all patients have high serum T 4 and T 3 levels and low serum TSH levels during this phase. However, unlike in hyperthyroid states such as Graves disease, radioactive iodine uptake is diminished. After recovery, generally in 6 to 8 weeks, normal thyroid function returns
Riddle thyroiditis
a rare disorder characterized by extensive fibrosis involving the thyroid and contiguous neck structures. The presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma. It may be associated with fibrosis in other sites in the body, such as the retroperitoneum, and appears to be another manifestation of a systemic autoimmune IgG4-related disease, which is associated with fibrosis and tissue infiltration by plasma cells producing IgG4
Most common cause of hypothyroidism in regions where dietary iodine levels are sufficient
Hashimoto thyroiditis
What is hashimoto
▪ Hashimoto thyroiditis is an autoimmune thyroiditis characterized by progressive destruction of thyroid parenchyma, Hürthle cell change, and mononuclear (lymphoplasmacytic) infiltrates, with germinal centers and with or without extensive fibrosis.
Subacute lymphocytic thyroiditis
bacute lymphocytic thyroiditis often occurs after a pregnancy ( postpartum thyroiditis ), typically is painless, and is characterized by lymphocytic inflammation in the thyroid. It is also a type of autoimmune thyroiditis
Granulomatous (de quervain) thyroiditis
▪ Granulomatous (de Quervain) thyroiditis is a self-limited disease, probably secondary to a viral infection, and is characterized by pain and the presence of a granulomatous inflammation in the thyroid
Graves’ disease
Graves disease is the most common cause of endogenous hyperthyroidism. Graves reported in 1835 his observations of a disease characterized by “violent and long continued palpitations in females” associated with enlargement of the thyroid gland
Three triad of clincial findings graves
- Hyperthyroidism associated with diffuse enlargement of the gland
- Infiltrative ophthalmopathy with resultant exophthalmos
- Localized, infiltrative dermopathy , sometimes called pretibial myxedema , which is present in a minority of patients
Epidemiology graves
Graves disease has a peak incidence between 20 and 40 years of age. Women are affected as much as 10 times more frequently than men . This disorder is said to affect 1.5% to 2% of women in the United States
Graves disease is an autoimmune disorder characterized by the production of autoantibodies against multiple thyroid proteins, most importantly the TSH receptor
. A variety of antibodies that can either stimulate or block the TSH receptor are detected in the circulation. The most common antibody subtype, known as thyroid-stimulating immunoglobulin (TSI), is observed in approximately 90% of patients with Graves disease. In contrast to antibodies reactive with thyroglobulin and thyroid peroxidase, TSI is almost never observed in other autoimmune diseases of the thyroid. TSI binds to the TSH receptor and mimics its actions, stimulating adenyl cyclase and increasing the release of thyroid hormones. As stated, some patients also have TSH receptor blocking antibodies in the circulation, and in a minority of patients these may lead to hypothyroidism
Graves and hashimoto
Graves disease (hyperthyroidism) and Hashimoto thyroiditis (hypothyroidism) represent two extremes of autoimmune thyroid disorders, and not surprisingly share many underlying features. For example, as with Hashimoto thyroiditis, genetic factors are important in the etiology of Graves disease. The concordance rate in monozygotic twins is 30% to 40%, compared with less than 5% among dizygotic twins, and like Hashimoto thyroiditis, genetic susceptibility is linked to polymorphisms in immune-function genes like CTLA4 and PTPN22 and the HLA-DR3 allele
Infiltrating ophthalmopathy
Autoimmunity also plays a role in the development of the infiltrative ophthalmopathy that is characteristic of Graves disease. In Graves ophthalmopathy, the protrusion of the eyeball (exopthalmos) is associated with increased volume of the retroorbital connective tissues and extraocular muscles, for several reasons. These include (1) marked infiltration of the retroorbital space by mononuclear cells, predominantly T cells; (2) inflammation with edema and swelling of extraocular muscles; (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate; and (4) increased numbers of adipocytes (fatty infiltration). These changes displace the eyeball forward and can interfere with the function of the extraocular muscles. Studies performed in animal models suggest that orbital preadipocyte fibroblasts, which express the TSH receptor, appear to stimulate the autoimmune reaction. Activated CD4+ helper T cells secrete cytokines that stimulate fibroblast proliferation and synthesis of extracellular matrix proteins (glycosaminoglycans), leading to progressive infiltration of the retroorbital space and ophthalmopathy
Morphology graves
The thyroid gland is usually symmetrically enlarged due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells ( Fig. 24-13 A ). Increases in weight to over 80 gm are not uncommon. On cut section, the parenchyma has a soft, meaty appearance resembling muscle. Histologically, the follicular epithelial cells in untreated cases are tall and more crowded than usual. This crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles ( Fig. 24-13 B ). Such papillae lack fibrovascular cores, in contrast to those of papillary carcinoma (see later). The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, along with scattered B cells and mature plasma cells, are present throughout the interstitium. Germinal centers are common.
Graves’ disease histology
Graves disease. A, There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. Compare with gross photograph of multinodular goiter in Figure 24-15 . B, Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid
Prep therapy graves
Preoperative therapy alters the morphology of the thyroid in Graves disease. Administration of iodine causes involution of the epithelium and the accumulation of colloid by blocking thyroglobulin secretion. Treatment with the antithyroid drug propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia by stimulating TSH secretion
Changes one extrathyroidal tissue graves
Changes in extrathyroidal tissue include lymphoid hyperplasia, especially enlargement of the thymus in younger patients. The heart may be hypertrophied, and ischemic changes may be present, particularly in patients with preexisting coronary artery disease. In patients with ophthalmopathy, the tissues of the orbit are edematous because of the presence of hydrophilic mucopolysaccharides. In addition, there is infiltration by lymphocytes and fibrosis. Orbital muscles are edematous initially but may undergo fibrosis late in the course of the disease. The dermopathy, if present, is characterized by thickening of the dermis due to deposition of glycosaminoglycans and lymphocyte infiltration
Clinical graves
The clinical findings in Graves disease include some changes associated with thyrotoxicosis and others associated uniquely with Graves disease, such as diffuse hyperplasia of the thyroid , ophthalmopathy , and dermopathy . The degree of thyrotoxicosis varies from case to case and is sometimes less conspicuous than other manifestations of the disease. Diffuse enlargement of the thyroid is present in all cases. The thyroid enlargement may be accompanied by increased flow of blood through the hyperactive gland, often producing an audible “bruit.” Sympathetic overactivity produces a characteristic wide, staring gaze and lid lag. The ophthalmopathy of Graves disease results in abnormal protrusion of the eyeball ( exophthalmos ). The extraocular muscles are often weak. The exophthalmos may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. The infiltrative dermopathy, or pretibial myxedema , is most common in the skin overlying the shins, where it presents as scaly thickening and induration. The basis of such localization is not clear, and it is present only in a minority of patients. Sometimes individuals spontaneously develop thyroid hypofunction. Patients are at increased risk for other autoimmune diseases, such as systemic lupus erythematosus, pernicious anemia, type 1 diabetes, and Addison disease
Diagnosis graves
Laboratory findings in Graves disease include elevated free T 4 and T 3 levels and depressed TSH levels. Because of ongoing stimulation of the thyroid follicles by thyroid-stimulating immunoglobulins, radioiodine scans show a diffusely increased uptake of iodine
Treat graves
Graves disease is treated with β-blockers, which address symptoms related to the increased β-adrenergic tone (e.g., tachycardia, palpitations, tremulousness, and anxiety), and by measures aimed at decreasing thyroid hormone synthesis, such as the administration of thionamides (e.g., propylthiouracil), radioiodine ablation, and thyroidectomy. Surgery is used mostly in patients who have large goiters that are compressing surrounding structures
Graves’ disease
▪ Graves disease, the most common cause of endogenous hyperthyroidism, is characterized by the triad of thyrotoxicosis, ophthalmopathy, and dermopathy.
▪ Graves disease is an autoimmune disorder caused by activation of thyroid epithelial cells by autoantibodies to the TSH receptor that mimic TSH action ( thyroid-stimulating immunoglobulins ).
▪ The thyroid in Graves disease is characterized by diffuse hypertrophy and hyperplasia of follicles and lymphoid infiltrates; glycosaminoglycan deposition and lymphoid infiltrates are responsible for the ophthalmopathy and dermopathy.
▪ Laboratory features include elevations in serum free T 3 and T 4 and decreased serum TSH
Diffuse multinodular gaiters
Enlargement of the thyroid, or goiter is caused by impaired synthesis of thyroid hormone, which is most often the result of dietary iodine deficiency
Pathology diffuse and multinodular gaiters
mpairment of thyroid hormone synthesis leads to a compensatory rise in the serum TSH level, which, in turn, causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland overcomes the hormone deficiency, ensuring a euthyroid metabolic state in most individuals. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect or endemic iodine deficiency, discussed later), the compensatory responses may be inadequate, resulting in goitrous hypothyroidism . The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. Goiters can broadly be divided into two types: diffuse nontoxic and multinodular
Diffuse nontoxic (simple) goiter
Diffuse nontoxic (simple) goiter causes enlargement of the entire gland without producing nodularity. Because the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition. This disorder occurs in both an endemic and a sporadic distribution
Endemic goiter
occurs in geographic areas where the soil, water, and food supply contain low levels of iodine. The term endemic is used when goiters are present in more than 10% of the population in a given region. Such conditions are particularly common in mountainous areas of the world, including the Andes and Himalayas, where iodine deficiency is widespread. The lack of iodine leads to decreased synthesis of thyroid hormone and a compensatory increase in TSH, leading to follicular cell hypertrophy and hyperplasia and goitrous enlargement. With increasing dietary iodine supplementation, the frequency and severity of endemic goiter have declined significantly, although as many as 200 million people worldwide continue to be at risk for severe iodine deficiency. Variations in the prevalence of endemic goiter in regions with similar levels of iodine deficiency point to the existence of other causative influences, particularly dietary substances, referred to as goitrogens . The ingestion of substances that interfere with thyroid hormone synthesis at some level, such as vegetables belonging to the Brassicaceae (Cruciferae) family (e.g., cabbage, cauliflower, Brussels sprouts, turnips, and cassava), has been documented to be goitrogenic. Native populations subsisting on cassava root are particularly at risk. Cassava contains a thiocyanate that inhibits iodide transport within the thyroid, worsening any possible concurrent iodine deficiency
