Endocrine System Pathology_ Ppt Lecture Series (5 in 1)

Pathology of Endocrine System
Photos: The surgeon in this photo is transfusing donor islet cells into a diabetic patient. The islet cells may take residence in the pancreas and secrete insulin for the patient. Note the new islet
cells in the right-hand photo. They are now functioning normally. This patient will never again need to inject insulin. From: Seeley’s Anatomy & Physiology 10th ed. New York, NY: McGraw-Hill 2010.
Prepared and presented by:
Marc Imhotep Cray, M.D.

Marc Imhotep Cray, MD
Learning Objectives
2
1. List types of pituitary adenomas and describe their
morphology.
2. List the causes of hypopituitarism.
3. Classify thyroiditis and describe the pathogenesis,
complications and morphology of Hashimoto’s thyroiditis in
particular.
4. Define Graves’ disease and describe its pathogenesis and
morphology and correlate with the clinical features.

Learning Objectives cont.
3
5. Describe different types of goiters and their pathology
and clinical features.
6. Classify tumors of thyroid gland and describe the
morphology and clinical features of thyroid adenoma and
thyroid carcinoma
7. Describe causes, pathology, clinical features and
complication of parathyroid hypo and hyperfunction.
8. Describe etiology, pathophysiology, clinical features and
complications of adrenocortical hyperfunction and
hypofunctions.

Learning Objectives cont.
4
9. Describe etiology, pathophysiology , clinical features and
complications of adrenomedullary lesions
10. Define Diabetes mellitus (DM), classify it and describe its
pathogenesis of the different types.
11. Describe the morphological changes of blood vessels in
different organs in DM.
12. List and classify the long-term complications of DM.
13. Describe the primary cause, signs, symptoms and
treatment of hypoglycemia and other acute complications of
DM.

Topics Outline
5
This sequence will cover the following topics:
Lect. 1 Overview and the pituitary gland (hyperpituitarism,
hypopituitarism, mass effect as related to pituitary gland lesions,
and posterior pituitary gland pathology)
Lect. 2 Diseases of the thyroid gland (goiter, hyperthyroidism,
hypothyroidism, thyroiditis, and thyroid neoplasms)
Lect. 3 Diseases of the parathyroid glands (hyperparathyroidism and
hypoparathyroidism)
Lect. 4 Diseases of the adrenal glands (hyperadrenalism
hypoadrenalism, hyperaldosteronism, and adrenal neoplasms)
Lect. 5 Diabetes mellitus (T1DM & T2DM) and complications

Function of Endocrine System
and
Overview of Endocrine Disease
6
A working knowledge of the pathways that regulate normal hormone
levels helps to interpret the symptoms, signs and diagnostic studies in
patients being worked up for suspected endocrine disorders.

Function of Endocrine System
7
 Main function of endocrine system is communication
orchestrates metabolic equilibrium among organs of
body
 Although nervous and endocrine systems use some of same
mediators and sometimes overlap functionally
(=neuroendocrine integration) endocrine system is unique in
its ability to communicate at a distance using soluble
mediators= hormones
 Ultimately, body’s chemical messenger systems(nervous & endocrine)
interact with one another to maintain homeostasis

Function of Endocrine System (2)
8
 Term hormone (from Greek, horman, “set in motion”)
applies to chemicals secreted by “ductless” (i.e.,
endocrine) glands into circulation carries it to target
organ= classic endocrine pathway
 Many hormones, such as thyroid hormone, corticosteroids
and pituitary hormones, fit this definition
o Biological messages may also be transmitted by
mechanisms other than classic endocrine pathway (see
next 2 slides)

9
 Some hormones, such as catecholamines, are produced in
multiple sites and act either locally or through circulation
 Other mediators function only in restricted circulation
compartments:
 e.g., hypothalamic hormones only act on pituitary and reach it via
portal tributaries without entering systemic circulation
 Some hormones exert their effects in very tissues that make
them (autocrine), e.g., MIF (Müllerian inhibitory factor)
Biological messages of endocrine system may also be transmitted by
autocrine, paracrine, neuroendocrine & cytokine modes of communication

Mechanisms of chemically mediated cell-to-cell
communication illustrated.
10
Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.
Learn more: Molecular and Cell Biology of Endocrine System Ppt.

11
NB: To qualify as a hormone, a chemical messenger must bind a
receptor, whether on cell’s surface or inside (cytoplasm or nucleus)
 Hormones act either on final effector target or on other
glands that in turn produce other hormones
 For example, thyroid stimulating hormone (TSH) released by
pituitary promotes thyroid hormone (TH) secretion by
thyroid gland TH, then, directly affects many types of
peripheral cells TH will in turn down-regulate activity of
pituitary TSH (as well as hypothalamic TRH)= a process known
as feedback inhibition

 At the core of endocrine system are endocrine organs, include:
pituitary, adrenals, thyroid, parathyroids, pancreas & gonads
 Endocrine glands synthesize and secrete hormones into
bloodstream hormones are carried to distant sites to exert their
physiologic effects
 In this way endocrine glands are able to influence function of distant
target organs and tissues
 Disorders of endocrine system are usually due to either
overproduction or underproduction of a particular hormone, or
mass lesions (mass effect)
 To aid understanding, these lectures will be presented in a similar scheme
12

Major Endocrine Organs
13Merali Z, Woodfine JD (eds.) Toronto Notes 2016, 33rd Ed. Toronto, Ontario, Canada, 2016.

Overview of Endocrine Disease/Disorders
 Endocrine system plays an important part in regulation of
reproduction, growth and development, maintenance of internal
environment, and energy production, utilization and storage
 Disorders of endocrine system are therefore important b/c they
can have far-reaching and devastating effects in some cases
can be life-threatening (e.g. thyroid storm, myxedema coma,
addisonian crisis, diabetic ketoacidosis, pituitary apoplexy etc.)
14
NB: Study of endocrine diseases requires integration of morphologic
findings w biochemical measurements of levels of hormones, their
regulators, and other metabolites.

Overview of Endocrine Disease (2)
15
 Several processes can disturb normal activity of
endocrine system, including (3):
1) impaired synthesis or release of hormones
2) abnormal interactions betw. hormones and their target tissues
3) abnormal responses of target organs
 Endocrine diseases can be classified as
1) diseases of underproduction or overproduction of hormones
and their resulting biochemical and clinical consequences
2) diseases associated w development of mass lesions
 These lesions might be nonfunctional, or assoc. w overproduction or
underproduction of hormones

Tumors (benign & malignant), hyperplasia, or
inflammatory lesions of endocrine organs can cause
endocrine hypofunction and hyperfunction
 Pathogenesis is frequently autoimmune and (or) genetic
 Since hypothalamus and pituitary gland control
hormone secretion by many endocrine organs there
is potential for lesions at this level to result in abnormal
hormone secretion by downstream endocrine organs
16

 Identifying root cause of abnormal hormone
production is critical for establishing correct diagnosis
and managing treatment
 Simultaneous measurement of conc. of pituitary
hormones (e.g., TSH or ACTH) and downstream
hormones (e.g., thyroid hormone or cortisol) often
allows localization of endocrine abnormality
 Assessing stimulation or inhibition of hormone release
using various pharmacologic agents is also applied
17

Stimulation tests
 Evaluate hypofunctioning disorders
 Example—adrenocorticotropic hormone (ACTH)= Cosyntropin
stimulation test is used in workup of hypocortisolism
Causes of hypofunction
• Autoimmune destruction (most common) Examples—Addison’s
disease, Hashimoto’s thyroiditis, Grave’s disease
• Infarction Example—Sheehan’s postpartum necrosis, Waterhouse-
Friderichsen syndrome
• Decreased hormone stimulation Example—decreased thyroid-
stimulating hormone in hypopituitarism
• Enzyme deficiency, infection, neoplasia, congenital disorder
18

 Suppression tests
 Evaluate hyperfunctioning disorders
Examples
o dexamethasone suppression test evaluates hypercortisolism
o saline infusion test evaluations of hyperaldosteronism
o glucose tolerance test evaluations GH excess
 Most hyperfunctioning disorders cannot be suppressed
• Notable exceptions prolactinoma and pituitary Cushing's
syndrome (= Cushing's Disease)
 Causes of hyperfunction
• Adenoma (most common), acute inflammation,
hyperplasia, cancer 19

20
Also remember, it is important to understand
hypothalamic-pituitary axis so you can distinguish 1°
from 2° disorders
 primary diseases are diseases that originate within gland in
question
 e.g., primary hyperthyroidism is due to a defect in thyroid gland),
and
 secondary diseases represent change in one organ as a result
of disease in another organ
 e.g., secondary hyperthyroidism may be due to a TSH-secreting
pituitary adenoma

Negative feedback loops
 Normally, control an increase or decrease in hormone production
 Example—↑ calcium, ↓ PTH; ↓ calcium, ↑ PTH
Hormone synthesis and release are governed at multiple
levels typically involves regulation by a pituitary hormone
which itself is regulated by a hypothalamic hormone (=releasing
factor)
 This general pathway structure is commonly referred to as a
hypothalamic-pituitary-(organ) axis  e.g., HPO axis, where O refers to
ovary, HPA axis, where A refers to adrenal gland etc.
o NB: These various axes represent examples of nervous system-endocrine system
integration (or “neuroendocrine systems”)
21

22
 As indicated above, important to understand
hypothalamic–pituitary axis so you can distinguish
primary from secondary disorders
 In primary endocrine disturbances, gland itself is
malfunctioning (e.g., from tumor, inflammation, enzyme
deficiency), but pituitary and hypothalamus are functioning
normally and exhibit appropriate response to gland's action
o For example, thyroid-stimulating hormone (TSH) is low in Graves
disease b/c thyroid is overproducing thyroid hormone (TH) in response
to presence of thyroid-stimulating antibody appropriate response is
for pituitary to secrete less TSH b/c of feedback inhibition

23
 In a secondary endocrine disturbance, gland is perfectly
normal, but pituitary or hypothalamus is malfunctioning
 For example, if pituitary secretes low or normal levels of TSH
in pts w low thyroid hormone levels, then pituitary is
malfunctioning b/c it should be secreting higher levels of TSH
in response to inadequate levels of TH

Neuroendocrine System (Neuroendocrinology)
24
Neuroendocrine cells receive neuronal input (NTs released by
nerve cells or neurosecretory cells) and release message molecules
(hormones) into blood
 In this way they bring about an integration betw. nervous system and
endocrine system known as neuroendocrine integration
o Example of a neuroendocrine cell is a cell of adrenal medulla which
releases Epi & NE (=neuroendocrine hormones) into bld
A major center of neuroendocrine integration is hypothalamus
and pituitary gland hypothalamic neurosecretory cells release
factors (=neuroendocrine hormones) in blood
 Some of these hormones released at hypothalamic median eminence,
control secretion of anterior pituitary hormones, while others (oxytocin
& vasopressin) are released directly into blood

Hypothalamic-pituitary axis feedback loops
are neuroendocrine integration systems
25
 In most cases, a hypothalamic– pituitary–target gland
axis is regulated by negative feedback, whereby
 tropic hormone of anterior pituitary gland has negative
feedback effects on hypothalamus and
 target gland hormone has negative feedback effects on both
hypothalamus and anterior pituitary
o By way of these mechanisms levels of target gland hormone are
maintained within normal physiological range

26
Hormones of hypothalamic-pituitary axis
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Ed. Wolters
Kluwer, 2015.
Major neuroendocrine systems
(Hormonal Feedback Regulatory Systems)
Individual Axes:
Anterior Pituitary Gland
Hypothalamic-Pituitary–GH Axis
Hypothalamic-Pituitary–Prolactin Axis
Hypothalamic-Pituitary–Thyroid Axis
Hypothalamic-Pituitary–Adrenal Axis
Hypothalamic-Pituitary–Gonadal Axis
Posterior Pituitary Gland
Antidiuretic Hormone (ADH) & Oxytocin

“the negative feedback principle”
 It is essential to understand “the negative
feedback principle” of hypothalamic
/pituitary/ target organ axis
 A negative feedback mechanism is an
example of a negative effect
 Negative feedback occurs when a product
downstream of an axis inhibits production of
a reactant by which it is regulated
 for example, thyroid hormone inhibition of
thyroid-stimulating hormone (TSH)
Solidlines=positiveeffect
Dashedlines=negativeeffect
Pazdernik TL, Kerecsen L. Rapid Review
Pharmacology, 3rd Ed. Mosby, 2010 27

Example, thyroid hormone feedback loop
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
28
A small reduction of TH triggers
a rapid increase of TRH and TSH
secretion, resulting in thyroid
gland stimulation and increased
thyroid hormone production
When thyroid hormone reaches
a normal level, it feeds back to
suppress TRH and TSH, and a
new steady state is attained

Example of no feedback loop in Endemic Goiter
Iodine deficiency no TH synthesis no feedback >>↑TSH>>follicular hyperplasia
Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function,
11th ed. New York, NY: McGraw-Hill, 2008. 28

The Pituitary Gland
30
Topics discussed Outline:
Anatomy: Gross and Microscopic and
Hypothalamic–Pituitary Axis
Anterior Pituitary Tumors
Pituitary Adenomas: General Features
Functioning Adenomas and Hyperpituatarism
Hypopituitarism
Posterior Pituitary Syndromes

Pituitary Gland
31
Anatomy
 Pituitary gland (hypophysis) a small gland that weighs
0.5-1.0 g and measures 1.3 × 0.9 × 0.5 cm
 It sits at base of brain in a bony cavity called sella turcica,
within sphenoid bone
Anatomically, it is composed of two lobes
 Anterior lobe, or adenohypophysis arises from ectoderm,
makes up 80% of gland is populated by epithelial cells
 Posterior lobe, or neurohypophysis originates from
neuroectoderm as a prolongation of hypothalamus

Pituitary gland anatomy illustration
32
 Anterior pituitary is formed
from an out-pouching of
pharyngeal roof and is called
Rathke's pouch
 Posterior pituitary gland arises
from an extension of
hypothalamic neurons
 NB: pituitary gland sits in a
protective bony enclosure
called sella turcica (Turkish
chair/saddle)
Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations
of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

33
Normal pituitary gland, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

34
Normal pituitary, microscopic

35
Normal pituitary, microscopic (2)

Pituitary Gland (6)
36
Histologic sections of anterior pituitary reveals cells that contain
eosinophilic cytoplasm (acidophil), basophilic cytoplasm (basophil), or
poorly staining cytoplasm (chromophobe) cells
 Note also presence of a fine reticulin network between cells
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
 Basophils:
FSH, LH, ACTH, TSH (B-FLAT)
 Acidophils:
GH, PRL

Hypothalamic–Pituitary Axis
37
 Endocrine function responds to feedback control
 Hypothalamus, pituitary stalk and pituitary gland
constitute an anatomically and functionally integrated
“neuroendocrine system”
 Neuron groups in hypothalamus secrete a number of
factors that stimulate anterior pituitary secretion of
hypothalamic factors, in turn, are antagonized by
hormones secreted by peripheral target organs, thereby
completing a feedback loop
 In addition, specific hypothalamic inhibitory hormones
have been identified
o For example, dopamine inhibits pituitary secretion of prolactin

Hypothalamic-pituitary axis cont.
38
Hypothalamus regulates secretion of hormones from
adenohypophysis (anterior pituitary gland) by releasing
 stimulatory factors (corticotropin-releasing hormone, CRH;
growth hormone-releasing hormone, GHRH; gonadotropin-
releasing hormone, GnRH; thyrotropin-releasing hormone TRH,
and
 inhibitory factors (growth hormone inhibitory hormone, GHIH
or somatostatin; prolactin inhibitory factor, PIF or dopamine) 
these in turn modulate release of six hormones from anterior
pituitary (next slide)

Anterior pituitary (6 major hormones)
39
 Anterior pituitary synthesizes and releases six hormones:
1. Growth hormone (GH): regulated by growth hormone-releasing
hormone (GHRH)
2. Prolactin (PRL): inhibited by dopamine from hypothalamus, stimulated
by thyrotrophin-releasing hormone (TRH)
3. Adrenocorticotrophic hormone (ACTH): regulated by corticotrophin-
releasing hormone (CRH)
4. Thyroid-stimulating hormone (TSH): regulated by TRH
5. Follicle-stimulating hormone (FSH): regulated by gonadotrophin-
releasing hormone (GnRH)
6. luteinizing hormone (LH): regulated by GnRH
FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH

hypothalamic-hypophysial portal system
40
Hall JE. Guyton and Hall Textbook of Medical Physiology, 13e. Philadelphia: Elsevier , 2016.

Hypothalamic-pituitary axis illustrated
41
Production of pituitary hormones is controlled by positively
and negatively acting factors from hypothalamus  carried
to anterior pituitary by a portal vascular system
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

Pituitary Gland (7)
42
Posterior pituitary contains pituicytes modified glial
cells w no secretory function, axon terminals and
unmyelinated nerve fibers containing ADH and oxytocin
 Both are synthesized in neurons of hypothalamus
and transported along axons to neurohypophysis
(=stored and released here)
o ADH promotes water resorption from distal renal tubules
o oxytocin stimulates contraction of pregnant uterus at
term and also of cells around lactiferous ducts in breasts

Pituitary Gland (8)
43
Clinical Manifestations of Pituitary Disease
 Manifestations of pituitary disorders are related to either excess
or deficiency of pituitary hormones, or to mass effects
 Hyperpituitarism: Arising from excess secretion of trophic hormones
o Causes include pituitary adenoma, hyperplasia & carcinomas of
anterior pituitary, secretion of hormones by nonpituitary tumors, &
certain hypothalamic disorders
o Symptoms (Sx) of hyperpituitarism are discussed later in context of
individual tumors
 Hypopituitarism: Arising from deficiency of trophic hormones
o Caused by destructive processes, including ischemic injury, surgery
or radiation, inflammatory reactions, and nonfunctional (silent)
pituitary adenomas

Pituitary Gland (9)
44
 Local mass effects: Among earliest changes referable to mass
effect are radiographic abnormalities of sella turcica, including
sellar expansion, bony erosion, and disruption of diaphragma sella
o b/c of close proximity of optic nerves & chiasm to sella expanding
pituitary lesions often compress decussating fibers in optic chiasm gives
rise to visual field abnormalities, classically, defects in both lateral
(temporal) visual fields called bitemporal hemianopsia (See next slide)
• may also invade cavernous sinus compromising cranial nerves III, IV,
and VI
o Like any expanding intracranial mass pituitary adenomas can produce
signs (Sn) and symptoms (Sx) of elevated intracranial pressure, including
headache, vomiting, ocular palsies, altered level of consciousness, back
pain and papilledema

Effects of Pituitary Tumors
on Visual Apparatus
45
Young WF. The Netter Collection of Medical Illustrations Vol 2- The
Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.
To learn more study:
Endocrinology Tutorial 3_Anterior Pituitary
Endocrine Pathology Case 2 SDL Tutorial
 Graphic shows compression of
optic chiasm causing defects in
both lateral (temporal) visual
fields= bitemporal hemianopsia
 In addition, a variety of other visual
field abnormalities may be caused
by asymmetric growth of many
tumors

Anterior Pituitary Tumors
46
 Most common cause of anterior pituitary disorders
are pituitary tumors most are benign adenomas
 Some produce hormones and result in endocrine
abnormalities
 Others are nonfunctional, but produce mass effects
o Non-functioning (or silent) adenomas progressively enlarge until
they break out of sella turcica in an upwards direction,
compressing optic chiasm
 Following, we will first discuss general features of pituitary
adenomas, then specific tumors

Pituitary Adenomas: General Features
47
 Most common cause of hyperpituitarism is a hormone
producing adenoma arising in anterior lobe
 Other, less common, causes include hyperplasia and
carcinomas of anterior pituitary; secretion of hormones by
some extrapituitary tumors; hypothalamic disorders
 Main features of pituitary adenomas are:
 Classified on basis of hormone(s) produced by neoplastic
cells detected by immunohistochemical stains of tissue
sections (see slide 50)

Pituitary Adenomas: General Features (2)
48
Main features cont.
 Pituitary adenomas can be functional (hormone producing)
or nonfunctioning (not producing hormone) , or silent (i.e.,
demonstration of hormone production at tissue level only,
without clinical manifestations of hormone excess)
o Both functional and nonfunctioning pituitary adenomas
usually are composed of a single cell type and produce
at most a single predominant hormone but there are
exceptions
• Some pituitary adenomas secrete two different
hormones (GH and PRL most common combination)

Pituitary Adenomas: General Features (3)
49
 Main features cont.
 Pituitary adenomas are designated as microadenomas if less
than 1 cm in diameter and macroadenomas if they exceed 1 cm
 Nonfunctioning adenomas more likely to come to clinical
attention at a later stage are, therefore, more likely to be
macroadenomas
o b/c of larger size, nonfunctioning adenomas may encroach
upon and destroy adjacent anterior pituitary parenchyma
leading to hypopituitarism

50
Classification of Pituitary Adenomas
Note: PRL producing adenomas (prolactinoma) are most common hormone
secreting tumors in both adults and children. Gonadotroph adenomas are more
common in elderly.

Marc Imhotep Cray, MD 51
Kemp WL, Burns DK, Brown TG, Pathology: The Big Picture.
New York:McGraw-Hill,2008.
Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St.
Louis: Mosby-Elsevier, 2009.
CT scan (a) of a large pituitary adenoma
(A) expanding upwards to compress optic
chiasma (arrows)
Large pituitary adenoma was an incidental finding at
autopsy. As would be suggested by size of tumor, this
pituitary adenoma did not secrete any hormones.

Important point regarding pituitary adenomas:
Stalk effect
52
 Secretion of all of AP hormones, except prolactin, is stimulated
by delivery of releasing hormones including TRH, GnRH, and
CRH, from hypothalamus via hypophyseal portal system
 Secretion of PRL, however, is tonically inhibited by delivery of
dopamine via same portal system
 A mass pressing on stalk will prevent dopamine from reaching
pituitary gland thus causing increased levels of prolactin without
actually producing prolactin
o However, level of PRL in “stalk effect” less than that produced by a
PRL secreting adenoma
 This stalk effect will, simultaneously, cause inhibition of secretion of
other AP hormones

Pituitary Adenomas: Pathogenesis
53
Several genetic abnormalities associated w pituitary
adenomas have been identified:
 G-protein mutations are one of most common genomic
alterations causing pituitary adenomas
o G-proteins play a critical role in signal transduction transmitting
signals from cell surface receptors e.g. growth hormone-releasing
hormone (GHRH) receptor to intracellular effectors (e.g., adenyl
cyclase) which then generate second messengers (e.g., cAMP)
o G-proteins are heterotrimeric proteins, composed of a specific α-
subunit that binds guanine nucleotides and interacts w both cell
surface receptors and intracellular effectors
• β- and γ-subunits are noncovalently bound to α-subunit

G-protein signaling in
endocrine neoplasia
54
 Mutations that lead to G-protein
hyperactivity are seen in a variety of
endocrine neoplasms, including
pituitary, thyroid, and parathyroid
adenomas
 G proteins play a critical role in signal
transduction, transmitting signals from
cell surface receptors (GHRH, TSH or
PTH receptor) to intracellular effectors
(e.g., adenyl cyclase) which generate
second messengers (cAMP)
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.
For Hormone-Receptor Interactions and
Signal Transduction Mechanisms
see Molecular and Cell Biology of
Endocrine System : Ppt.

Pituitary Adenomas: Pathogenesis (3)
55
 Gs is a stimulatory G protein that has a pivotal role in signal
transduction in several endocrine organs, including pituitary
o α-subunit of Gs (Gsα) is encoded by GNAS gene
o In basal state, Gs exists in an inactive state, w guanosine diphosphate
(GDP) bound to guanine nucleotide-binding site of Gsα
o On interaction w ligand-bound cell surface receptor, GDP dissociates,
and guanosine triphosphate (GTP) binds to Gsα, activating G protein
activation of Gsα results in generation of cAMP= a potent mitogenic
stimulus in several endocrine cells (e.g., pituitary somatotrophs and
corticotrophs, thyroid follicular cells, parathyroid cells) promoting
cellular proliferation and hormone synthesis and secretion

Pituitary Adenomas: Pathogenesis (4)
56
Normally, Gsα activation is transient b/c of an intrinsic GTPase
activity in α-subunit hydrolyzes GTP into GDP
 Approx. 40% of somatotroph cell adenomas bear GNAS
mutations that nullify GTPase activity of Gsα leading to
continual activation of Gsα persistent generation of cAMP
unchecked cellular proliferation
 GNAS mutations also occur in minority of corticotroph adenomas
Contrastly,
 GNAS mutations are absent in thyrotroph, lactotroph, & gonadotroph
adenomas b/c these arise from cells whose hypothalamic release
hormones do not signal via cAMP-dependent pathways

57
Pituitary adenoma, gross and microscopic
Monomorphism of these cells contrasts with admixture of cells seen in
normal anterior pituitary gland. Note also absence of reticulin network.
Massive, nonfunctioning adenoma that has grown far beyond
confines of sella turcica and has distorted overlying brain.
Two distinctive morphologic features cellular
monomorphism and absence of a reticulin network.

Functioning Adenomas & Hyperpituatarism
58
 Adenomas arising from different pituitary cells produce
hormones characteristic of that cell type and cause clinical
syndromes that reflect activity of hormones
 Lactotroph Adenomas
 Prolactin-secreting lactotroph adenomas are most frequent type of
hyperfunctioning pituitary adenoma accounting for 30% of all
clinical cases
 Hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido,
and infertility
 b/c manifestations of hyperprolactinemia (e.g., amenorrhea) are
obvious in premenopausal women prolactinomas are diagnosed
at an earlier stage in women of reproductive age than in others w
these tumors

Functioning Adenomas & Hyperpituatarism (2)
59
 Lactotroph Adenomas cont.
 Compared to premenopausal women effects of
hyperprolactinemia are subtle in men and older women
thus, tumor may reach a large size before coming to clinical
attention= mass effect
 Hyperprolactinemia also is a feature of other conditions,
including pregnancy, high-dose estrogen therapy, renal failure,
hypothyroidism, hypothalamic lesions, and dopamine-
inhibiting drugs (e.g., antipsychotic agents)

60
Somatotroph Adenomas
 Growth hormone–secreting somatotroph adenomas
are second most common type of functioning
pituitary adenoma, and cause gigantism in children
or acromegaly in adults
 b/c clinical manifestations of excess GH may be
subtle somatotroph cell adenomas may be quite
large by time they come to clinical attention

Physiologic actions of
Growth hormone (GH)
(somatotropin or STH)
61
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.

62
 Somatotroph Adenomas cont.
Persistent GH excess stimulates hepatic secretion of
insulin-like growth factor 1 (IGF1, somatomedin C), which
acts in conjunction w GH to induce overgrowth of bones
and muscle
 If a GH-secreting adenoma develops before
epiphyses close, as is case in prepubertal children,
result in gigantism
o Characterized by a generalized increase in body size, w
disproportionately long arms and legs

63
 Somatotroph Adenomas cont.
 If elevated levels of GH and IGF1
persist or develop after closure
of epiphyses, affected individuals
develop acromegaly
o growth is most conspicuous in soft
tissues, skin, viscera, and bones of
face, hands, and feet
o Enlargement of jaw results in its
protrusion (prognathism),
broadening of lower face, and
separation of teeth
o hands and feet are enlarged, and
fingers are broad and sausage-like
Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations
of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

64
Somatotroph Adenomas cont.
 Persistent GH excess also is assoc. w metabolic
abnormalities most important is diabetes mellitus
o DM arises b/c of GH-induced peripheral insulin resistance
“blunts” body’s response to elevated glucose levels=GH is
diabetogenic
• Failure to suppress GH production in response to an oral load of
glucose most specific tests to Dx acromegaly
• IGF1 provides most sensitive lab test for the Dx of acromegaly
 Other manifestations of GH excess include gonadal
dysfunction, generalized muscle weakness, hypertension,
arthritis, congestive heart failure, increased risk for GI cancers

Question
A 38-year-old man presents complaining of gradually enlarging
hands and feet over past several years. In comparison with a photo
from 15 years ago, his facial features have become obviously
coarsened. Laboratory evaluation shows mildly elevated plasma
glucose, and MRI of brain reveals an enlarged mass in sella turcica.
Given suspected diagnosis, specialized testing is performed in
which GH levels are measured following administration of an oral
glucose load; no measurable decrease is seen.
What is the diagnosis?
Note: One good way to diagnose this disorder is to look at an old picture of pt.
and compare it w patient’s current appearance. Because physical changes take
place over decades, family members and friends often do not recognize them.
65

A. A 26-year-old attractive woman prior to acromegaly changes.
B. Facial changes 20 years later in the same woman.
Note the coarse facial features with large nose, lips, and chin.
Protrusion of lower jaw is visible.
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013 66

Features of acromegaly /gigantism
 A 22-year-old man w
gigantism due to excess GH
is shown to left of his
identical twin
 increased height and
prognathism (A) and
enlarged hand (B) and foot
(C) of affected twin are
apparent
 Their clinical features began
to diverge at age of approx.
13 years
67

Functioning Adenomas & Hyperpituatarism(10)
68
Corticotroph Adenomas
 Excess production of ACTH by functioning corticotroph
adenomas leads to adrenal hypersecretion of cortisol
and development of hypercortisolism (also known as
Cushing syndrome)
o Cushing syndrome (discussed later w diseases of adrenal
gland) may be caused by other conditions as well
o When hypercortisolism is caused by excessive production
of ACTH by pituitary, it is called Cushing disease  after
neurosurgeon Harvey Cushing who first described disorder

Corticotroph Adenomas cont.
 Most corticotroph adenomas are microadenomas
at time of diagnosis
o Stain positively w periodic acid–Schiff (PAS) stains
due to accumulation of glycosylated ACTH protein
o ACTH can also be specifically detected by
immunohistochemistry methods

70
 Corticotroph Adenomas cont.
 Large, clinically aggressive corticotroph cell adenomas may
develop after surgical removal of adrenal glands for Tx of
Cushing syndrome
o In most cases this condition, known as Nelson syndrome, results
from loss of inhibitory effect of adrenal corticosteroids on a
preexisting corticotroph microadenoma
o b/c adrenals are absent, hypercortisolism does not develop
instead, pts present w mass effects of pituitary tumor
Note: Pts w Cushing syndrome often have hyperpigmented skin b/c of ↑
production of melanocyte stimulating hormone (MSH) derived from same
precursor as ACTH (=pro-opiomelanocortin), so its synthesis accompanies
that of ACTH (see slide 195)

Hypopituitarism
71
In hypopituitarism secretion of one or more pituitary hormones is
lacking has many causes and various clinical presentations
 Most often, only one or a few of pituitary hormones are deficient
 Occasionally, total failure of pituitary function, or panhypopituitarism
(pituitary cachexia), occurs
 Effects of hypopituitarism depend on
1) extent of loss
2) specific hormones involved and
3) age of patient
 Symptoms usually relate to deficient function of thyroid, adrenal
glands and reproductive system
 Growth retardation and delayed puberty may occur in children

Hypopituitarism (2) Causes
72
Pituitary Tumors:
More than half of all cases of hypopituitarism in
adults are caused by pituitary tumors, usually
adenomas (discussed above)
 Tumor itself may be functional but symptoms of
hypopituitarism result from compression of
adjacent tissue by tumor mass

Hypopituitarism (3) Causes
73
Sheehan Syndrome:
 Panhypopituitarism may be caused by ischemic necrosis of
gland, commonly due to severe hypotension caused by
intrapartum or postpartum hemorrhage/necrosis
 enlargement of pituitary reduces its blood flow, rendering it particularly
vulnerable
Clinical manifestations due at first to loss of gonadotropins, then to
subsequent loss of TSH and ACTH
 Agalactia (lactation failure), amenorrhea, hypothyroidism and
adrenocortical insufficiency are important consequences
o w modern obstetric care, Sheehan syndrome is rare
Note: Occurrence of similar process wo preceding
pregnancy, as well as, its occurrence in males is
termed Simmond’s disease (=Pituitary cachexia)

See Endocrinology Tutorial 1_Postpartum Necrosis
Young WF. The Netter Collection of Medical Illustrations Vol 2-
The Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

75
Hypopituitarism, Mild=FSH and LH are usually affected first
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

76
Hypopituitarism, Moderate=TSH and ACTH affected
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014. 77
Hypopituitarism: Severe=Frank TSH and ACTH deficiency

78
Hypopituitarism, Pituitary Cachexia=AP & PP deficiency
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014.

Question
79
A 53-year-old woman is diagnosed with hypopituitarism.
Which of the following hormones is most likely to be
affected first?
A. Follicle stimulating hormone (FSH) and luteinizing
hormone (LH)
B. Thyroid stimulating hormone (TSH)
C. Adrenocorticotropic hormone (ACTH)
D. Prolactin
E. Growth hormone

Question
80
A 25-year-old woman is diagnosed with hypopituitarism.
Which of the following hormones is essential to replace
first when managing her condition?
A. Thyroid hormone
B. Estrogen
C. Growth hormone
D. Luteinizing hormone
E. Follicle stimulating hormone

Other Causes of Hypopituitarism
81
 Pituitary Apoplexy: acute hemorrhage or impaired bld supply to
pituitary can occur in nml pituitary  but at least half cases
assoc. w endocrinologically inactive adenomas
 On occasion, pituitary apoplexy  leads to hypopituitarism
 Iatrogenic Hypopituitarism: radiation damage to hypothalamic–
pituitary axis during therapy or prophylactic irradiation may cause
neuroendocrine abnormalities, including hypopituitarism
 Similarly, neurosurgical procedures may damage pituitary
 Trauma: traumatic brain injury is assoc. w significant risk to
pituitary gland w potential development of diabetes insipidus ,
hypopituitarism & other endocrinopathies

Other Causes of Hypopituitarism cont.
82
 Infiltrative Diseases: bacterial and viral infections may lead to
inflammation can damage gland
 Hypothalamic–pituitary axis involvement in Langerhans cell histiocytosis
(formerly Hand-Schüller-Christian syndrome) results in endocrine
abnormalities including diabetes insipidus and panhypopituitarism

 Empty Sella Syndrome: primarily a radiologic term that describes
an enlarged sella containing a thin, flattened pituitary at base
secondary to a congenitally defective or absent diaphragma
sella permits transmission of CSF pressure into sella
 can cause pituitary dysfunction and endocrine abnormalities
 Genetic Abnormalities of Pituitary Development

Empty Sella
Syndrome CT Scan
83
A computed tomography (CT) scan of cranium in an axial
section demonstrates an empty sella turcica (arrows).
BS=brainstem; E=eye; TL=temporal lobe.

Posterior pituitary (neurohypophysis)
84
Posterior pituitary bright spot. Sagittal T1-MRI image
showing hyperintensity (arrow) in the posterior aspect
of the sella turcica.
Young WF. The Netter Collection of Medical Illustrations Vol 2- The Endocrine System, 2nd Edn. Saunders, 2011

Hormones of Posterior Pituitary
85
Oxytocin
 Used in obstetrics to stimulate uterine contraction and induce labor
 Oxytocin also causes milk ejection
Vasopressin (antidiuretic hormone, ADH) is structurally related
to oxytocin
 Has both antidiuretic and vasopressor effects
 In kidney, it binds to V2 receptor to increase water permeability and
reabsorption in collecting tubules Thus, major use of vasopressin is
to treat diabetes insipidus
 Other effects of vasopressin are mediated by V1 receptor, which is
found in liver, vascular smooth muscle (where it causes constriction),
and other tissues

Summary of posterior pituitary hormones & their
effects
86
Hormone Synthesized by Stimulated by Inhibited by Target Organ Effect
Antidiuretic
hormone
(ADH)
Supraoptic
vasopressinergic
neurons
Raised osmolarity;
low blood volume
Lower
osmolarity
Kidney Increases
permeability of
collecting duct to
reabsorb water
Oxytocin Paraventricular
oxytocinergic
neurons
Stretch receptors
in the nipple
and cervix,
estrogen
Stress Uterus and
mammary
glands
Smooth muscle
contraction
leading to birth or
milk ejection
 Diseases of posterior pituitary often come to clinical attention b/c of
decreased (Diabetes insipidus ) or increased (Syndrome of inappropriate
antidiuretic hormone secretion ) secretion of ADH

Diabetes insipidus (DI)
 Deficient hormone release by neurohypophysis results in
inadequate ADH availability DI
 failure of resorption of free water in renal collecting tubules
hence ↑ dilute urine w higher serum osmolality and
hypernatremia
 Dx can be made by water deprivation test
o However, still need to distinguish central vs nephrogenic
 Diabetes insipidus characterized by uncontrolled water
diuresis/polyuria, and polydipsia (excessive thirst)
 Although pts. consume large amounts of water daily, they may
experience life-threatening dehydration
87

Diabetes insipidus (2)
88
 DI can be caused by deficient ADH production
(central) or resistance to ADH in kidneys (nephrogenic)
 DDx injection of exogenous ADH can distinguish betw.
central vs nephrogenic DI
o ADH increases urine osmolality in pts w central DI,
whereas,
o pts w nephrogenic DI have no significant change in
urine osmolality after ADH administration
 ADH is synthesized in paraventricular and supraoptic
nuclei of hypothalamus and stored and released from
neurohypophysis

89
 DI caused by variety of processes head trauma, infection,
neoplasm are most common
 many cases develop without recognizable underlying disease
 Note: Damage to PP produces only transient central DI, whereas damage
to hypothalamic nuclei [paraventricular & (or) supraoptic]
 will cause permanent central DI
 Craniopharyngioma is a tumors that compresses & destroys
neurohypophysis resulting in DI
 Benign childhood tumor (betw ages of 5 & 10 yrs.) from remnants of
Rathke pouch
 Often cystic and calcified not a true pituitary tumor but can have mass
effects that cause pituitary hypofunction
 Radiographic detection often possible b/c of calcification

90
 Craniopharyngioma symptoms include:
 headaches
 visual field defects, and
 hypopituitarism may be evidenced by growth retardation
 ultimately, compression of pituitary stalk leads to
hyperprolactinemia due to loss of dopaminergic inhibition
 Typically, craniopharyngiomas have three components: solid,
comprised of actual tumor cells; cystic, filled w liquid; and a
calcified component
 Any suprasellar mass w these three components is highly suggestive
of craniopharyngioma

Craniopharyngioma
91
Coronal section of brain shows a large, cystic tumor mass replacing
midline structures in region of hypothalamus.
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of
Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
 One fourth of cases of
central DI are assoc. w
brain tumors, notably
craniopharyngioma
• As stated above, tumor
arises above sella turcica
from remnants of
Rathke pouch & invades
& compresses adjacent
tissues

DI Illustrated
 ADH level is ↓ in central diabetes
insipidus ; nml or ↑ in nephrogenic DI
o Nephrogenic DI can be caused by mutation
in V2-receptor
o Nephrogenic DI can be caused by drugs eg.,
lithium, demeclocycline
Management
 Desmopressin acetate (ADH analog) along w
hydration Tx for central DI
 HCTZ or amiloride along w hydration, dietary
salt restriction, & avoidance of offending
agent Tx for Nephrogenic DI
92
Rubin R , Strayer DS Eds. Rubin’s Pathology:
Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: Lippincott Williams & Wilkins, 2012.

Syndrome of inappropriate antidiuretic
hormone secretion (SIADH)
SIADH is characterized by:
 Excessive free water retention
 Euvolemic hyponatremia w continued urinary Na + excretion
 Urine osmolality > serum osmolality
Body responds to water retention w ↓ aldosterone and ↑ANP &
BNP ↑urinary Na+ excretion normalization of extracellular
fluid volume  euvolemic hyponatremia
 Very low serum Na+ levels lead to cerebral edema, seizures
 Must correct Na+ slowly to prevent osmotic demyelination syndrome
(formerly known as central pontine myelinolysis)
93

Question
94
A 32-year-old man with a recent diagnosis of mania is treated with
lithium. Three weeks later he returns complaining of feeling thirsty
and going to pass urine up to 8 times a day. Which of the following
investigations is most likely to confirm the diagnosis?
A. Urine volume measurement
B. Plasma sodium concentration
C. Urine osmolality
D. Plasma osmolality
E. Water deprivation test

SIADH cont.
 SIADH causes include:
 Ectopic ADH (eg, small cell lung cancer)=most common cause
 CNS disorders/head trauma
 Pulmonary disease
 Drugs (eg, cyclophosphamide)
 Treatment: fluid restriction, salt tablets, IV hypertonic saline,
diuretics, conivaptan, tolvaptan ADH antagonists=block action
of ADH at V2-receptor or demeclocycline
NB: Increased urine osmolality during water deprivation test
indicates psychogenic polydipsia.
95

The Thyroid Gland
96
Discussion topics outline:
Anatomy
Function
Nontoxic Goiter
Toxic Multinodular Goiter
Hypothyroidism
Primary (Idiopathic) Hypothyroidism
Goitrous Hypothyroidism
Congenital Hypothyroidism
Hyperthyroidism
Graves Disease
Thyroid Storm
Thyroiditis
Acute Thyroiditis
Chronic Autoimmune Thyroiditis
Subacute Thyroiditis
Follicular Adenoma of Thyroid
Thyroid Cancer
Papillary Thyroid Carcinoma
Follicular Thyroid Carcinoma
Medullary Thyroid Carcinoma
Anaplastic (Undifferentiated) Thyroid
Carcinoma

Anatomy of Thyroid Gland
97
 Thyroid is one of largest endocrine organs
 It forms early in fetal life can be recognized as early as 24 days
of development
 Primitive thyroid descends to its eventual location in lower anterior neck
by elongation of its tubular attachment to tongue=thyroglossal duct
which then atrophies around seventh week of life
 Adult thyroid has two lobes connected by an isthmus is
situated below thyroid cartilage anterior to trachea
 Each lobe is about 4 cm in greatest dimension
 Entire gland weighs 25 to 35 g

Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.
Thyroid Gland Structure
Widmaier EP, Raff H & Strang KT. Vander’s Human
Physiology : The Mechanisms of Body Function,
11th ed. New York: McGraw-Hill, 2008.
98

99
Normal thyroid in situ, gross

100
Normal thyroid, microscopic

Function of Thyroid hormone
101
 Thyroid hormone affects almost all organs
 It stimulates basal metabolic rate (BMR) and metabolism of
carbohydrates, lipids and proteins
 It increases body heat and hepatic glucose production by increasing
gluconeogenesis and glycogenolysis
 It promotes synthesis of many structural proteins, enzymes and
other hormones
 Glucose use, fatty acid synthesis in liver, and adipose tissue lipolysis
are all increased
 In general, thyroid hormone upregulates body’s overall
metabolic activities, both anabolic and catabolic

102
Homeostasis in hypothalamus-pituitary-thyroid axis and
mechanism of action of thyroid hormones:
 Secretion of T3 and T4 is controlled by trophic factors
secreted by both hypothalamus and anterior pituitary
gland
 Decreased levels of T3 and T4 stimulate release of TRH
from hypothalamus and TSH from anterior pituitary,
causing T3 and T4 levels to rise
 Elevated T3 and T4 levels, in turn, suppress secretion of
both TRH and TSH (negative-feedback loop)
 TSH binds to TSH receptor on thyroid follicular epithelium,
which causes activation of G proteins, release of cAMP,
and cAMP mediated synthesis and release of THs (i.e., T3
and T4)
 In periphery, T3 and T4 interact w thyroid hormone
receptor (TR) and form a complex that translocates to
nucleus and binds to so-called “thyroid response
elements” (TREs) on target genes, thereby initiating
transcription

Function of Thyroid hormone (3)
Thyroid gland is responsible for regulating normal growth and
development by maintaining a level of metabolism in body
tissues that is optimal for normal function
 TH is central to normal brain development
Thyroid synthesizes, stores, and releases 2 major*, metabolically
active hormones: triiodothyronine (T3) and thyroxine (T4)
 T3= active form of TH, is 4 times more potent than T4
(prohormone) but its serum concentration is lower
103
*Thyroid gland secretes 3 hormones essential for regulation of metabolism:
Follicular cells T3, T4
Parafollicular cells Calcitonin (contrebalance to PTH from parathyroids)

Function of Thyroid hormone (4)
Approximately 80% of gland’s total daily production of T3 results
from conversion of T4 to T3 through deiodination of T4
 T3 & T4 exist in either free (active) or protein-bound (inactive)
forms
 More than 99% of circulating T4 is bound to plasma proteins,
so only a small fraction exists in free form
o As a result, T4 is metabolized very slowly & has a long half-life (7
days)
o T3 is less bound to plasma proteins and thus undergoes faster
metabolism and has a shorter half-life (1.5 days)
104

Summary of physiological effects of TH
105
 Principal effects of TH are:
 stimulation of metabolism-
raised BMR
 promotion of normal growth
and maturation, particularly
 of CNS and skeleton
 sensitization to effects of
catecholamines
 Other effects:
 ↑Body temperature
 ↑Cardiac rate and contractility
 ↑Peripheral vasodilatation
 ↑Red cell mass
 ↑Circulatory volume
 ↑Respiratory drive
 ↑Peripheral nerves (reflexes)
 ↑Hepatic metabolic enzymes
 ↑Bone turnover
 Skin and soft tissue effects

Nontoxic Goiter
 Goiter, or thyroid enlargement, may be nodular or diffuse It
is classified by its functionality
 Nontoxic goiter (from Latin, guttur, “throat”), also
called simple, colloid, multinodular goiter or nodular hyperplasia,
is thyroid enlargement without functional, inflammatory
or neoplastic alterations
 Patients are euthyroid and without any thyroiditis
 Far more likely to be women than men (8:1)
 Diffuse goiter is common in adolescence and during
pregnancy, whereas multinodular type usually occurs in
people older than 50 years

107
Nontoxic goiter
A. In a middle-aged woman w
nontoxic goiter, thyroid has
enlarged to produce a
conspicuous neck mass
B. Coronal section of enlarged
thyroid gland shows numerous
irregular nodules, some w cystic
degeneration & old hemorrhage
C. Microscopic view of one of
macroscopic nodules shows
marked variation in size of
follicles

Toxic nodular goiter (TNG)
108
 TNG (or Plummer syndrome) = when a hyper-
functioning nodule develops within a longstanding
nontoxic goiter results in hyperthyroidism without
ophthalmologic effects seen in Grave's disease
 most common in women age 40- 60
 a cause of hyperthyroidism due to excess production of TH
from functionally autonomous thyroid nodules do not
require stimulation from TSH (as in Grave's disease)
 second most common cause of hyperthyroidism (after
Graves' disease) in developed world

Thyroid, multinodular goiter, gross and
scintigraphic scan (“Hot nodules”)
109

Hypothyroidism
110
 Hypothyroidism refers to clinical manifestations of thyroid
hormone deficiency can be consequence of three general
processes:
1. Defective thyroid hormone synthesis, w compensatory
goitrogenesis (goitrous hypothyroidism)
2. Inadequate thyroid function, usually due to thyroiditis,
surgical resection of gland or therapeutic administration of
radioiodine
3. Inadequate secretion of TSH by pituitary or TRH by
hypothalamus

111
Hypothyroidism cont.
Symptoms develop insidiously & reflect ↓ circulating TH
 90% of all problems involving thyroid are due to dysfunction of thyroid itself,
such as primary hypothyroidism
Pts. presents w Sx of “slowing down” including:
weight gain, fatigue, sluggishness, cold intolerance, constipation,
muscle aches and goiter may or may not be present
 Pts. w end-stage hypothyroidism = myxedema coma may experience
hypothermia, confusion, stupor or coma, carbon dioxide retention,
hyponatremia, and ileus
NB: Sick euthyroidism= During systemic illness circulating levels of all thyroid
hormones tend to be low. These need to be rechecked once patient has recovered.
As pt. recovers from underlying disease, thyroid function usually returns to normal.

Dominant clinical
manifestations of
hypothyroidism
112

Hypothyroidism
Most common cause of primary hypothyroidism is
Hashimoto thyroiditis (=chronic thyroiditis)
 autoimmune disorder in which unsuppressed T lymphocytes
produce excessive amounts of antibodies that destroy thyroid
cells
Certain drugs, such as amiodarone (antiarrhythmic),
lithium (bipolar disorder ), nitroprusside, iodides, and
sulfonylureas, can also induce hypothyroidism
Hypothyroidism is more prevalent in females and
persons older than 60 years
113

114
Hashimoto thyroiditis, microscopic

115
Hashimoto thyroiditis, gross

Hypothyroidism
116
 Laboratory findings include increased TSH and low free
T4 levels
 Pts. w primary hypothyroidism have decreased T3 and T4
levels and elevated TSH
 Pts. w pituitary (secondary) hypothyroidism and
hypothalamic (tertiary) hypothyroidism have decreased T3,
T4, and TSH
 Anemia = typically normocytic or macrocytic

Primary (Idiopathic) hypothyroidism is most often
autoimmune (2)
117
 Primary hypothyroidism occurs in fifth & sixth decades  like
most thyroid disorders, is more common in women than in men
 Three fourths of pts have circulating antibodies to thyroid
antigens suggesting these cases represent end stage of
autoimmune thyroiditis
 Nongoitrous hypothyroidism may also result from antibodies
that block TSH or TSH receptor without activating thyroid

Goitrous hypothyroidism reflects inadequate
secretion of thyroid hormone (3)
118
 Thyroid enlargement (goiter) may occur in hypothyroidism
 Etiology includes iodine deficiency (most common), antithyroid
agents (drugs or dietary goitrogens), long-term iodide intake
and a number of hereditary defects in TH synthesis
 Evolution of pathology of goitrous hypothyroidism is similar to
that described above for nontoxic goiter

Goitrous Hypothyroidism & Endemic goiter
Epidemiology
119
 One form of hypothyroidism that exists around world is caused
by iodine deficiency
 Worldwide, goiter is most common endocrine disorder w rates of
4% to 15% in areas of adequate iodine intake & more than 90%
where there is iodine deficiency
 Endemic goiter is defined as goiter that affects more than 5% of
population
 Most goiters are not associated w thyroid dysfunction
o FM-to-M ratio of goiter is lower than goitrous hypothyroidism

Worldwide iodine nutrition
See: WHO and the International Council for the Control of Iodine Deficiency Disorders
(http://indorgs.virginia.edu/iccidd/mi/cidds.html) 120

Endemic goiter
121
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013.
 Massive goiter in an
Ethiopian woman who
lives in an endemic area
for goiters
 Many adults have large
goiters in Ethiopia
where there is little
iodine in their diets

Goitrous Hypothyroidism: Pathophysiology
 With inadequate iodine consumption
synthesis of TH is compromised leading to a
decrease in plasma levels of T3 & T4
 This, in turn, releases negative feedback on
hypothalamus and pituitary TRH levels
become chronically elevated in portal circ. of
anterior pituitary plasma TSH conc. is also
elevated due to increased TRH
 Resulting overstimulation of thyroid can
produce goiters that can achieve astounding
sizes if untreated
Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The
Mechanisms of Body Function, 11th ed. New York, NY: McGraw-Hill, 2008.
Goiter at an advanced stage
122
Note: This form of hypothyroidism is reversible if iodine is added to diet.

123
Thyroid, goiter, microscopic

Myxedema
124
Can be described as hypothyroidism of adult
Causes
 Hashimoto thyroiditis
 Idiopathic causes
 Iodine deficiency
o A problem in geographic areas with poor nutrition
o Deficiency in pregnant women can lead to cretinism in
child (remember, TH is vital to CNS development)
 Paradoxically, high doses of iodine lead to a ↓ in TH
production
 Over-irradiation of thyroid using iodine-131 for treatment
of hyperthyroidism

Myxedema coma
125
Myxedema coma is a state of decompensated hypothyroidism
It is a medical emergency with a high mortality rate
 Patient may have lab values identical to a "normal" hypothyroid state
but a stressful event (infection, myocardial infarction or stroke)
precipitates myxedema coma state, usually in elderly
 Primary symptoms of myxedema coma are
 Altered mental status, low body temperature, hypoglycemia, low blood
pressure, hyponatremia, hypercapnia, hypoxia, bradycardia , and
hypoventilation
Treatment Levothyroxine IV
Note: Myxedema, although included in name,
is not necessarily seen in myxedema coma.

Congenital Hypothyroidism (Cretinism)
126
 Cretinism (infantile hypothyroidism) severe fetal hypothyroidism
due to maternal hypothyroidism
 may be endemic, sporadic or familial
 twice as frequent in girls as boys
 In nonendemic regions, 90% of cases result from developmental
defects of thyroid (dysgenesis/agenesis)
 remainder have a variety of inherited metabolic defects including
mutations in genes for TRH and its receptor, TSH and its receptor,
sodium-iodide symporter, thyroglobulin and thyroid oxidase
 By 6 months clinical syndrome is well developed
 Mental retardation, stunted growth (owing to defective osseous
maturation) and characteristic facies are evident
 Serum T4 and T3 are low, and TSH levels high (unless problem relates to a
lack of TSH secretion itself)

Sx and Sn of infantile hypothyroidism
127
Cray MI. Hormones and Their Actions Illustrated Notes.pdf. 2017 update.
Clinical findings: the 6 P’s
Pot-bellied,
Pale,
Puffy-faced child with
Protruding umbilicus,
Protuberant tongue, and
Poor brain development

Hyperthyroidism is condition that occurs due to excessive
production of thyroid hormone by thyroid gland
Thyrotoxicosis is condition that occurs due to excessive
thyroid hormone of any cause therefore includes
hyperthyroidism
 Some use the terms interchangeably
Hyperthyroidism

Hyperthyroidism occurs more often in FM than in M
Hyperthyroidism ↑ metabolism in all body tissues
Most common cause of hyperthyroidism is Graves disease an
autoimmune disorder in which an Abn. thyroid immunoglobulin
binds to TSH receptor (mimic TSH) causes uncontrolled TH
production
 Autoantibodies are called long acting thyroid stimulators (LATS)
 In older patients, most common cause of hyperthyroidism is
multinodular toxic goiter
Drugs such as amiodarone, iodides, and lithium can also cause
hyperthyroidism, as well as hypothyroidism
129
Hyperthyroidism (2)

130
Graves disease, microscopic

131
Graves disease, microscopic (2)

Hyperthyroidism (5)
 Symptoms of hyperthyroidism include goiter, exophthalmos,
nervousness, heat intolerance, palpitations, weight loss,
insomnia, and new or worsening cardiac findings (atrial
fibrillation, angina)
Untreated hyperthyroidism can progress to thyroid storm, a
possibly fatal state with acute onset of high fever, exaggerated
thyrotoxicosis symptoms, cardiovascular collapse, and shock
 Laboratory findings include high serum levels of free T4,
undetectable TSH levels, or both, radioactive iodine uptake is
increased and radioiodine scans show a diffuse uptake
132

133
Graves disease
A young woman w hyperthyroidism
displays a mass in neck & exophthalmos. Major clinical manifestations of Graves disease.
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Graves disease pathophysiology
134
Triad of Clinical Findings
1. Hyperthyroidism: due to diffuse hyperplasia of thyroid
2. Infiltrative ophthalmopathy → results in exophthalmos
3. Localized, infiltrative dermopathy (pretibial myxedema) in
some patients
Pathophysiology
 Pretibial myxedema is a nonpitting edema caused by accumulation of
interstitial glycosaminoglycans (GAGs) within dermis. Paradoxically, pretibial
myxedema can also be seen in severe hypothyroidism.
 Exophthalmos-systemic or local-production of antibodies that stimulate
orbital fibroblasts to proliferate and produce collagen and
glycosaminoglycans. Increase osmotic muscle swelling, muscle inflammation,
and adipocyte count>> exophthalmos

Thyroid storm
135
 Uncommon but serious complication that occurs when
hyperthyroidism is incompletely treated/untreated and then
significantly worsens in setting of acute stress such as infection,
trauma, surgery
 Presents w agitation, delirium, substantial elevation in BMR &
extreme fever, diarrhea, coma, and tachyarrhythmia (cause of
death)
 Treat with 4 P’s:
β-blockers (e.g., Propranolol),
Propylthiouracil,
corticosteroids (e.g., Prednisolone),
Potassium iodide (Lugol iodine)
NB: Treatment of thyroid storm is
same as that for hyperthyroidism,
except that drugs are given in higher
doses & more frequently
IV administration of medication is
most efficacious

Immune mechanisms of Graves disease and
Hashimoto thyroiditis (schematic next slide)
136
 CD4 T cells stimulate antibody production by
autoreactive B cells
 Anti-thyroid-stimulating hormone receptor antibodies
stimulate TH synthesis in Graves disease
 Antibodies induce thyrocyte cell death in Hashimoto
thyroiditis by complement-dependent cytotoxicity &
antibody-dependent cell-mediated cytotoxicity (ADDC)
o Thyrocyte death also results from attack by CD8 (cytotoxic) T cells

Immune mechanisms of Graves disease & Hashimoto thyroiditis

Thyroid Disorders Labs Capsule
138
 High TSH and high T4 can be due to either thyroid hormone
resistance or a TSH secreting tumor
 Low TSH and normal T4 suggest subclinical hyperthyroidism
should be monitored be physician if clinical signs develop,
patient may benefit from Tx  risks and benefits must be
evaluated
 Hypothyroidism results in low levels of T4 and high TSH
 Hyperthyroidism is assoc. w high levels of T4 and low TSH

Thyroiditis
139
 Thyroiditides are a heterogeneous group of inflammatory
disorders of thyroid gland, including those caused by
autoimmune mechanisms, and infectious agents
1. Acute Thyroiditis usually reflects thyroid involvement in
acute systemic infections
o Responsible infectious agent reaches thyroid by hematogenous
spread
o most common causative organisms are Streptococcus,
Staphylococcus and Pneumococcus
o Patients present w fever, chills, malaise and a painful, swollen neck

Thyroiditis (2)
140
2. Hashimoto thyroiditis is an autoimmune disease
characterized by progressive destruction of thyroid
parenchyma, Hürthle cell metaplasia, and massive
mononuclear (lymphoplasmacytic) infiltrates, with or
without extensive fibrosis
 Chronic Autoimmune Thyroiditis (=Hashimoto Thyroiditis) is
most common cause of goitrous hypothyroidism in U. S.
 Transient phase of hyperthyroidism not uncommon
 8% develop papillary thyroid cancer
Etiopathogenesis
 As explained above, multiple autoimmune mechanisms account
for thyroid injury, including cytotoxicity mediated by CD8+ T cells,
cytokines (IFN-γ), and anti-thyroid antibodies

Thyroiditis (3)
141
3. Subacute granulomatous (de Quervain) thyroiditis is a self-
limited disease secondary to a viral infection (e.g. mumps,
coxsackie virus, adenovirus), and is characterized by pain and
presence of a granulomatous inflammation in thyroid
4. Subacute lymphocytic thyroiditis is a self-limited disease often
occurs after a pregnancy (postpartum thyroiditis), typically is
painless, and is characterized by lymphocytic inflammation in
thyroid
 no fibrosis or Hürthle cell metaplasia on microscopy as in
Hashimoto’s

Thyroiditis (4)
142
5. Riedel thyroiditis is very rare and characterized by
progressive and extensive fibrosis of thyroid gland
 fibrosis may extend from thyroid gland to involve
contiguous structures of neck leading to recurrent
laryngeal nerve paralysis and tracheal compromise
 It is easily mistaken for a malignant process
 gland is hard, fixed, and often described as “stony”
 Circulating anti-thyroid antibodies can be detected

Follicular Adenoma of Thyroid
143
 Follicular adenoma is a benign neoplasm showing follicular
differentiation
 most common thyroid tumor typically presents in euthyroid
persons as a “cold” nodule (i.e., a tumor that does not take up
radiolabeled iodine)
 It is a solitary encapsulated neoplasm cells are arranged in follicles
resembling normal thyroid gland or mimicking stages in the gland’s
embryonic development
 Multiple adenomas may occur
NB: In up to 90% of cases, palpable, solitary follicular lesions are
actually dominant nodule in a multinodular goiter, and follicular
adenomas are correspondingly infrequent

144
A. Colloid adenoma. cut surface of an
encapsulated mass reveals
hemorrhage, fibrosis and cystic
change
B. Embryonal adenoma. tumor
features a trabecular pattern w
poorly formed follicles that contain
little if any colloid
C. Fetal adenoma. A regular pattern
of small follicles is noted
D. Hürthle cell adenoma. Tumor is
composed of cells w small, regular
nuclei and abundant eosinophilic
cytoplasm
Follicular adenoma
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: Lippincott Williams & Wilkins, 2012.

Thyroid Cancer
To be studied along with Endocrine Pathology Case 1_SDL Tutorial.
145
 Malignant thyroid tumors cause 0.4% of all cancer deaths in US
 Approximately 10,000 new cases are diagnosed each year
 Mortality from thyroid cancer exceeds that from malignant
tumors of all other endocrine organs
 Most cases of thyroid carcinoma occur between third and
seventh decades, but children can also be affected
 Tumors occur in women 2.5 times more often than in men

Thyroid Cancer (2) Investigations
146
 Fine-needle biopsy (FNB) of thyroid nodules makes a diagnosis
in most cases
 Prognosis is a function of morphology of tumor range from a
very indolent clinical course to a rapidly fatal disease
 Radioscintigraphy of gland may help in assessing thyroid
tumors
 hyperfunctioning (“hot”) nodules are usually benign
 “Cold” or nonfunctioning nodules, more frequently malignant, but
may also be benign (i.e., adenoma)
Clinical Correlation:
FINE-NEEDLE ASPIRATION OF THYROID NODULES
 Fifteen percent of people have a detectable nodule in thyroid, either
by palpation, or by ultrasound imaging
 Fine-needle aspiration (FNA) is a minimally invasive method to biopsy
nodules and screen for rare cases of carcinoma

Thyroid Ca (4) Etiopathogenesis
147
 Most important environmental factor is external
radiation
1. External radiation single most important environmental
factor assoc. w increased risk of developing thyroid
carcinoma esp. many years of exposure to of high dose
2. Iodine excess and TSH In regions where endemic goiter
is widespread, addition of iodine to diet has resulted in
increase in incidence of papillary cancer

148
3. Genetic basis familial clustering of thyroid cancer
has been observed especially in medullary
carcinoma
 Molecular studies reveal thyroid Ca is a multistep
process:
i. Papillary thyroid carcinoma: mutation in RET gene
(overexpression) located on chromosome 10q is seen
in about 20% cases of papillary thyroid carcinoma
ii. Follicular thyroid carcinoma: About 50% cases of
follicular thyroid carcinoma have mutation in RAS
family of oncogenes includes H-RAS, N-RAS and
K-RAS

149
3. Genetic basis familial clustering cont.
iii. Medullary thyroid carcinoma: Medullary thyroid
carcinoma arises from parafollicular C-cells in thyroid
point mutation in RET-proto-oncogene is seen in both
familial (MEN2) as a well as sporadic cases of medullary
thyroid carcinoma
iv. Anaplastic thyroid carcinoma: This tumor either arises
from further dedifferentiation of differentiated papillary
or follicular thyroid Ca, or by inactivating point mutation
in p53 tumor suppressor gene or by mutation in gene
coding for β-catenin pathway

Thyroid Cancer (7)
150
 Major subtypes of thyroid cancer and their relative
frequencies are as follows:
 Papillary carcinoma (more than 85% of cases)
 Follicular carcinoma (5% to 15% of cases)
 Medullary carcinoma (5% of cases)
 Anaplastic (undifferentiated) carcinoma (<5% of cases)
Remember genetic markers:
Papillary thyroid carcinoma—RET gene
Follicular thyroid carcinoma—RAS family of oncogenes
Medullary thyroid carcinoma—-RET-proto-oncogene
Anaplastic thyroid carcinoma—p53 tumor suppressor gene

Papillary adenocarcinoma
151
Epidemiology
 Most common endocrine cancer
 Papillary carcinoma most common thyroid cancer (>75%)
 More common in women than men (3:1)
o Usually occur in second and third decades
 Main risk factor: assoc. w radiation exposure
Gross and microscopic findings
 Usually multifocal
 Papillary leafs intermixed w follicles
 Psammoma bodies (35–45% of cases)
o Dystrophically calcified cancer cells
 Empty-appearing nuclei
o Called Orphan Annie nuclei
 Lymphatic invasion
Metastasize to cervical nodes, lung
Diagnose with FNA

Papillary carcinoma cont.
152
Treatment
 Subtotal thyroidectomy w sampling of cervical nodes
 Followed in a few weeks by radiotherapy w 131I
 Suppressive therapy w thyroid hormone
o Tumor is TSH dependent
Five-year survival rate > 95%

A. Cut surface of a surgically
resected thyroid displays a
circumscribed pale tan mass w
foci of cystic change
B. Branching papillae are lined by
neoplastic columnar
epithelium w clear nuclei
 A psammoma body is
evident (arrow)
Papillary carcinoma of thyroid

Follicular carcinoma
154
 Epidemiology
 Most common thyroid cancer presenting as a solitary cold
nodule
 Female dominant cancer
 Gross and microscopic findings
 Invasion of capsule (distinguishing from follicular adenoma)
 Neoplastic follicles invade blood vessels
 Lymph node metastasis is uncommon
 Metastasize to lung and bone (hematogenous)
 Treatment similar to papillary cancer
 Five-year survival rate >80% w treatment

 Evaluating integrity of capsule is
critical in distinguishing follicular
adenomas from follicular carcinomas:
(A) In adenomas, a fibrous capsule, usually thin
but occasionally more prominent, surrounds
neoplastic follicles and no capsular invasion
is seen; compressed normal thyroid parenchyma
usually is present external to capsule (top)
(B) By contrast, follicular carcinomas
demonstrate capsular invasion that may be
minimal, as in this case, or widespread, with
extension into local structures of neck
Capsular invasion in follicular
carcinoma

Medullary carcinoma
156
Epidemiology
 Types
o Sporadic (80% of cases)
o Familial (20% of cases)
 Familial type
o Associated w autosomal dominant MEN IIa/IIb
o MEN IIa syndrome
• Medullary carcinoma, hyperparathyroidism (HPTH), pheochromocytoma
o MEN IIb (III) syndrome
• Medullary carcinoma, mucosal neuromas (lips/tongue), pheochromocytoma
 Familial type has a better prognosis than sporadic type
 Ectopic hormones
o ACTH, which can produce Cushing syndrome
 Male: female ratio is equal

Pathogenesis
 Tumors derive from parafollicular C cells
 C cells synthesize calcitonin
o Tumor marker
o May produce hypocalcemia
o Converted into amyloid can be stained w Congo-red for histologic ID
 C-cell hyperplasia is a precursor lesion
o Calcitonin levels increase w infusion of pentagastrin
Diagnosis
 FNA
 Serum calcitonin
Treatment
 Total thyroidectomy
 Genetic screening for familial cases
o Detection of mutation of RET proto-oncogene
o Thyroidectomy is performed if family member is a gene carrier
Medullary carcinoma cont.

Medullary thyroid carcinoma. A. Coronal
section of a total thyroid resection shows
bilateral involvement by a firm, pale tumor.
B. The tumor features nests of polygonal
cells embedded in a collagenous framework.
The connective tissue septa contain
eosinophilic amyloid. C. A section stained
with Congo red and viewed under polarized
light demonstrates the pale green
birefringence of amyloid.
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore:
Lippincott Williams & Wilkins, 2012.

Anaplastic thyroid cancer
159
 Epidemiology
 Most often occurs in elderly women
 Risk factors
o Multinodular goiter, history of follicular cancer
 Rapidly aggressive and uniformly fatal
 Treatment
o Palliative surgery often compresses trachea
o Irradiation or chemotherapy
 Five-year survival rate is 5%

Anaplastic carcinoma of thyroid
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams &
Wilkins, 2012.
A. tumor in transverse section partially surrounds the trachea and extends
into the adjacent soft tissue
B. tumor is composed of bizarre spindle and giant cells with polyploid
nuclei and numerous mitoses

Thyroid Carcinoma Treatment
161
 1° treatment for thyroid carcinoma is total
thyroidectomy w lymph node dissection depending
on tumor stage
 Radioactive iodine is administered postoperatively to ablate
thyroid remnant
 Thyroglobulin (Tg) can then be used as a tumor
marker Tg is undetectable in absence of functioning
thyroid tissue Rising Tg following 131I ablation
indicates recurrence

Investigations to assess thyroid nodule
162
Investigation Result
Thyroid function tests T3, T4 & TSH (nml or Abn)
Thyroglobulin Post Ca Tx monitoring (raising=recurrence)
Radioactive iodine scan inactive “cold” or active “hot” nodule
Ultrasound scan Is nodule solid or cystic in consistency
FNA cytology Benign or malignant (if carcinoma, what type
based on histology)
Chest CT If malignant lesion R/O tracheal compression
or retrosternal extension
See: Endocrine Pathology Case 1 SDL Tutorial (Thyroid nodule)
NB: A short clinical history and an asymmetrically enlarged, hard thyroid
nodule with adjacent cervical lymphadenopathy are all suggestive of cancer.
 When presented w a thyroid nodule, your job is to exclude presence of a
malignant thyroid lesion

Investigating a thyroid nodule (2)
163
 About 5% of all thyroid nodules are malignant, regardless of size
 Be suspicious of cancer in any of following scenarios:
o cold nodule on a nuclear scan
o male patient
o history of childhood irradiation,
o nodule described as “stony hard”
o recent or rapid enlargement, and
o ↑calcitonin level (medullary thyroid cancer usually in pts
w MEN type II)
 Next slide shows algorithm for investigation of a thyroid nodule

Steps in investigating a thyroid nodule
164
Thyroid nodule
Check TSH
High Normal Low
FNACheck free T4 and T3
(investigate for Hashimoto’s
nodule)
Nuclear medicine
uptake scan
(investigate for hot/cold)

Parathyroid Gland Disorders and
Disorders of Calcium Homeostasis
165
Topics discussed Outline:
Anatomy of Parathyroid Gland
Physiology of Parathyroid Gland
Hypoparathyroidism
Hyperparathyroidism
Calcium-relate Diseases & Disorders

Anatomy of Parathyroid Gland
166
Embryologically, parathyroids derived from third and fourth
pharyngeal pouches and present on posterior aspect of thyroid
gland as superior and inferior pairs
 Occasionally an ectopic parathyroid is located substernally in thymus
Normal parathyroid gland comprised of variable numbers of
adipocytes, mixed w small nests of chief cells that secrete PTH
 Clear cells are chief cells whose cytoplasm is packed w glycogen
 Oxyphil cells appear after puberty, are larger than chief cells and have
deeply eosinophilic cytoplasm, owing to numerous mitochondria they
have no secretory granules and do not secrete PTH (function is obscure)
Parathyroid has rich vascular supply PTH is release into
bloodstream inversely to ionized Ca+2 and Mg+2 levels in blood

167
Parathyroid gland, normal

168
Physiology of Parathyroid Gland
 Parathyroid glands are key regulators of calcium homeostasis
 Activity of parathyroid glands is controlled by level of free (ionized)
calcium in blood
 Normally, ↓levels of free calcium stimulate synthesis & secretion of
PTH PTH has following effects on its target tissues= kidneys and bones:
 ↑renal tubular reabsorption of calcium
 ↑urinary phosphate excretion, thereby lowering serum phosphate levels (since
phosphate binds to ionized calcium)
 ↑ conversion of vitamin D to its active dihydroxy form in kidneys which in turn
augments GI calcium absorption
 Enhanced osteoclastic activity (i.e., bone resorption, thus releasing ionized
calcium) mediated indirectly by promoting differentiation of osteoclast
progenitor cells into mature osteoclasts

Hypoparathyroidism
169
 Hypoparathyroidism results from decreased secretion of
PTH or end-organ insensitivity to it (pseudohypoparathyroidism)
owing to congenital or acquired conditions
 Characterized by hypocalcemia & hyperphosphatemia
Etiology (common causes):
 Thyroid* and other head & neck surgery
 Infiltration and destruction of parathyroid glands e.g., Wilson disease,
hemachromatosis, and radiation
 Congenital absence of parathyroid glands (as seen in DiGeorge syndrome)
 PTH production may be suppressed in hypomagnesemia (magnesium
important for PTH homeostasis)
*Note: Hypoparathyroidism is most often due to surgical removal
of parathyroids at time of thyroidectomy.

Symptoms (related to hypocalcemia)
 Seizures
 Constipation
 Muscle cramps
 Hyperreflexia
 Tetany
 Abdominal pain
 Lethargy
 Cardiac dysrhythmia
 Neuropsychiatric
 depression
 paranoia
 psychoses
Hypoparathyroidism (2) Clinical manifestations
 Chvostek’s sign (facial twitching when
zygomatic arch is tapped)
 Trousseau’s sign (forearm spasms
induced by inflating BP cuff on upper arm)

Pseudohypoparathyroidism: Caused by target
organ insensitivity to PTH
171
Molecular Pathogenesis of Pseudohypoparathyroidism:
 Hypocalcemia in this group of hereditary conditions reflects mutation of
GNAS1 gene on long arm of chromosome 20 resulting in decreased
activity of Gs (G protein that couples hormone receptors to stimulation of
adenyl cyclase)
 Consequently, renal tubular cell production of cAMP in response to PTH
is impaired leading to inadequate resorption of calcium from
glomerular filtrate
 These patients have a characteristic phenotype (Albright hereditary
osteodystrophy) including short stature, obesity, mental retardation,
subcutaneous calcification and congenital anomalies of bone,
particularly abnormally short metacarpals and metatarsals

Reference scale graphic.Pseudohypoparathyroidism. A radiograph
of the hand reveals characteristic shortness
of fourth and fifth metacarpal bones.
RubinR,StrayerDSEds.Rubin’sPathology:ClinicopathologicFoundationsofMedicine,
6thEd.Baltimore:LippincottWilliams&Wilkins,2012.

DiGeorge Syndrome
173
 Etiology
 Caused by microdeletion on chr 22q11 results in failure of
development of third and fourth pharyngeal pouches
 Pathology & Pathophysiology
 Thyroid & parathyroid tissue hypoplasia
o Thymic hypoplasia results in T-cell deficiency
o Parathyroid hypoplasia results in hypocalcemia
 Clinical Manifestations
 recurrent viral, fungal, and protozoal infections
 tetany (owing to hypocalcemia)
 congenital cardiovascular defects
 facial abnormalities including cleft palate
 Treatment
 Fetal thymus transplanted to restore T-cell immunity

 Laboratory
 Decreased serum PTH
 Hypocalcemia
 Hyperphosphatemia
 Normal 25-hydroxyvitamin D level
 Decreased 1,25- dihydroxyvitamin D levels
Hypoparathyroidism (3)

 Diagnosis
 Increased urine calcium to creatinine ratio and
hypophosphaturia (hyperphosphatemia)
 ECG: prolonged Q-T interval  due to hypocalcemia
 Treatment
 Supplementation w Ca+2 & 1,25-dihydroxyvitamin D
 Caution w IV calcium admin. can result in
vasodilation, cardiac arrhythmias, decreased BP &
bradycardia
Hypoparathyroidism (3)

Hyperparathyroidism
176
Definition High levels of PTH usually due to excessive
release
 Types of HPT
 Primary Hyperparathyroidism
 Secondary Hyperparathyroidism
 Tertiary Hyperparathyroidism

Primary Hyperparathyroidism
177
 Parathyroid adenoma is most common cause
 85% of all hyperparathyroid cases
 Hyperplasia of parathyroid glands (10-15% of cases)
 Parathyroid carcinoma (rare, 1%)
Clinical Findings
 Hypercalcemia, hypercalciuria (renal stones), polyuria (thrones),
hypophosphatemia
 Labs ↑ PTH,↑ ALP, ↑cAMP in urine
 Sn & Sx Most often asymptomatic may present w weakness and
constipation (“groans”), abdominal/flank pain (kidney stones,
acute pancreatitis), depression (“psychiatric overtones”), osteitis
fibrosa cystica cystic bone spaces filled w fibrous tissue
“Stones, thrones, bones, groans, and psychiatric overtones”

178
Parathyroid adenoma, microscopic

179
Parathyroid, adenoma, scintigraphic scan

Parathyroid hyperplasia, gross
180

Secondary Hyperparathyroidism
181
 Feedback response to hypocalcemia stimulates
parathyroid glands leading to hyperplasia & excessive
PTH production
o Causes of hypocalcemia:
• Renal failure is most common cause
• Vitamin D deficiency
• Malabsorption of intestinal calcium

182
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th
Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Tertiary Hyperparathyroidism
183
 Constant stimulation of parathyroids in secondary
hyperparathyroidism  causes autonomous secretion
of PTH by gland
o End result is hypercalcemia b/c feedback response is
functional
 Tx: Correction of hypercalcemia assoc. w tertiary HPT
requires surgical resection of most of four parathyroid
glands

Summary of Ca++ Regulation by PTH and
Vitamin D
184
Miksad RA, Meyer GK & DeLaMora PA. Last Minute Internal Medicine. New York: McGraw-Hill, 2008.

Calcium-relate Diseases & Disorders
185
Osteoporosis, Paget disease, & osteomalacia disorders of bone
 Osteoporosis is characterized by progressive loss of
bone mass and skeletal fragility
 Patients w osteoporosis have an increased risk of fractures,
which can cause significant morbidity
 Osteoporosis occurs in older men and women but is most
pronounced in postmenopausal women

Changes in bone morphology in osteoporosis
186
Whalen K. Lippincott Illustrated Reviews:
Pharmacology 6th Ed. Wolters Kluwer, 2015
 Trabecular (spongy) and cortical bone
lose mass and interconnections despite
normal bone mineralization and lab
values (serum Ca2+ and PO43−)
 Most commonly due to ↑bone resorption
related to↓ estrogen levels and old age
 Can be secondary to drugs (eg, steroids,
alcohol, anticonvulsants, anticoagulants,
thyroid replacement therapy) or
 Other medical conditions (eg,
hyperparathyroidism, hyperthyroidism,
multiple myeloma, malabsorption syndromes)

187
Osteoporosis
Can lead to vertebral compression fractures small
arrows (large arrows show normal-for-age vertebral body height
for comparison)acute back pain, loss of height, kyphosis
Diagnosed by a bone mineral density scan (dual energy
x-ray absorptiometry [DEXA]) w a T-score of ≤ −2.5 or by
a fragility fracture of hip or vertebra
 Screening recommended in women > 65 years old
Prophylaxis: regular weight-bearing exercise and
adequate Ca2+ and vitamin D intake
Tx: bisphosphonates, teriparatide, SERMs, calcitonin
Le T, Bhushan V. First Aid for the USMLE Step 1
2017. New York: McGraw-Hill Education, 2017.

Calcium-relate Diseases & Disorders (4)
188
Paget disease is a disorder of bone remodeling that
results in disorganized bone formation and enlarged or
misshapen bones
 Unlike osteoporosis, Paget disease is usually limited to one or
a few bones
 Patients may experience bone pain, bone deformities, or
fractures
Osteomalacia is softening of bones that is most often
attributed to vitamin D deficiency
 Osteomalacia in children is referred to as rickets

Adrenocortical Dysfunction
189
Topics discussed outline:
Anatomy of Adrenal Gland
Physiologic, Biochemical & Immunologic Effects of Cortisol
ACTH (corticotropin)
Congenital adrenal hyperplasia (CAH)
Waterhouse-Friderichsen syndrome
Cushing Syndrome
Adrenocortical insufficiency: 1°, 2° , 3° and Adrenal crisis
Hyperaldosteronism
Adrenomedullary pathology: Pheochromocytoma and
Neuroblastoma

Hormones of adrenal gland (cortex)
190
Principal hormone is glucocorticoid cortisol secreted from largest
zone, fasciculata; mineralocorticoid aldosterone is secreted by
glomerulosa, and of androgens and estrogens are secreted by
zona reticularis
Hypothalamic–pituitary system, through corticotropin releasing
factor (CRF) and ACTH (corticotropin), controls cortisol and, to a
lesser extent, aldosterone secretion
 synthesis and secretion of aldosterone is regulated mainly by the renin–
angiotensin system (ATII) , and by variation in plasma K + levels

191
Hormones of adrenal gland cont.
 Adrenal cortex (derived from mesoderm) &
Adrenal medulla (derived from neural crest)
 Adrenal cortex, think GFR:
 Glomerulosa (Na+)
 Fasciculata (glucocorticoids)
 Reticularis (androgens)
Mnemonic To remember hormones produced by
each layer “the deeper you go, the sweeter it
gets”:
• Mineralocorticoid (salt hormone)
o aldosterone
• Glucocorticoid (sugar hormone)
o hydrocortisone
• Androgen (sex hormone)
o dehydroepiandrosterone McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

192
Adrenal gland
Reisner HM. Pathology: A Modern Case Study. New York: McGraw-Hill Education,2015.

193
Normal adrenal gland, gross

194
Normal adrenal gland, microscopic

195
Comparison of atrophic, normal,
and hyperplastic adrenal glands

Cortisol
196
 Cortisol is a steroid hormone, in glucocorticoid class of hormones
 When used as a medication, known as hydrocortisone
 Produced in humans by zona fasciculata of adrenal cortex within
adrenal gland
 Released in response to stress and low blood-glucose concs.
 Functions to
 to increase blood sugar through gluconeogenesis,
 to suppress immune system, and
 to aid in metabolism of fat, protein, and carbohydrates
 It also decreases bone formation

197
Physiologic, Biochemical & Immunologic Effects of Cortisol
↑Blood pressure:
 Upregulates α1-receptors on arterioles↑sensitivity to
NE and Epi
 At high concs., can bind to mineralocorticoid receptors
↑Insulin resistance (diabetogenic)
↑Gluconeogenesis, lipolysis, and proteolysis
↓Fibroblast activity (causes striae)
↓Inflammatory and Immune responses:
 Inhibits production of leukotrienes and prostaglandins
 Inhibits WBC adhesion neutrophilia (neutrophil
demargination)
 Blocks histamine release from mast cells
 Reduces eosinophils
 Blocks IL-2 production
↓Bone formation (osteoblast activity)
N.B Exogenous corticosteroids can cause
reactivation of TB and candidiasis (blocks IL-2
production), as IL-2 stimulates growth of helper,
cytotoxic, and regulatory T cells, and NK cells.
“Cortisol is a BIG FIB”
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.

ACTH (corticotropin)
198
 ACTH is a single polypeptide of 39-amino acid
 Amino acids 1 to 24 is required for full biological activity
 Amino terminal sequence (1–13) of ACTH is identical to alpha-
melanocyte-stimulating hormone (α-MSH)
 Thus, excess secretion of ACTH from pituitary in 1° adrenocortical
insufficiency, causes hyperpigmentation due to its α-MSH activity
o In 2°and 3° forms of adrenal insufficiency, skin darkening does not occur, as ACTH
is not overproduced
 A Synthetic corticotropin-derivative is used clinically to assess
adrenocortical status
 Synthetic human ACTH(1-24) is called Cosyntropin
 In adrenocortical insufficiency (Addison’s disease), adrenocortical
response to cosyntropin administration of is reduced

Endocrine System Pathology_ Ppt Lecture Series (5 in 1)

Endocrine System Pathology_ Ppt Lecture Series (5 in 1)

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