Endocrine System Pathology PPT Lecture Series

Pathology of Endocrine System
Prepared and presented by:

Marc Imhotep Cray, M.D.
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.
Learning Objectives
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.
Marc Imhotep Cray, MD 2

Learning Objectives cont.
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.
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
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
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
 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)
 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)

Biological messages of endocrine system may also be transmitted by
autocrine, paracrine, neuroendocrine & cytokine modes of communication
 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)
Mechanisms of chemically mediated cell-to-cell
communication illustrated.
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. 10

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

 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
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

 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,
Marc Imhotep Cray, MD hyperplasia, cancer 19
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”)

 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

 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 ()
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
 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

Hormones of hypothalamic-pituitary axis
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
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Ed. Wolters
26
Kluwer, 2015.
“the negative feedback principle”
 It is essential to understand “the negative
feedback principle” of hypothalamic
Dashed lines = negative effect

Solid lines = positive effect
/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)
Pazdernik TL, Kerecsen L. Rapid Review
Pharmacology, 3rd Ed. Mosby, 2010
Example, thyroid hormone feedback loop
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
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

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,
Marc Imhotep Cray, MD 11th ed. New York, NY: McGraw-Hill, 2008. 28
The Pituitary Gland
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
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
 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
Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations
chair/saddle)
Marc Imhotep Cray, MD of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012. 32
Normal pituitary gland, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
33
Normal pituitary, microscopic
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 34
Normal pituitary, microscopic (2)
35
Pituitary Gland (6)
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
 Basophils:
FSH, LH, ACTH, TSH (B-FLAT)
 Acidophils:
GH, PRL
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Marc Imhotep Cray, MD Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 36
Hypothalamic–Pituitary Axis
 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.
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)
 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
Hall JE. Guyton and Hall Textbook of Medical Physiology, 13e. Philadelphia: Elsevier , 2016.
Hypothalamic-pituitary axis illustrated
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)
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)
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)
 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
Marc Imhotep Cray,and
MD papilledema 44
Effects of Pituitary Tumors
on Visual Apparatus
 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
To learn more study:

Endocrinology Tutorial 3_Anterior Pituitary
Endocrine Pathology Case 2 SDL Tutorial
Young WF. The Netter Collection of Medical Illustrations Vol 2- The
Marc Imhotep Cray, MD Endocrine System 2nd Edn. Philadelphia: Saunders, 2011. 45
Anterior Pituitary Tumors
 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
 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, and hypothalamic disorders
 Main features of pituitary adenomas are:

 Pituitary adenomas are classified on basis of hormone(s)
produced by neoplastic cells detected by
immunohistochemical stains of tissue sections (see slide 49)

Pituitary Adenomas: General Features (2)
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)
 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

Classification of Pituitary Adenomas
Note: PRL producing adenomas are most common hormone secreting tumors in
both adults and children. Gonadotroph adenomas are more common in elderly.
50
CT scan (a) of a large pituitary adenoma Large pituitary adenoma was an incidental finding at
(A) expanding upwards to compress optic autopsy. As would be suggested by size of tumor, this
chiasma (arrows) pituitary adenoma did not secrete any hormones.
Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Kemp WL, Burns DK, Brown TG, Pathology: The Big Picture.
Marc Imhotep Cray, MD New York:McGraw-Hill,2008. 51
Louis: Mosby-Elsevier, 2009.
Important point regarding pituitary adenomas:
Stalk effect
 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
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
 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 then generate
second messengers (cAMP)
Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of
Marc Imhotep Cray, MD Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015. 54
Pituitary Adenomas: Pathogenesis (3)
 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 the GNAS gene
o In basal state, Gs exists in an inactive state, w guanosine diphosphate
(GDP) bound to the 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)
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

Pituitary adenoma, gross and microscopic
Two distinctive morphologic features cellular
monomorphism and absence of a reticulin network.
Monomorphism of these cells contrasts with admixture of cells seen in

Massive, nonfunctioning adenoma that has grown far beyond
normal anterior pituitary gland. Note also absence of reticulin network.
confines of sella turcica and has distorted overlying brain.
57
Functioning Adenomas & Hyperpituatarism
 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)
 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)

 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
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.
 Somatotroph Adenomas cont.
Persistent GH excess stimulates hepatic secretion of
insulin-like growth factor 1 (IGF1), which acts in
conjunction w GH to induce overgrowth of bones and
muscle
 If a growth hormone-secreting adenoma develops
before epiphyses close, as is case in prepubertal
children, result in gigantism
o Characterized by a generalized increase in body size, with
disproportionately long arms and legs
 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 63
of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.
Somatotroph Adenomas cont.
 Persistent GH excess also is associated w metabolic
abnormalities most important is diabetes mellitus
o DM arises b/c of growth hormone-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 is one of 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,
Marc Imhotep Cray, MD congestive heart failure, increased risk for GI cancers 64
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.
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.
Marc Imhotep Cray, MD 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)
 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

 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
thatImhotep
Marc of ACTH
Cray, MD(see slide 195) 70
Hypopituitarism
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
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
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
Marc Imhotep Cray, MD termed Simmond’s disease (=Pituitary cachexia) 73
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. Young WF. The Netter Collection of Medical Illustrations Vol 2-
The Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.
See Endocrinology Tutorial 1_Postpartum Necrosis
Hypopituitarism, Mild
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014. 75
Hypopituitarism, Moderate
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014. 76
Hypopituitarism: Severe
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014. 77
Hypopituitarism, Pituitary Cachexia
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014. 78
Question
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
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
 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.
 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
A computed tomography (CT) scan of cranium in an axial

section demonstrates an empty sella turcica (arrows).
BS=brainstem; E=eye; TL=temporal lobe.
Marc Imhotep Cray, MD of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 83
Posterior pituitary (neurohypophysis)
Posterior pituitary bright spot. Sagittal T1-MRI image

showing hyperintensity (arrow) in the posterior aspect
of the sella turcica.
Young WF. The Cray,
Marc Imhotep Collection of Medical Illustrations Vol 2- The Endocrine System, 2nd Edn. Saunders, 2011
NetterMD 84
Hormones of Posterior Pituitary
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
Hormone Synthesized by Stimulated by Inhibited by Target Organ Effect
Antidiuretic Supraoptic Raised osmolarity; Lower Kidney Increases
hormone vasopressinergic low blood volume osmolarity permeability of
(ADH) neurons collecting duct to
reabsorb water
Oxytocin Paraventricular Stretch receptors Stress Uterus and Smooth muscle
oxytocinergic in the nipple mammary contraction
neurons and cervix, glands leading to birth or
estrogen 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
Diabetes insipidus (2)
 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
 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
 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
 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 Coronal section of brain shows a large, cystic tumor mass replacing
midline structures in region of hypothalamus.
tissues
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of
Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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
Rubin R , Strayer DS Eds. Rubin’s Pathology:
Clinicopathologic Foundations of Medicine, 6th Ed.
Marc Imhotep Cray, MD Baltimore: Lippincott Williams & Wilkins, 2012. 92
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)
Question
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.

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

Anatomy of Thyroid Gland
 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
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.
Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.
98
Normal thyroid in situ, gross
99
Normal thyroid, microscopic
100
Function of Thyroid hormone
 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
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
102
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
*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)

Summary of physiological effects of TH
 Principal effects of TH are:  Other effects:
 stimulation of metabolism-  ↑Body temperature
raised BMR  ↑Cardiac rate and contractility
 promotion of normal growth  ↑Peripheral vasodilatation
and maturation, particularly  ↑Red cell mass
 of CNS and skeleton  ↑Circulatory volume
 sensitization to effects of  ↑Respiratory drive
catecholamines  ↑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
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
107
Toxic nodular goiter (TNG)
 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”)
Hypothyroidism
 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

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.
111
Dominant clinical
manifestations of
hypothyroidism

Marc Imhotep Cray, MD Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 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
Hashimoto thyroiditis, microscopic
114
Hashimoto thyroiditis, gross
115
Hypothyroidism
 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)
 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)
 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
 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
Marc Imhotep Cray, MD (http://indorgs.virginia.edu/iccidd/mi/cidds.html) 120
Endemic goiter
 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
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013.

Goitrous Hypothyroidism: Pathophysiology
 With inadequate iodine consumption Goiter at an advanced stage
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 Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The
Mechanisms of Body Function, 11th ed. New York, NY: McGraw-Hill, 2008.
produce goiters that can achieve astounding
sizes if untreated
Note: This form of hypothyroidism is reversible if iodine is added to diet. 122
Thyroid, goiter, microscopic
123
Myxedema
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
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,
Marc Imhotep Cray, MD is not necessarily seen in myxedema coma. 125
Congenital Hypothyroidism (Cretinism)
 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
Clinical findings: the 6 P’s

Pot-bellied,
Pale,
Puffy-faced child with
Protruding umbilicus,
Protuberant tongue, and
Poor brain development Cray MI. Hormones and Their Actions Illustrated Notes.pdf. 2017 update.
Hyperthyroidism
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 (2)
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
Graves disease, microscopic
130
Graves disease, microscopic (2)
131
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
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. 133
Graves disease pathophysiology
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
 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: NB: Treatment of thyroid storm is
β-blockers (e.g., Propranolol), same as that for hyperthyroidism,
except that drugs are given in higher
Propylthiouracil,
doses & more frequently
corticosteroids (e.g., Prednisolone), IV administration of medication is
Potassium iodide (Lugol iodine) most efficacious
Immune mechanisms of Graves disease and
Hashimoto thyroiditis (schematic next slide)
 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
 Hypothyroidism results in low levels of T4 and high TSH
 Hyperthyroidism is assoc. w high levels of T4 and low TSH
 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
 High TSH and high T4 can be due to either thyroid hormone
resistance or a TSH secreting tumor

Thyroiditis
 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)
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 140
Thyroiditis (3)
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)
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
 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
Follicular adenoma
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
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
cytoplasm Baltimore: Lippincott Williams & Wilkins, 2012.
144
Thyroid Cancer
To be studied along with Endocrine Pathology Case 1_SDL Tutorial.
 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
 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
Marcnodules and
Imhotep Cray, MDscreen for rare cases of carcinoma 146
Thyroid Ca (4) Etiopathogenesis
 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

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
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)
 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
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.
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%

Papillary carcinoma of thyroid
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)

Marc Imhotep Cray, MD of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 153
Follicular carcinoma
 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

Capsular invasion in follicular
carcinoma
 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
Medullary carcinoma
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
Medullary carcinoma cont.
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 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
 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
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
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams &
Wilkins, 2012.

Thyroid Carcinoma Treatment
 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
 When presented w a thyroid nodule, your job is to exclude presence of a
malignant thyroid lesion
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
NB: A short clinical history and an asymmetrically enlarged, hard thyroid
nodule with adjacent cervical lymphadenopathy are all suggestive of cancer.
See:Imhotep
Marc Endocrine Pathology
Cray, MD Case 1 SDL Tutorial (Thyroid nodule) 162
Investigating a thyroid nodule (2)
 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
Thyroid nodule
Check TSH
High Normal Low
Check free T4 and T3 FNA Nuclear medicine

(investigate for Hashimoto’s uptake scan
nodule) (investigate for hot/cold)

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

Anatomy of Parathyroid Gland
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
Parathyroid gland, normal
167
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 168
Hypoparathyroidism
 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)
 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.
Hypoparathyroidism (2) Clinical manifestations
Symptoms (related to hypocalcemia)
 Seizures  Chvostek’s sign (facial twitching when
 Constipation zygomatic arch is tapped)
 Muscle cramps  Trousseau’s sign (forearm spasms
 Hyperreflexia induced by inflating BP cuff on upper arm)
 Tetany
 Abdominal pain
 Lethargy
 Cardiac dysrhythmia
 Neuropsychiatric
 depression
 paranoia
 psychoses
Pseudohypoparathyroidism: Caused by target
organ insensitivity to PTH
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

Pseudohypoparathyroidism. A radiograph Reference scale graphic.
of the hand reveals characteristic shortness
of fourth and fifth metacarpal bones.
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine,
6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Hypoparathyroidism (3)
 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

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

Primary Hyperparathyroidism
 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”
Parathyroid adenoma, microscopic
177
Parathyroid, adenoma, scintigraphic scan
178
Parathyroid hyperplasia, gross

Secondary Hyperparathyroidism
 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

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th
Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 181
Tertiary Hyperparathyroidism
 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
Miksad RA, Meyer GK & DeLaMora PA. Last Minute Internal Medicine. New York: McGraw-Hill, 2008.

Calcium-relate Diseases & Disorders
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
 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)
Whalen K. Lippincott Illustrated Reviews:
Pharmacology 6th Ed. Wolters Kluwer, 2015

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
Le T, Bhushan V. First Aid for the USMLE Step 1
2017. New York: McGraw-Hill Education, 2017.
Prophylaxis: regular weight-bearing exercise and

adequate Ca2+ and vitamin D intake
Tx: bisphosphonates, teriparatide, SERMs, calcitonin
186
Calcium-relate Diseases & Disorders (4)
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
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)
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

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. Wolters190
Kluwer, 2015
Adrenal gland
Reisner HM. Pathology: A Modern Case Study. New York: McGraw-Hill Education,2015.
191
Normal adrenal gland, gross
192
Normal adrenal gland, microscopic
193
Comparison of atrophic, normal,
and hyperplastic adrenal glands
194
Cortisol
 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
Physiologic, Biochemical & Immunologic Effects of Cortisol
“Cortisol is a BIG FIB”
↑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: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.
 Inhibits production of leukotrienes and prostaglandins
 Inhibits WBC adhesion neutrophilia (neutrophil
demargination)
 Blocks histamine release from mast cells N.B Exogenous corticosteroids can cause
 Reduces eosinophils reactivation of TB and candidiasis (blocks IL-2
 Blocks IL-2 production production), as IL-2 stimulates growth of helper,
↓Bone formation (osteoblast activity) cytotoxic, and regulatory T cells, and NK cells.
196
ACTH (corticotropin)
 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, adrenocortical response to cosyntropin
administration of is reduced
ACTH Synthesis
[A pro-opiomelanocortin(POMC)-derived melanocortins]
Melanocortins POMC-derived melanocortin peptides include α-MSH 

generated as a proteolytic cleavage product from ACTH , which is in turn
Marc Imhotep Cray, MD is a cleavage product of proopiomelanocortin (POMC) 198
Clinical Vignette
A 16-year-old girl is brought to your office complaining of delayed
menarche. She denies sexual activity and pregnancy test was
negative. Physical examination reveals the absence of breasts, hair
on her upper lip, chin, and axillary region, and hypertension.
When laboratory results reveal decreased cortisol and aldosterone
levels, you suspect that this girl may have a rare autosomal
recessive enzyme deficiency.
What is the enzyme deficiency?

Congenital adrenal hyperplasia (CAH)
Etiology: Autosomal recessive deficiency in enzymes involved in
biosynthesis of cortical steroids
Pathology & Pathophysiology: Bilateral nodular hyperplasia of
adrenal gland w lipid-depleted cortical cells
 21-Hydroxylase deficiency (95% cases): Interferes w aldosterone and
cortisol production results in shunting of precursor molecules to form
sex hormones
 11β-Hydroxylase deficiency: Interferes w aldosterone and cortisol
production results in shunting of precursor molecules to form sex
hormones
 17α-Hydroxylase deficiency: Interferes w cortisol and sex hormone
production results in shunting of precursor molecules to form
aldosterone
CAH cont.
 Clinical Manifestations
 21-Hydroxylase deficiency: Masculinization; hypotension;
hyperkalemia; hyponatremia (salt wasting can lead to
hypovolemia)
 11β-Hydroxylase deficiency: Masculinization; hypertension
(weak mineralocorticoid precursor activity); no salt wasting
 17α-Hydroxylase deficiency: Hypertension; hypokalemia; no
sexual maturation
 Treatment Replacement of deficiency hormones;
symptomatic treatment
See: Schematic and companion table (Adrenal steroids and congenital
adrenal hyperplasias). In: First Aid for the USMLE Step 1 2017; pg. 317.
Pathophysiology of CAH
In CAH, 21α-hydroxylase is deficient, such that production of aldosterone and cortisol
decrease owing to metabolic block leads to an overproduction of steroid precursors
(such as 17-hydroxyprogesterone)these precursors are shunted into pathway of sex
hormone biosynthesis leading to excessive accumulation of adrenal androgens causes
in utero masculinization of external genitalia in developing females
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.
Learn more and test your understanding:

Steroidogenesis
Marc Imhotep Cray, MD and Application to CAH Diagnosis.PDF 202
Congenital adrenal hyperplasia
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.
203
Congenital adrenal hyperplasia
Gynecomastia. M/5 yrs. Precocious puberty. M/11 months.

Cooke RA. Color Atlas of Anatomical Pathology. Edinburgh: Churchill Livingstone-Elsevier, 2004.
Question
 What adrenal disease should be
suspected in a young patient
with bacterial meningitis due to
Neisseria meningitidis who also
becomes acutely hypotensive?
 Sn & Sx:
 septicemia, hypotension
 disseminated intravascular
coagulation (DIC)
 adrenal hemorrhage, and
 petechial rash
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated
Marc Imhotep Cray, MD Pharmacology, Updated Edn. Saunders, 2014
Waterhouse-Friderichsen syndrome
Ques. What adrenal disease should be suspected in a young patient
with bacterial meningitis due to Neisseria meningitidis who also
becomes acutely hypotensive?
Ans. Waterhouse-Friderichsen syndrome typically causes bilateral

adrenal hemorrhage, which can be rapidly fatal acute adrenal
cortical insufficiency syndrome
Responsible bacterium is Neisseria meningitidis
Sn & Sx:
 septicemia, hypotension
 disseminated intravascular coagulation (DIC)
 adrenal hemorrhage, and
 petechial rash
Waterhouse-Friderichsen syndrome, gross
207
Waterhouse-Friderichsen syndrome, CT
208
Cushing Syndrome
Cushing syndrome is a group of clinical symptoms that result from
prolonged exposure to excess glucocorticoids
May be caused by exogenous factors, such as long-term

corticosteroid use, or
 May be of endogenous origin due to either

 excess ACTH secretion (ACTH dependent) = Cushing Disease or
 autonomous cortisol hypersecretion (ACTH independent)
 adrenocortical adenomas, carcinomas, ectopic ACTH & CRH

syndromes are responsible for endogenous syndrome
Etiology Cushing Syndrome
Increase cortisol due 3 major causes:
1. Exogenous corticosteroids result in ↓ ACTH, bilateral adrenal
atrophy (most common cause)
2. Primary adrenal adenoma, hyperplasia, or carcinoma result in

↓ACTH, atrophy of uninvolved adrenal gland
3. ACTH-secreting pituitary adenoma (Cushing disease) or

paraneoplastic ACTH secretion (eg, small cell lung cancer, bronchial
carcinoids) result in ↑ACTH, bilateral adrenal hyperplasia
Note: Cushing disease is responsible for majority

of endogenous cases of Cushing syndrome.
Schematic representation of various forms of Cushing syndrome

Adrenal adenoma, gross
212
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.
Clinical findings in Cushing Syndrome
 Clinical manifestations affect multiple organ systems and depend
on degree and duration of hypercortisolism
 Most common sign is progressive obesity seen in face, neck,
trunk, and abdomen
 Facial fat accumulation produces a moon-face appearance,
enlarged dorsocervical fat pad produces a buffalo hump
 Other Sx include:
o weight gain
o weakness
o muscle wasting (reduced arm muscle mass)
o osteoporosis
o cardiovascular (hypertension)
o hyperglycemia (insulin resistance)
o amenorrhea
o immunosuppression 213
Diagnosis of Cushing Syndrome
 Screening tests include:
 increase free cortisol on 24-hr urinalysis
 increase midnight salivary cortisol, and no suppression w overnight low-dose
dexamethasone test
 Measure serum ACTH

 If decrease suspect adrenal tumor or exogenous glucocorticoids
 If increase distinguish between Cushing disease and ectopic ACTH
secretion w a high-dose (8 mg) dexamethasone suppression test and
CRH stimulation test
o Ectopic secretion will not decrease w dexamethasone b/c source
is resistant to negative feedback
o Ectopic secretion will not increase w CRH b/c pituitary ACTH is
suppressed
Cushing syndrome ↑24-hr urine free cortisol,↑ late night salivary cortisol, and/or
Diagnostic Algorithm inadequate suppression on 1 mg overnight dexamethasone test
Measure ACTH
Suppressed Elevated
ACTH-independent ACTH-dependent
Cushing syndrome Cushing syndrome
Exogenous glucocorticoids
or adrenal tumor High-dose (8mg) dexamethasone CRH stimulation test
(consider adrenal CT to confirm) suppression test
No suppression Adequate No ↑in ACTH

Ectopic ACTH suppression ↑ ACTH and cortisol and cortisol
secretion Cushing disease Cushing disease Ectopic ACTH
secretion
Redrawn after: Le T, Bhushan, et al. First Aid for the

USMLE Step 1 2017. McGraw-Hill Education, 2017. CT of chest/abdomen/pelvis MRI of the pituitary CT of chest/abdomen/pelvis
Adrenocortical insufficiency
1. Primary adrenocortical insufficiency most commonly caused by
autoimmune destruction of adrenal cortex can be chronic
(=Addison disease) or causes acute adrenal crisis (Addisonian
crisis)
Characterized by following Sn & Sx:
 ↓ adrenal glucocorticoid, androgen, and mineralocorticoid
 ↑ ACTH (Low cortisol stimulate ACTH secretion by negative feedback)
 Hypoglycemia (caused by cortisol deficiency)
 Weight loss, weakness, nausea, and vomiting
 Hyperpigmentation (low cortisol stimulate ACTH secretion) ACTH
contains MSH fragment
 ↓ pubic & axillary hair in FM (caused by deficiency of adrenal androgens)
 ECF volume contraction (hyponatremic), hypotension, hyperkalemia, and
metabolic
Marc Imhotep Cray, MD acidosis (caused by aldosterone deficiency) 216
Addison’s disease (1° adrenal insufficiency)
Symptoms, caused by reduced production of
 glucocorticoids
 mineralocorticoids, and
 sex hormones
Biochemical abnormalities (eg, hyponatremia,

hyperkalemia) usually exist
Dx ACTH stimulation test (cosyntropin) can be used to

diagnose Addison's disease
 failure of serum cortisol levels to increase after administration
makes a Dx of primary adrenocortical insufficiency more likely

1o Adrenal Insufficiency
(Addison’s disease)
Caused by
 autoimmune-mediated
destruction of adrenal cortex
 Mycobacterial infection (TB)
 adrenal metastases
 use of certain drugs
Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed.
Philadelphia: Saunders-Elsevier, 2014.
Pathophysiology of adrenal cortex (2)
2. Secondary adrenocortical insufficiency
 Caused by primary deficiency of ACTH
 does not exhibit hyperpigmentation (b/c there is a deficiency of
ACTH)
 does not exhibit volume contraction, hyperkalemia, or metabolic
acidosis (b/c aldosterone levels are normal)
 Symptoms are otherwise similar to those of Addison disease
3. Tertiary adrenal insufficiency

 Seen in patients w chronic exogenous steroid use, precipitated by
abrupt withdrawal adrenal crisis
 Aldosterone synthesis unaffected

Acute Adrenal Insufficiency (3)
 life-threatening acute adrenal crisis, also occurs in cases of undiagnosed
adrenal insufficiency & untreated stress; mimics septic shock, presents w
 severe anorexia (lack or loss of appetite for food)
 dehydration, and
 hypotension cardiovascular collapse>>death
 Treatment: IV fluids and high-dose IV glucocorticoids immediately after

taking a blood sample for random cortisol
 Chronic disease is managed w a glucocorticoid (hydrocortisone) plus a

mineralocorticoid (fludrocortisone) w dosage tailored to avoid Cushing
syndrome or inadequate therapy
 Pts should be monitored for fludrocortisone (mineralocorticoid) adverse

effects
Marc Imhotep Cray,(eg,
MD electrolyte changes, hypertension, edema, and hyperglycemia) 220
Abrupt corticosteroid withdrawal & adrenal crisis
 Use of high-dose steroids for more than a week begins to
produce suppression of pt's adrenal glands b/c exogenous
glucocorticoids suppress CRH and pituitary ACTH
 With prolonged suppression, adrenal glands atrophy can take
months to recover full function after D/C of exogenous glucocorticoid
 During this recovery time, patient is vulnerable to acute adrenal

insufficiency (adrenal crisis)  during times of stress, such as illness,
due to both adrenal atrophy and suppression of CRH and ACTH release
NB: Adrenal crisis is a medical emergency and potentially life-

threatening situation requiring immediate emergency treatment.

Pathophysiology of acute adrenal crisis
 As stated, occur in pts w undiagnosed ACTH deficiency, in
patients receiving corticosteroids and who are not given
increased steroid dosage during periods of stress
Precipitants include:
o Infection
o Trauma
o Surgery, and
o Dehydration
o GI infections  particularly challenging b/c of assoc. inability to ingest or
absorb oral hydrocortisone replacement  can lead to adrenal crisis
despite other treatments
 If unrecognized and untreated, coma, severe hypotension, or shock

unresponsive to vasopressors may rapidly lead to death
Pathophysiology of acute adrenal crisis (2)
 Pts. w acute adrenal crisis have Sx of fever, weakness, apathy, & confusion
 Anorexia, nausea/vomiting may lead to volume depletion & dehydration
 Abdominal pain may mimic that of an acute abdominal process
 Evidence suggests Sx of acute glucocorticoid deficiency are mediated by

significantly elevated plasma levels of cytokines particularly IL-6 and, to
a lesser extent, IL-1 and TNF
 Hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and

hypoglycemia occur frequently

Question
A 37-year-old kidney transplant recipient presents to her primary
care physician for follow-up. Among other immunosuppressant
drugs, she has been taking daily prednisone for the past 2 months
since her transplant. With only a few doses of prednisone left, she
gets snowed into her house and cannot refill her prescription (but
she has enough of the other medications to last a few more weeks).
If she runs out of prednisone and cannot get it refilled, what is she
most at risk for developing?
(A)Cardiovascular collapse
(B) Osteoporosis
(C) Increased risk of infection
(D)Insomnia
(E) Nausea/vomiting
The correct answer is A: Cardiovascular collapse (acute adrenal crisis)
Chronic use of glucocorticoids (such as prednisone) will lead to adrenal atrophy
b/c exogenous steroid suppresses hypothalamic-pituitary-adrenal (HPA) axis. If
exogenous steroid is abruptly withdrawn, atrophied adrenal gland is unable to
compensate by producing endogenous steroids quickly enough. Sudden loss of
adrenal steroids is termed “adrenal crisis” and can result in cardiovascular
collapse and death.
Incorrect answers
(B) Osteoporosis is a possible result of continued chronic glucocorticoid therapy, not abrupt
cessation.
(C) Increased risk of infection is a result of continued chronic glucocorticoid therapy, not abrupt
cessation.
(D) Insomnia is a possible side effect from short-term oral or parenteral glucocorticoid therapy.
(E) Nausea/vomiting are possible side effects from short-term oral or parenteral glucocorticoid
therapy.

Hyperaldosteronism
Increased secretion of aldosterone from adrenal gland
 Clinical features include hypertension (2°), hypokalemia, metabolic
alkalosis
 No edema due to aldosterone escape mechanism
Primary hyperaldosteronism
 Seen w adrenal cortex adenoma (Conn syndrome) 33% or
idiopathic bilateral adrenal hyperplasia (66%) ↑aldosterone,
↓renin
Secondary hyperaldosteronism
 Seen in pts. w renovascular HTN/renal artery stenosis,
juxtaglomerular cell tumor, edema (eg, cirrhosis, heart failure,
nephrotic syndrome)
 due to independent activation of renin-angiotensin-
aldosterone system) ↑aldosterone, ↑renin
Clinical Vignette
A 29-year-old man presents to the emergency department
complaining of a crushing headache and heart palpitations. He tells
you that he has had similar episodes in the past. Physical
examination reveals a pulse of 140 and a BP of 200/110. A 24-hour
urine collection reveals increased vanillylmandelic acid (VMA) and
metanephrine levels and blood tests demonstrate increased plasma
catecholamine levels. You immediately prescribe phenoxybenzamine
for the patient and tell him that it is likely that he will need surgery
to definitively treat his condition.

Pheochromocytoma (usually benign)
See Endocrinology Tutorial 2 MEN Syndromes
 Most common tumor of adrenal medulla in adults

 Derived from chromaffin cells (arise from neural crest)
 Etiology Most (90%) cases occur sporadically
 Other cases are assoc. w MEN IIa, MEN IIb, neurofibromatosis, or
von Hippel-Lindau disease
 Pathology
 Gross: Variable changes in adrenal medulla range from
small, circumscribed lesions to large, hemorrhagic lesions
w lobular pattern
 Microscopic: Tumor composed of nests of polygonal
chromaffin cells containing catecholamine-rich
granules giant, pleomorphic cells are sometimes seen
Pheochromocytoma cont.
 Clinical Manifestations release of Epi & NE from tumors
results in intermittent attacks of hypertension, headache,
palpitations, and diaphoresis
 Lab findings: ↑ 24-hour urinary catecholamine and VMA,
metanephrine levels, ↑ plasma metanephrine levels
 Treatment Initial treatment w α-adrenergic blocking agents

(phenoxybenzamine) followed by surgical resection of mass
Note:
 Pheochromocytomas are assoc. w rule of 10s: 10% malignant, 10%
bilateral, 10% familial, 10% extra-adrenal, & 10% occur in children
 can occur outside adrenal called paragangliomas
Pheochromocytoma. (a) adrenal contains a well-circumscribed, spherical, brown tumor
w small foci of hemorrhage. (b) Histology shows a typical neuroendocrine tumor with
cells resembling those of normal adrenal medulla.
Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009.
230
Neuroblastoma (malignant)
 Most common tumor of adrenal medulla in children (usually < 4
years old)
 Originates from neural crest cells
 Occurs anywhere along sympathetic chain
 Most common presentation is abdominal distension and a firm,

irregular mass that can cross midline (vs Wilms
tumor[nephroblastoma], which is smooth and unilateral)
 Less likely to develop hypertension than w pheochromocytoma
 Can also present w opsoclonus-myoclonus syndrome (“dancing eyes-
dancing feet”).
 ↑HVA and VMA (catecholamine metabolites) in urine

Neuroblastoma (2)
Homer-Wright rosettes
Neuroblastoma (arrows) characteristic of neuroblastoma
Circular grouping of dark tumor cells
surrounding pale neurofibrils
Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.
 Associated with overexpression of N-myc oncogene

 Classified as an APUD (amine precursor uptake decarboxylase) tumor
Diabetes Mellitus (DM)
Discussion topics outline:
Blood glucose regulation & endocrine pancreas cell types
Preproinsulin, proinsulin, Insulin and C-peptide
Lack of lnsulin
Diabetes Mellitus: Etiologic Classification
Type I DM pathogenesis & clinical features
Type II DM pathogenesis & clinical features
MODY “type one-and-a half”
Other Specific Causes of DM
Acute Manifestations and Diagnosis
Chronic Complications and Consequences
Intended to be studied along with:

Diabetes mellitus Type 1 SDL Tutorial
Diabetes mellitus Type 2 SDL Tutorial
Blood glucose regulation
Insulin is an important hormone in glucose metabolism made
by pancreatic β cells and is cleaved from a precursor molecule
called proinsulin
 Glucagon is another hormone (of arguably lesser importance)

in glucose metabolism
 Glucagon is made in α cells and is an antagonist to insulin
therefore important in recovering from hypoglycemia
 Insulin is an anabolic hormone that promotes energy storage

while, glucagon is catabolic (i.e., it breaks down molecules)

Blood glucose regulation
Marc Imhotep Cray, MD Merali Z, Woodfine JD (eds.) Toronto Notes 2016, 33rd Ed. Toronto, Ontario, Canada, 2016. 235
Endocrine pancreas cell types
 Islets of Langerhans are collections of α, β, and δ endocrine cells
Islets arise from pancreatic buds
 α = glucagon (peripheral)
 β = insulin (central)
 δ = somatostatin (interspersed)
 Preproinsulin (synthesized in RER)  cleavage of “presignal

”to proinsulin (stored in secretory granules)  cleavage of
proinsulin  exocytosis of insulin and C- peptide equally
 Insulin and C-peptide increased in insulinoma and
sulfonylurea use, whereas
 Exogenous insulin lacks C-peptide

Structure of insulin (A) & formation of
human insulin from preproinsulin (B)
Marc Imhotep Cray, MD McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015 237
Lack of lnsulin
Without insulin glucose is not transported across cell
membranes leads to a cascade of metabolic events
 Body reacts by inducing gluconeogenesis (liver converts glycogen to
glucose)
To produce energy skeletal muscle converts its structural
proteins to amino acids which are carried to liver where they
are converted to glucose
 Resultant excess glucose, still not being used by cells, leads to
hyperglycemia
Insulin deficiency increases fat catabolism: free fatty acids are

broken down into keto acids to increase energy sources
Lack of lnsulin (2)
 Kidneys eliminate keto acids produces ketonuria and
ketonemia
 Keto acids also reduce blood pH can result in ketoacidosis,

coma, and death
 Diabetes is caused by a relative or absolute lack of insulin w

hyperglycemia being hallmark medical finding
 Once thought of as 1 disease, diabetes is now believed to be a

chronic heterogeneous group of disorders that result from
pathologic processes that depend on diabetes type
Diabetes Mellitus: Etiologic Classification
Most common and important disease assoc. w endocrine pancreas is
DM
DM is a multisystem disease w both biochemical and structural
consequences
 It is a chronic disease of carbohydrate, fat and protein metabolism resulting
from inadequate action of hormone insulin
Two main types of DM are identified, largely on clinical grounds
 Type I (insulin- dependent diabetes mellitus – IDDM), and
 Type II (non-insulin dependent diabetes –NIDDM)
----------
 Type III diabetes refers to specific types of diabetes caused by rare genetic defects
in islet insulin-secreting cell function and genetic defects in insulin action
 Type IV disease refers to diabetes related to pregnancy
240
Pre-Diabetes (Impaired Glucose Tolerance/
Impaired Fasting Glucose)
 1-5% per yr. of pre-diabetes go on to develop T2DM
 50-80% revert to normal glucose tolerance
 weight loss may improve glucose tolerance
 ↑ risk of developing macrovascular complications (IGT >IFG)
 lifestyle modifications ↓ progression to DM by 58%
 IGT is defined as: two-hour glucose levels of 140 to 199 mg per dL on 75-g oral glucose tolerance
test. A patient is said to be under condition of IGT when he/she has an intermediately raised
glucose level after 2 hours, but less than level that would qualify for T2DM.
 IFG is a type of prediabetes, in which blood sugar level during fasting is consistently higher than
what are considered normal levels; however, level is not high enough to be diagnosed as DM
NB: It is likely that pre-diabetes and metabolic syndrome (next 2 slides)

denote same disorder, defining it by different sets of biological markers.
Metabolic syndrome
Metabolic syndrome is a clustering of at least three of five of following
medical conditions:
 abdominal (central) obesity
 elevated blood pressure
 elevated fasting plasma glucose
 high serum triglycerides
 low high-density lipoprotein (HDL) levels
Syndrome is thought to be caused by an underlying
disorder of energy utilization and storage
Metabolic syndrome is assoc. w ↑ risk of developing CVD and T2DM
Some studies have shown prevalence in USA to be an estimated 34% of adult

population  prevalence ↑ w age
NB: Insulin resistance, metabolic syndrome, and pre-diabetes are closely

Marcrelated toMDone another and have overlapping aspects
Imhotep Cray, 242
Metabolic syndrome cont.
Metabolic syndrome quintuples (X5) risk of T2DM T2DM is
considered a complication of metabolic syndrome
In people w IGT or IFG presence of metabolic syndrome

doubles risk of developing T2DM
 As stated above, prediabetes and metabolic syndrome probably denote
same disorder, defining it by different sets of biological markers
 Presence of metabolic syndrome is assoc. w higher prevalence of

CVD than found in pts w T2DM or IGT without syndrome
Hypoadiponectinemia , known to increase insulin resistance , is

considered a risk factor for developing metabolic syndrome
Diabetes Mellitus cont.
In simplest terms, DM is inability to properly manage
glucose metabolism (glucose intolerance) b/c of either
 inability to produce and secrete insulin as a result of
autoimmune destruction of pancreatic β-cells (T1DM)
or
 inability of peripheral tissues to respond to circulating
insulin as a result of diminished or impaired insulin receptor
signaling (T2DM)

Type 1 Diabetes Mellitus
In T1DM, insulin-producing β cells of pancreas are
destroyed by either intrinsic genetic factors or extrinsic
factors such as viruses or chemical toxins
 In one theory that involves an autoimmune-mediated
mechanism predisposed pts. react abnormally to
environmental triggers by producing antibodies that are
directed against β cells insulin secretion is impaired early
in disease and eventually stops absolutely
 In serum, autoantibodies to insulin appear early followed

by antibodies to beta cell antigen glutamic acid
decarboxylase (GAD-65) and islet cell antigen (ICA-512)
Type 1 Diabetes Mellitus (2)
 Type 1 DM usually develops abruptly during childhood
or adolescence and usually presents w polydipsia,
polyuria, polyphagia and weight loss
 C-peptide levels are low or undetectable
 Ketoacidosis is more likely to occur in type 1 DM than in

type 2 DM
 Signs and Symptoms of DKA: Kussmaul respirations, fruity
breath, abdominal pain, N/V, polyuria, polydipsia, dehydration
and fatigue
 Patients require lifelong Tx w exogenous insulin to control bld
glucose levels and prevent short-term and long-term
macrovascular and microvascular complications, such as
 nephropathy
 neuropathy
 retinopathy, and
 cardiovascular disease
NB: Oral hypoglycemic agents are ineffective

in pts w type 1 DM b/c functioning β cells are
required for these agents to work.

Pathogenetic stages in development of (T1DM)
 Disease develops from an initial genetic BCM, beta cell mass.
susceptibility to defective recognition of beta
cell epitopes and ends with essentially complete
beta cell destruction in most patients.
 An environmental event is believed to trigger
immune attack, and persons with certain
genetic markers (human leukocyte antigen
[HLA]-DR3 and -DR4) are particularly
susceptible to autoimmune disease.
 Pts w islet cell antibodies and normal blood
glucose levels are considered to have a state of
“pre-type 1 diabetes.”
 Rate of decline in beta cell mass (blue line)
determines the length of time between onset of
beta cell destruction and eventual
hyperglycemia (red line, fasting blood glucose)
owing to loss of greater than 90% of functioning
beta cells. Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: Lippincott Williams & Wilkins, 2012.
249
Klatt EC. Robbins and Cotran Atlas of Pathology,

3rd Ed. Philadelphia: Saunders, 2015.
Insulitis, microscopic
Diabetic Ketoacidosis
 In pts w T2DM, significant deviations from normal dietary
intake, unusual physical activity, infection, or any other
forms of stress may worsen metabolic imbalance
leading to diabetic ketoacidosis
 Plasma glucose usually is in range of 500 to 700 mg/dL as a result
of absolute insulin deficiency and unopposed effects of
counterregulatory hormones (epinephrine, glucagon)
Marked hyperglycemia causes an osmotic diuresis and

dehydration characteristic of ketoacidotic state

DKA (2)
 Second major effect is activation of ketogenic machinery
insulin deficiency leads to activation of hormone-sensitive
lipase w resultant excessive breakdown of adipose stores,
giving rise to ↑ FFAs oxidized by liver to produce ketones
 Ketogenesis is an adaptive phenomenon in times of starvation,
generating ketones as a source of energy for consumption by vital
organs (e.g., brain)
 Rate ketones are formed may exceed rate they can be used by
peripheral tissues leading to ketonemia and ketonuria
 If urinary excretion of ketones is compromised by

dehydration accumulating ketones ↓ blood Ph resulting
in metabolic acidosis
Sx and Sn of uncontrolled hyperglycemia in T1DM
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: Lippincott Williams & Wilkins, 2012.
Type 2 Diabetes Mellitus
Central defects in type 2 DM are decreased insulin
secretion and insulin resistance
 Before diabetes is diagnosed, patients, often obese

have hyperinsulinemia caused by excess dietary
carbohydrates
NB: Obesity is a major risk factor for development of T2DM
 incidence of T2DM ↑ w obesity & consumption of glucose (in all
nutritional forms)
T2DM is much more common than T1DM accounting
for 95% of cases
Pancreas malfunctions and fails to supply high insulin demands
 Also, impaired secretion is complicated by insulin resistance:

 insulin resistance means insulin cannot decrease plasma
glucose levels through suppression of hepatic glucose
production and stimulation of glucose use in skeletal muscle
and adipose tissue
 Resistance develops in several possible ways, eg,
o chronic hyperinsulinemia causes insulin receptor down-
regulation leads to defects in insulin binding and post-receptor
insulin signaling pathways

Pathogenesis of obesity-related T2DM
 Expanded visceral fat mass in upper body obesity
elaborates several factors that contribute to tissue insulin
resistance include ↑ in circulating free (nonesterified)
fatty acids (FFAs) and cytokines that inhibit insulin action,
as well as a↓ in factors that enhance insulin signaling, such
as adiponectin
 These changes result in a block to insulin action in liver
and skeletal muscle at level of insulin receptor and at
postreceptor signaling sites resulting in a failure of
insulin to suppress hepatic glucose production and to
promote glucose uptake into muscle
 Resulting hyperglycemia is normally countered by ↑ insulin
secretion by pancreatic beta cells
 In persons w T2DM, combination of resistance to insulin
action and a genetically determined impairment of beta
cell response to hyperglycemia results in hyperglycemia,
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
and T2DM ensues Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams &
Wilkins, 2012.
255
Glucose regulation and metabolic activity during
development of T2DM
 Insulin resistance alone rarely
causes T2DM since increased
insulin secretion (hyperinsulinism)
by beta cells will compensate for
insulin resistance and thereby
prevent blood glucose levels from
rising
 It is only when beta cells start
showing evidence of dysfunction
that blood glucose levels start to
NGT, normal glucose tolerance ;IGT, impaired glucose tolerance; IFG,
increase impaired fasting glucose
Insulin response in T2DM
Insulin resistance and
hyperinsulinemia of T2DM
(“metabolic syndrome”) are
very harmful to body
contribute to ↑ incidence of
HTN, CVD, obesity, and
hyperlipidemia in pts w T2DM
Typical patterns of insulin production in response to glucose

challenge in normal (blue) and type 2 diabetic (red) patients.
 Unlike type 1 DM, T2DM
 has a more gradual onset
 may not present w classic symptoms, and
 usually occurs in overweight pts older than 35 years
 Oral hypoglycemic agents

 decrease plasma glucose levels
 improve insulin resistance, and
 reduce long-term complications
 Note: Many pts require insulin therapy as well

Hyperosmolar Non-ketotic Coma
 T2DM also may manifest w polyuria and polydipsia
 In some cases, medical attention is sought b/c of unexplained
weakness or weight loss
 Most frequently, however, diagnosis is made after routine blood or
urine testing in asymptomatic individuals
 In decompensated state, pts w T2DM may develop

hyperosmolar nonketotic coma
 Syndrome is engendered by severe dehydration resulting
from sustained osmotic diuresis and urinary fluid loss due
to chronic hyperglycemia

HNC (2)
 Typically, affected older adult diabetic disabled by stroke or
infection  unable to maintain adequate water intake
 Absence of ketoacidosis and its symptoms (nausea, vomiting,

respiratory difficulties) delays recognition of seriousness of
situation until onset of severe dehydration and coma

Comparison of type 1 and type 2 DM
T1DM T2DM
Childhood and adolescence onset Late middle-age/elderly onset
Thin Obese
Ketoacidosis (DKA) common Ketoacidosis rare
Hyperosmolar hyperglycemic
nonketotic syndrome (HHNS)
Severe insulin deficiency Relative deficiency and end-organ
resistance
Islet-cell antibodies No islet-cell antibodies
Autoimmune mechanism No autoimmune mechanism
Genetic predisposition associated Polygenic inheritance
with HLA-DR genotype
Redrawn after: Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009.
Mature onset diabetes of the young (MODY)
MODY also called “type one-and-a half,” stems from
genetic defects in beta-islet cells
 clinical presentation is different than type 1 diabetes
o Ketoacidosis can be presenting manifestation.
o There are no circulating autoantibodies, and MODY presents later
in patient’s life than type 1 diabetes
 Treatment is insulin therapy

Other Specific Causes of DM
Diseases of exocrine pancreas:
 Pancreatitis, pancreatectomy, neoplasia, cystic fibrosis,
hemochromatosis (“bronze diabetes”)
Endocrinopathies:
 Acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma,
hyperthyroidism
Drug-induced:
 Glucocorticoids, thyroid hormone, β-adrenergic agonists, thiazides,
phenytoin, clozapine
Infections:
 Congenital rubella, CMV, coxsackie
Genetic syndromes associated w DM:
 Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome
DM Acute Manifestations and Diagnosis
Acute Manifestations
Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1),
Hyperosmolar hyperglycemic state (HHS) (type 2)
Rarely, can be caused by unopposed secretion of GH and
epinephrine
 Also seen in pts on glucocorticoid therapy (steroid diabetes)
Diagnosis
TEST DIAGNOSTIC CUTOFF NOTES
HbA1c ≥ 6.5% Reflects average blood glucose over prior 3 months
FPG ≥ 126 mg/dL Fasting for > 8 hours
2-hour OGTT ≥ 200 mg/dL 2 hours after consumption of 75 g of glucose in water

DM Chronic Complications
 Morbidity assoc. w long-standing diabetes of any type results
from chronic complications of hyperglycemia, and resulting
damage induced in both large- and medium-sized muscular
arteries (diabetic macrovascular disease) and small-vessels
(diabetic microvascular disease)
 Macrovascular disease causes accelerated atherosclerosis among
diabetics resulting in increased myocardial infarction, stroke, and
lower-extremity ischemia
 Effects of microvascular disease most profound in retina, kidneys,
and peripheral nerves resulting in diabetic retinopathy,
nephropathy, and neuropathy, respectively

DM Chronic
Complications
Marc Imhotep Cray, MD Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. 266
Philadelphia: Saunders-Elsevier, 2015.
DM Chronic Complications cont.
 NB: Complications of DM are far less common and less
severe in people who have well-controlled blood sugar
levels hence need for tight control of hyperglycemia
 Wider health problems accelerate deleterious effects of

diabetes
 These include
o smoking,
o elevated cholesterol levels,
o obesity,
o high blood pressure, and
o lack of regular exercise
Consequences of
DM Complications
As a result of aforementioned
complications, diabetics of both
types have a predisposition to
develop
 ischemic heart disease,
 cerebrovascular disease
 gangrene of lower limbs
 chronic renal disease
 reduced visual acuity leading
to blindness
 peripheral neuropathy
Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed.
Marc Imhotep Cray, MD St. Louis: Mosby-Elsevier, 2009. 268
Nonenzymatic glycation:
 Small vessel disease= microvascular (diffuse thickening of
basement membrane) retinopathy (hemorrhage, exudates,
microaneurysms, vessel proliferation), glaucoma, neuropathy,
nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-
Wilson nodules) progressive proteinuria [initially
microalbuminuria/ACE inhibitors are renoprotective] and
arteriolosclerosis hypertension
 both nephropathy & arteriolosclerosis lead to chronic renal failure
(CRF)
NB: The following terms are similar, yet distinct, in both
spelling and meaning, and can be easily confused:
arteriosclerosis, arteriolosclerosis, and atherosclerosis.
Hyaline arteriolosclerosis, microscopic
270
Nodular glomerulosclerosis, microscopic
271
Atherosclerosis, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 272
 Large vessel atherosclerosis= macrovascular
o CAD (NB: MI most common cause of death in DM)
o peripheral vascular occlusive disease
o gangrene limb loss
o cerebrovascular disease stroke

Atherosclerosis, gross
274
Peripheral vascular disease, grafts, CT image
275
Osmotic damage (sorbitol accumulation in organs w
aldose reductase and decrease or absent sorbitol
dehydrogenase):
 Neuropathy (motor, sensory [glove and stocking distribution],
and autonomic degeneration)
 Cataracts

Diabetic neuropathy, microscopic
277
Cataract, gross
278
279
Diabetic retinopathy, funduscopy
Normal retina, funduscopy
Acute Complications of DM
 Diabetic ketoacidosis
 Hyperglycemia hyperosmolar state
 Hypoglycemia
 Diabetic coma
 Erectile Dysfunction
 Respiratory infections
 Periodontal disease
 Skin infections

Hypoglycemia
Hypoglycemia (low blood sugar) is when blood sugar decreases to
below normal levels
 May result in a variety of symptoms including clumsiness, trouble talking,
confusion, loss of consciousness, seizures, or death
 A feeling of hunger, sweating, shakiness, and weakness may also be
present
o Symptoms typically come on quickly
Cause
Most common cause of hypoglycemia is medications used to treat
DM, such as insulin and sulfonylureas
 Risk is greater in diabetics who have eaten less than usual, exercised
more than usual, or have drunk alcohol

Hypoglycemia cont.
 Hypoglycemic symptoms and manifestations can be divided
into those produced by counterregulatory hormones
(epinephrine and glucagon) triggered by falling glucose, and
neuroglycopenic effects produced by the reduced brain sugar:
 Shakiness, anxiety, nervousness
 Palpitations, tachycardia
 Sweating, feeling of warmth (sympathetic muscarinic rather than
adrenergic)
 Pallor, coldness, clamminess
 Dilated pupils (mydriasis)
 Hunger, stomach rumble
 Nausea, vomiting, abdominal discomfort
 Headache
Acute Hypoglycemia
Antidote Use of sugar packets,
candy, or pure glucose products
can help w hypoglycemia
 Unconscious pts must be
injected w glucagon or IV
glucose or dextrose
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn. Saunders,283
2014
THE END
See next slide for hypermedia to further study tools and resources.
284
Further study tools and resources:
Inside Endocrine System BMS Cloud Folder:
 Endocrine System Pathology Outline
 Molecular and Cell Biology of Endocrine System Ppt.
 Endocrine Pathology Case 1 SDL Tutorial
 Endocrine Pathology Case 2 SDL Tutorial
 Endocrinology Tutorial 1 Postpartum Necrosis
 Endocrinology Tutorial 2 MEN Syndromes
 Endocrinology Tutorial 3 Anterior Pituitary
 Diabetes mellitus Type 1 SDL Tutorial
 Diabetes mellitus Type 2 SDL Tutorial
 Endocrine Pathology Clinical Vignettes
 Hormones and Their Actions_Illustrated Notes
 Endocrine Pathology Rapid Review Notes
Also see Medical Pathology Cloud Folder

Endocrine System Pathology PPT Lecture Series

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Pathology of Endocrine System

Prepared and presented by:

Marc Imhotep Cray, MD 2

Marc Imhotep Cray, MD 5

Marc Imhotep Cray, MD 6

Marc Imhotep Cray, MD 7

 Term hormone (from Greek, horman, “set in motion”)

Marc Imhotep Cray, MD 8

 Some hormones, such as catecholamines, are produced in

 Other mediators function only in restricted circulation

 Some hormones exert their effects in very tissues that make

Learn more: Molecular and Cell Biology of Endocrine System Ppt. 10

 Hormones act either on final effector target or on other

 Endocrine glands synthesize and secrete hormones into

 Disorders of endocrine system are usually due to either

 Disorders of endocrine system are therefore important b/c they

NB: Study of endocrine diseases requires integration of morphologic

 Endocrine diseases can be classified as

 Since hypothalamus and pituitary gland control

Marc Imhotep Cray, MD 16

 Simultaneous measurement of conc. of pituitary

Marc Imhotep Cray, MD 18

 Most hyperfunctioning disorders cannot be suppressed

Marc Imhotep Cray, MD 20

Hormone synthesis and release are governed at multiple

Marc Imhotep Cray, MD 21

Marc Imhotep Cray, MD 22

Marc Imhotep Cray, MD 23

A major center of neuroendocrine integration is hypothalamus

Marc Imhotep Cray, MD 25

Dashed lines = negative effect

 A negative feedback mechanism is an

 Negative feedback occurs when a product

When thyroid hormone reaches

Marc Imhotep Cray, MD 28

Marc Imhotep Cray, MD 30

Marc Imhotep Cray, MD 31

 Posterior pituitary gland arises

 NB: pituitary gland sits in a

Marc Imhotep Cray, MD 38

FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH

Marc Imhotep Cray, MD 41

Marc Imhotep Cray, MD 42

o Like any expanding intracranial mass pituitary adenomas can produce

 In addition, a variety of other visual

To learn more study:

 Following, we will first discuss general features of pituitary

Marc Imhotep Cray, MD 46

 Main features of pituitary adenomas are:

Marc Imhotep Cray, MD 47

 Nonfunctioning adenomas more likely to come to clinical

Marc Imhotep Cray, MD 49

 Secretion of PRL, however, is tonically inhibited by delivery of

o G-proteins are heterotrimeric proteins, composed of a specific α-

 G proteins play a critical role in

o On interaction w ligand-bound cell surface receptor, GDP dissociates,

 Approx. 40% of somatotroph cell adenomas bear GNAS

Marc Imhotep Cray, MD 56

Monomorphism of these cells contrasts with admixture of cells seen in

 Hyperprolactinemia also is a feature of other conditions,

Marc Imhotep Cray, MD 59

Marc Imhotep Cray, MD 60

 Other manifestations of GH excess include gonadal

Marc Imhotep Cray, MD 68

Marc Imhotep Cray, MD 69

Note: Pts w Cushing syndrome often have hyperpigmented skin b/c of ↑