Endo Notes

001 – Course Orientation

 Lesson objectives

002 – General Principles of Endocrinology

 Classic endocrine system functions
o Hypothalamus releases
 Releasing hormones:
 GHRH, CRH, TRH, GnRH,
 Inhibitory hormones:
 Somatostatin, Dopamine
 Hormones to Post pituitary:
 ADH, Oxytocin
o Pituitary hormone releases
 GH, Prolactin, ACTH, MSH, TSH, FSH, LH
o Thyroid releases
 T3, T4, Calcitonin
o Parathyroid releases
 PTH
o Adrenals release
 Cortisol, aldosterone, androgens, Epinephrine, Norepi
o Pancreas release
 Insulin, Glucagon, Somatostatin
o Ovaries release
 Estrogen, progesterone
o Testes release
 Testosterone
 Endocrine fxn notes
o Prolactin needed for production of breastmilk –→ controlled by
dopamine
o Classic question –→ if there is damage to anterior pituitary, there will
be inhibition of all hormones except prolactin –→
  Dopamine will not be released
 Dopamine release controlled by lactotrough
 Paracrine functions
o In islets of Langerhans
 Somatostatin secreted by Delta cells –→ acts on alpha and
beta cells
o Somatostatin is paracrine inhibition of insulin AND glucagon
o Testosterone is also paracrine and binds androgen binding protein
o Somatometin = insulin like growth factor
 IGF has paracrine and autocrine fxn
 Autocrine
o Hormone is released and acts on cell that released it
o IGF-1 acts on chondrocytes, breast epithelium, and gonadal cells
o Prostaglandins are autocrine as well
o IL-1, and IL-2 also have autocrine functions
 Intracrine
o When hormone peptides work intracellularly –→ seen in cancer
o Effects of parathyroid hormone related peptide in malignant cells
o Some androgen derived estrogen is also intracrine
 Hormones are classified as
o Protiens/peptides
o Catecholamines
o Steroid hormones
o Iodothyronines
 Chemical nature determines hormone pk
o Steroid hormones are lipophilic→ cannot be stored
 Synthesized as required
 Need binding proteins for transport
 Protein hormones don’t need binding proteins, but some have
them anyways like (IGF-1)
 If hormone is bound to protein, it increases t1/2 in serum
 Protein/peptide hormones
 o Pre-hormones have signal segment that is cleaved
 Make peptide hormone
 Cleavage done by signal peptidase
o Pre-prohormones are prohormones with signal segment
 Pre-prohormones are stored in golgi vesicles for transport
 Transport to target tissue
 Signal peptidase cleaves signal segment
 converted to active hormone in target tissue
 Usually circulate unbound to transport protein
 Given by injection
 If given PO –→ stomach will digest it
 Usually hydrophilic
 Signals through transmembrane receptors
 Catecholamines
o Modifications of tyrosine
 Tyrosine –→ dopamine –→ EPI, Norepi
o Transport by membrane bound secretory vesicles
o Regulated exocytosis and regulation of enzymatic pathway required
for synthesis
o Transported as free hormone (since hydrophilic)
 Or loosely bound to albumin
o Administered as an aerosol puff or taken orally
o Hydrophilic
 Signal through transmembrane G protein coupled adrenergic
receptors
 Steroid hormones
o Derived from cholesterol
o Lipophilic
 Cannot be stored in secretory granules
o Regulated at level of enzymatic pathway required for their synthesis
o Cholesterol converted to
 Progesterone, cortisol, aldosterone, testosterone, estradiol
 o Steroid hormones are transported in blood bound to transport
proteins (binding globulins)
 Because lipophilic –→ can go into cells easily if not bound to a
transport protein
o Signal through intracellular receptors
 Nuclear hormone receptor family
 Can be given orally
 Characteristics of Thyroid hormones
o Derived from iodination of thyronines
o Lipophilic, but stored in thyroid follicles by covalent attachment to
thyroglobulin
o T4 released into circulation
 Most T4 cleaved ot active T3
 Both can bind thyroid hormone receptor, but T3 has much
higher affinity
o Thyroid hormones are lipophilic, but can be stored in thyroid follicles
as thyroglobulin
o Regulated at level of
 Synthesis
 Iodination
 Secretion
o Transported in blood tightly bound to proteins
o Signal through intracellular receptors
 Nuclear hormone receptor family
o Can be given orally
 Hormone signaling occurs via Cell surface and intracellular receptors
 Adenylate Cyclase MoA
o Hormone binds receptor on Gs
o Alpha subunit dissociates
o Alpha subunit binds and activates adenylate cyclase
o Converts ATP –→ cAMP
o cAMP activates PKA
 o PKA phosphorylates proteins (Action)
 Hormones that use AC-cAMP second messenger system include
o ACTH
o Angiotensin II (epithelial cells)
o Calcitonin
o Catecholamines (binding Beta receptors)
o CRH
o FSH
o Glucagon
o GHRH
o hCG
o LH
o PTH
o Secretin
o Somatostatin
o TSH
o Vasopressin = ADH = AVP (arginine vasopressin) (V2 receptor on
epithelial cells)
 Binds V2 and V1
 V2 found on epithelial cells in nephron –→ use cAMP
 V1 receptors found on smooth muscle –→ don’t use cAMP
 Phospholipase C MoA
o Hormone binds Gq receptor
o Releases alpha subunit
o Alpha subunit activates PLC
o PLC releases PIP2
o PIP2 cleaved into diacylglycerol and IP3
 Diacylglycerol activates PKC –→ action
 IP3 releases Ca from ER and SR
 Ca activates PKC –→ action
 Hormones that use the PLC messenger system
o Angiotensin II (vascular smooth muscle)
 o Catecholamines (a receptors)
o GnRH
o GHRH
 Primarily uses cAMP messenger system
o PTH
o Oxytocin
o TRH
o Vasopressin (V1 receptors on vascular smooth muscle)
 Tyrosine kinase receptor
o Transmembrane receptor binds NGF (nerve growth factor)
 Activates tyrosine kinase
o Insulin receptor activates tyrosine kinase –→ activity
o Includes tyrosine kinase associated receptors
 JAK tyrosine kinase
 Hormones that use Tyrosine Kinase receptor
o FGF
o GH
o HGF
o Insulin
o IGF-1
o Leptin
 Binds receptor
 Activates JAK2 kinase
 JAK2 kinase activates STAT3
 STAT3 goes to nucleus and modifies nuclear signaling
o Prolactin
o VEGF
 Steps involved in steroid hormone mechanism of action
o Steroid hormone binds nuclear receptor
 Receptor has 2 zinc fingers
o DNA binding domain dimerizes and binds to SRE
o Causes altered transcription of new proteins
 o Slow action
o Steroids can also have action by binding membrane only
 Non genomic steroid hormone activity
 Minority of steroid hormone actions
 Most steroid hormones have genomic activity
 Regulation of Hormone Receptors
 Up-regulation
o –↑ synthesis of hormone
o –↓ degradation of hormone
o –↑ activated receptors
o –↓ deactivated receptors
 Downregulation
o –↓ synthesis of hormone
o –↑ degradation of hormone
o –↓ activated receptors
o –↑ inactivated receptors
 Hormone binding proteins
o If you bind a hormone to a protein –→ it can travel farther in the
blood and act on target tissues far away more equally
 Examples of transport proteins
o Corticosteroid binding globulin (transcortin)
 Cortisol
 Aldosterone
o Thyroxine-binding globulin
 Thyroxine
 T3
o Sex hormone binding globulin
 Testosterone,
 Estrogen
o Albumin
 Steroids
 Thyroxine
  T3
o Transthyretin (prealbumin)
 Thyroxine
 Some steroids
 Patterns of secretion
o The pineal gland
 Forms a neuroendocrine link between the
 Suprachiasmatic nucleus and physiological processes that
require circadian control
 Pineal gland forms melatonin
 Pulsatile Secretion of GH
 Increases in amplitude at night
 Cortisol has diurnal variation
 Secretion increases in morning
 Cortisol used for insulin secretion
 Rises in morning to prepare for eating
o Menstrual pattern
 LH, FSH
 Increases during puberty
 Stays there during reproductive years
 Increases in menopause
 Negative feedback short loops and long loops
 o
o Short loops are negative feedback from Ant pituitary on
hypothalamus
o Long loops are negative feedback from hormone on ant pituitary and
hypothalamus
 Positive feedback
 o
o Positive feedback rare, but exists with estrogen on ant pituitary
o Needed for LH surge
 Types of endocrine disorders
o In hyposecretion (hypothyroid)
o Hypothalamus makes TRH –→ ant pituitary TSH –→ Thyroid T3, T4
 Primary hyposecretion is low T3, T4, → ↑ TSH, ↑ TRH
 Secondary hyposecretion is ant pituitary problem,
 Low T3, T4
 Low TSH
 High TRH
 Tertiary hyposecretion is hypothalamus problem
 Everything low
o Hypo-responsiveness of receptors on target tissue is a problem
 E.g. T2DM –→ high insulin, but low responsiveness of tissues
 o Hyper-responsiveness of target tissue also a problem
 Interpretation of thyroid levels
o If –↓ T3, T4, and –↑ TSH
 Primary failure of thyroid organ
o If –↑ T3, T4, and –↑ TSH
 Autonomous secretion of TSH or resistance of tissue to T3/T4
action
o If –↓ T3,T4, and –↓ TSH
 Pituitary failure
o If –↑ T3, T4, and –↓ TSH
 Autonomous secretion of T3, T4 by thyroid
 Endocrine stimulation tests
Hormone Test Result Interpretation
Deficiency
Growth L-Dopa, A lack of Hypothalamic or pituitary
Hormone arginine, insulin Response disorder
stimulation
Gonadotropins GnRH A lack of Hypothalamic or pituitary
(LH, FSH) stimulation response injury or diseases (GnRH
normally increases LH and FSH)
Cortisol ACTH Lack of response Adrenal insufficiency
stimulation to ACTH
Response to Hypothalamic or pituitary
ACTH disease
  Endocrine Suppression Tests
Hormone Test Result Interpretation
overproduced
Growth Oral glucose Lack of Pituitary adenoma
Hormone tolerance suppression
Cortisol Dexamethasone Low dose (lack Cushing’s syndrome (may be false
suppression of suppression) positive in obesity and stress
High dose Pituitary ACTH releasing tumor
suppression (no suppression seen in adrenal or
ectopic Cushing’s)
Aldosterone Isotonic Saline Lack of Aldosterone secreting tumor
infusion suppression

 Causes of Organ hypofunction or Hyperfunction

Organ Hypofunction causes Hyperfunction causes

Pituitary Trauma, surgery, radiation,
ischemia, suppression by
exogenous hormones, congenital
dysgenesis
Endocrine Inadequate trophic hormones,
glands genetic defects, autoimmune
destruction, ischemia, non-
secreting tumors
Exogenous or Sudden withdrawal of exogenous
ectopic sources hormone
Peripheral target Tissue resistance, down-regulation
tissues of receptors, post-receptor defecs
Microadenoma, adenoma,
adenocarcinoma
Excessive trophic hormones,
secreting tumors,
autoimmune stimulation
Excessive hormone
administration, non-
endocrine tumor production
of hormone
003 – Embryology and Anatomy of Endocrine Organs
 Pituitary gland development
o Posterior pituitary ( stalk)
 From neuroectoderm
 Neuroectoderm also contributes to infundibular stalk
o Anterior pituitary (glandular portion)
 From oropharynx ectoderm
o Middle pituitary
 From Rathke’s pouch
 Not useful in humans
 Hypothalamus
o Regulates anterior pituitary output
 Via releasing inhibitory hormones
o Nuclei
 Ventral hypothalamus inhibits and release hormones
 Sends signals
 Gives rise to infundibulum/connecting stalk
 Signals down to anterior/glandular/secretory pituitary
 Paraventricular nuclei
 Have oxytocin and ADH
 Supraoptic nuclei
 Magnocellular –→ large neurons
o Synthesizes 2 hormones
 Exported to posterior pituitary for storage and release
 Oxytocin and ADH
 Pituitary
o Posterior is neural
 AKA Pars Nervosa
 Cells
 Herring bodies –→ store ADH and oxytocin
 Pituicytes –→ Glial cells
o Anterior is glandular/secretory
  AKA Pars Distalis/ adenohypophysis
 Contain Alpha cells, beta cells, chromophores
 Cells
 Somatotropes –→ secrete GH, 50%, acidophil
 Mammotropes/Lactotropes –→ secrete Prolactin, 15%,
acidophil
 Corticotropes –→ secrete ACTH, 15%, basophil
 Gonadotropes –→ secrete FSH, LH, 10%, basophil
 Thyrotropes –→ secrete TSH, 5%, basophil
o Intermediate pituitary/rathke’s pouch is non functional
 AKA Pars intermedia/ neurophysis
 Anterior Pituitary hormones
o GH –→ growth hormone
 Hypersecretion –→ gigantism in children, acromegaly in adults
 Hyposecretion –→ dwarfism
o TSH –→ Thyroid stimulating hormone
 For normal thyroid gland activity
 TRH stimulates TSH release
o ACTH –→ Adrenocorticotropic hormone
 Stimulates adrenal cortexto release corticosteroids
 CRH stimulates ACTH release
o FSH, LH –→ Follicle stimulating hormone, Leutenizing hormone
(gonadotropins)
 Regulate gonad function
 FSH stimulates gamete production
 LH is gonadal hormone
 Posterior Pituitary hormones
o ADH –→ Anti-diuretic hormone, AKA Vasopressin
 Stimulates kidney tubules to reabsorb water
 ADH released in response to high solute concentration in blood
 Hyposecretion seen in T1DM
 Pituitary tumor
 o –↑ somatotropes –→ ↑ GH
o Acromegaly
 Supraorbital protuberance
 Extraoccipital protuberance
 Prognathism
 Thyroid gland development
o Thyroid gland descends
 To base of larynx
o Remnants can become thyroid cysts
 Cysts can be found at
 Foramen cecum
 On hyoid bone
 On thyroid cartilage
 Thyroid follicles are filled with colloid
 Normal variation is pyramidal lobe
o Remnant of thyroglossal duct
 Normal variation is accessory thyroid gland
o Results from migration of thyroid gland down thyroglossal duct
 Arteries of thyroid
o Brachiocephalic trunk –→ External carotid –→ Superior thyroid artery
o Brachiocephalic trunk –→ thyrocervical trunk –→ inferior thyroid art
o Variant
 Brachiocephalic trunk –→ Ima artery (central)
 Veins of thyroid
o Superior, middle, inferior thyroid vein –→ SVC
 Thyroid follicle
o Thyrocytes line follicle
 Make iodine from iodide
 Make T3 and T4
o Follicles store colloid
 Hypothyroidism –→ goiter
 Hyperthyroidism –→ exophthalmos
 Parathyroid Gland development
o Comes from 3rd and 4th pouches
o Inferior parathyroid form 3rd pouch
o Superior parathyroid from 4th pouch
o Inferior parathyroid moves down during development past 4th pouch
o Ultimobranchial body
 Becomes C cells/parafollicular cells
 C cells/Parafollicular cells release calcitonin
 Parathyroid glands
o Secrete PTH
 ↑ osteoclast activity –→ ↑ bone breakdown
 Calcitonin breakdown
 ↑ serum calcium
o Hyperparathyroidism
 Hypercalcemia
 Extreme bone wasting
o Hypoparathyroidism (from thyroidectomy)
 Hypocalcemia
 Tetany
 Respiratory paralysis
o When hypocalcemic
 Principal cells –→ chief cells –→ release PTH
 Arteries of parathyroid (same as thyroid)
o Brachiocephalic trunk –→ External carotid –→ Superior thyroid artery
o Brachiocephalic trunk –→ thyrocervical trunk –→ inferior thyroid art
 Histo of parathyroid
o Thyrocytes
o Follicular cells
o Colloid
o C-cells/Parafollicular cells
 Release calcitonin
o Oxyphils have lots of cytoplasm, dunno what they do
  Adrenal gland development
o Neural tube folding in 5th week
o Neural crest cells become medulla of adrenal gland
o Cortex of adrenal gland comes from mesoderm
 Cortex secretes 3 steroid hormones
 Mineralocorticoids
 Glucocorticoids (Aldosterone)
 Gonadocorticoids
 Adrenal gland 5 layers from outside to inside
o Capsule
o Zona glomerulosa –→ mineralocorticoids exclusively
o Zona fasiculata –→ glucocorticoids (some gonadocorticoids)
o Zona reticularis –→ gonadocorticoids (some glucocorticoids)
o Medulla (from neural crest)
 Produces epinephrine, norepi
 In response to sympathetic stimulation
 Enhances fight/flight response
 Medulla has mostly chromaffin cells

004 – Thyroid Gland Pathology

 Normal thyroid
o 2 lobes joined by isthmus
o Normal variation has pyramidal lobe
 Pyramidal lobe is remnant of thyroglossal duct
 Thyroid embryology
o Originates from foramen cecum
o Then descends, attached to pyramidal duct
o Variations
 Pyramidal lobe (normal)
 Thyroglossal cyst –→ can be subclinical
 Lingual thyroid –→ when thyroid doesn’t migrate completely
o Develops from between 1st and 2nd pharyngeal pouch
 Thyroid histo
o Follicles lined by cuboidal cells (follicular cells or thyrocytes)
 Separated by scant fibrovascular stroma
o Thyroid hormones are collected within the follicle lumen and appear
as an eosinophilic proteinaceous material
 Called colloid
o Find C cells/parafollicular cells in interstitium
 Secrete calcitonin
 C cells from neural crest
 Tag calcitonin to be able to stain C cells
 Hyperthyroidism
o Hyperfunction of thyroid –→ increased T3 and T4
o Sx
 Palpitations, tachycardia
 Nervousness, restlessness
 Weight loss
 Muscle loss, muscle weakness
 Diarrhea, amenorrhea
 Wide gaze –→ due to increased sympathetic tone
o Primary hyperthyroidism is graves disease
 ↑ T3, T4, ↓ TSH
 Hyperfunctioning toxic goiter
 Or hyperfunctioning follicular adenoma
o Secondary hyperthyroid –→ pituitary adenoma
 Uncommon
 Thyrotoxicosis is not the same as hyperthyroid
o Thyrotoxicosis is a hypermetabolic state caused by elevated T3, T4
 Most common cause is hyperthyroidism
 Hyperthyroidism is hyperfunction of thyroid
o Thyrotoxicosis can be caused by other things too
 Subacute granulomatous thyroiditis
 Subacute lymphocytic thyroiditis
  Struma ovarii (ovarian teratoma containing thyroid tissue)
 Facticious thyrotoxicosis (exogenous)
 Types of thyrotoxicosis
o Exogenous (facticious)
 Supplement
o Ectopic endogenous
 Struma ovarii
 Bone metastasis from follicular thyroid cancer
o Thyroid leakage
 Hashimoto (lymphocytic)
 De Quervain (subacute granulomatous)
o Hyperthyroidism
 Graves Disease
 “Toxic” multinodular goiter
 “toxic” follicular adenoma
 Hypothyroidism
o Congenital form is cretinism
 Leads to mental retardation and stunted growth
o Adult form is myxedema
 Due to accumulation of mucopolysaccharideds (GAGs) in skin,
subcu tissue, and viscera
 Mostly Hyaluronic acid
 Attracts water
 Mechanism not fully understood
 Fibroblast stimulation
 Lymphocyte stimulation
o Primary
 Acquired
 Postablative (Radioactive Iodine (RAI), surgery, or
radiation)
 Autoimmune Hashimotos
 Iodine deficiency
  Drugs (lithium, iodides, 5-ASA)
 Congenital
 Iodine deficiency
 Dyshormogenetic goiter: biosynthetic defect (enzymes)
 Thyroid dysgenesis (PAX8, TTF2, TSHR mutations)
o Secondary
 Pituitary failure –→ TSH deficiency
o Tertiary
 Hypothalamic failure –→ TRH deficiency
 Cretinism
o Congenital hypothyroidism
o Endemic or sporadic (screening done)
o Clinical
 Impaired development of skeletal and Nervous systems
 Myxedema
o Acquired hypothyroidism
o Clinical
 CV - ↓ Cardiac output, bradycardia, cardiomegaly
 CNS –→ mental sluggishness, mimics depression
 Cold intolerance, constipation
 Coarse facial features, enlarged tongue, deep voice
 Graves disease
o Most common cause of endogenous hyperthyroidism
o Autoimmune
o Triad
 Hyperthyroidism caused by diffuse hyperplastic goiter
 Infiltrative opthalmopathy with exophthalmos
 Dermopathy (pretibial myxedema)
o Common in women
o HLA B8 and DR3
o Stimulatory autoantibodies against
 TSH receptor
  Thyroid stimulating Ig (IgG against TSH-R –→ drives dz)
 Thyroid growth-stimulating ig (TGI)
o Hypoertrophic fxn –→ goiter
 TSH binding inhibitor Ig (TBII)
o Can cause episodic hypothyroid in graves
 Thyroid peroxisomes (TPI)
 Thyroglobulin
o Gross
 Diffuse enlargement, red beefy parenchyma
o Histo
 Clusters of infolding
 See hyperplasia and hypertrophy of follicular cells
 Follicular cells become columnar
 Leads to scalloped colloid
 Cell eats colloid
 Columnar follicular cells that appear crowded and form
infoldings into center of follicle, “scalloped” colloid
o Opthalmopathy
 Exopthalmos due to T cell mediated autoimmune
phenomenon
 Retroorbital mononuclear cell infiltrate (T lymphocytes)
 Inflammatory edema of extraocular muscles
 Accumulation of ECM (hydrophilic GAGs, hyaluronic acid
mostly)
 Fatty infiltrate
 Diffuse multinodular goiter
o Impaired synthesis of thyroid hormone –→ ↑ TSH
 Enlargement of the gland
 First diffuse
 Then with nodule formation
o If endemic –→ due to iodine deficiency
 If sporadic –→ can be due to goitrogens
o Multinodular goiter cause unknown usually
 Problem with synthesis and secretion of T4
 Decrease in thyroid hormone T4
 Rebound increase in TSH
 Causes diffuse hyperplasia –→ will become lumpy bumpy
 Can cause compression of larynx or swallowing
o Clinically
 Mass effect: cosmetic/obstructive
 Most cases are euthyroid
 Toxic nodule causing hyperthyroidism –→ Plummer syndrome
 Plummer syndrome
 Toxic nodule causing hyperthyroidism
 Also known as toxic mutinodular goiter
 Multinodular goiter + hyperthyroidism
 No infiltrative opthalmopathy or dermopathy
o (vs graves Dz)
 Incidence of malignancy is <5%
o Gross
 Nodularity replaces follicles
 Calcified involution
o On histo
 Hyperplastic nodules
 Not encapsulated
 Follicles vary in size and can consist of colloid rich
follicles with flattened epithelium or hyperplastic
follicles
 Involution changes
 Hemorrhage
 Hemosiderin depositon
 Cysts
 Fibrosis and calcifications are common
 Due to hyperplasia
  No fibrous capsule
 Neoplasia has fibrous capsule
 Hashimoto Thyroiditis
o Most common cause of goitrous hypothyroidism
o Autoimmune
o Linked to HLA DR3 and DR5
o CTLA-4 polymorphisms present
 CTLA-4 is a regulator of T cells
o Higher risk for B-cell non-Hodgkin lymphoma
o And for papillary thyroid carcinoma
o Pathophys
 Breakdown in self-tolerance and induction of thyroid
autoimmunity
 CD8 cytotoxicity
o T cell mediated Cytotoxicity
 CD4 Th1 cells
o Release IFN-gamma
o Activates macrophages
o Thyrocyte injury
 Plasma cells
o Anti-thyroid antibodis
o NK cells bind via Fc receptors
o Ab-dependent cell-meidated cytotoxicity
o Gross
 Diffuse asymmetrical enlargement of gland
 Pale, gry-tan cut surgace
 Fibrosing variant: shrunken fibrotic gland
o Histo
 Thyroid tissue replaced by
 Dense lymphocytic infiltrates with plasma cells
 Shows well developed germinal centers
 Follicular cells present with abundant eosinophilic cytoplasm
  Hurthle cells/oncocytes/oxyphils/Ashkenazi cells present
 Hashimoto Thyroiditis – cytology
 Do FNA
 Mixture of oncocytic cells and follicular cells
 Polymorphous lymphoid population
 Subacute granulomatous thyroiditis (de Quervain)
o Viral infection or post-viral response
o Pain, fever, malaise, variable enlargement og gland
o Thyrotoxicosis may occur followed by hypothyroidism
o Self limited process
o Not autoimmune
o –↑ WBC and ESR
o Histo
 Granulomas seen
 Lots of macrophages
 Giant cells
 Subacute lymphocytic thyroiditis (postpartum)
o Painless neck mass or thyrotoxicosis
o No follicular oncocytic change (vs Hashimotos)
o Lymphocytic infiltrate
 Riedel fibrosing thyroiditis
o Fibrosis adjacent to neck
o Iron collar
o Manifestation of IgG 4 Sclerosing Dz
o Associates with idiopathic fibrosis in other sites
 Solitary thyroid nodule –→ thyroid neoplasms
o Carcinomas are uncommon
o Clues
 Solitary nodule –→ neoplastic
 Very young or old –→ neoplastic
 Male –→ neoplastic
 Hx radiation to neck –→ malignant
  Hot nodule –→ benign
o Do FNA beause thyroid is highly vascularized
 A biopsy leads to clot
 Adenoma
o Follicular adenoma
o Benign neoplasm with follicular cell differentiation
o Solitary nodule
o Gross
 Gray tan soft nodule with thin fibrosing capsule
o Histo
 Closely packed follicles surrounded by intact thin capsule
o Hyperplastic nodules don’t have capsule
o Thin capsule seen as interface between normal thyroid tissue and
neoplastic cells
 Thyroid carcinomas
o Papillary carcinoma
 Any age
 Due to ionizing radiation
 Presentation
 Painless neck nodule
 Palpable neck lymph nodes –→ metastatic dz
 Sometimes palpable neck lymph nodes without palpable
primary tumor
 May look like a fibrous scar
 Multifocal tumor –→ do total thyroidectomy
 Histo
 Papilla
 Has follicular variant (Lindsay tumor)
 Nuclear features:
o Enlargement and clearing
o Pseudoinclusions
o Grooves
 o Shingling
 Respect each other spaces, but there is nuclear
overlapping
o Orphan annie eyes
 Psammoma bodies –→ red little inclusions
 On FNA
 See nuclear grooves
 Nuclear pseudoinclusions
 Wright giemsa stain
 Butt crack/coffee bean/peach cleft
 Cytology
 Cytologic papillae
 Psammoma bodies
 Nuclear pseudoinclusions
 Papillary carcinoma –→ follicular variant
 Coffee bean butt crack peach cleft
o Follicular carcinoma
 Single cold nodule
 Older people
 Females
 Iodine deficient
 Not frequently associated with regional nodal metastasis when
compared to papillary carcinoma
 Has hematogenous metastasis
 Gross
 Thick capsule
 Need to see invasion outside capsule to call cancer
 Histo
 Nuclei lack features of papillary carcinoma
 Lesions form follicles
 Has invasion past fibrous capsule
 Follicular ADENOMA –→ thin capsule, no invasion
  Follicular CARCINOMA –→ Thick capsule, has invasion
 HYPERPLASTIC NODULE –→ no capsule
 Follicular cancer FNA
 Cytology
 Cellular smears
 Follicular arrangement of cells
 No nuclear features of papillary carcinoma
 Cant tell follicular adenoma from follicular carcinoma
 FNA can’t catch invasion
 Anaplastic undifferentiated Thyroid Carcinoma
o Aggressive
o Older women
o Rapidly enlarging bulky neck mass
o Dyspnea, dysphagia, hoarseness
o On histo
 Big cells that look like anything
 Undifferenitiated cells
 Genetics of follicular cell carcinoma
o MAPK –→ Papillary carcinoma
o PI3K-ATK –→ Follicular carcinoma
o Papillary thyroid carcinoma
 BRAF, RAS
 RAS causes follicular variant
o Follicular thyroid carcinoma
 RAS,
 PAX8/PPARy
 Rearrangement inhibits apoptosis
 Promotes independent proliferation
o Anaplastic thyroid carcinoma
 TP53
 Medullary thyroid Carcinoma
o Neuroendocrine neoplasm of parafollicular C cell differentiation
 o Secretes calcitonin
o Can be familial
 MEN2A or MEN2B
 FMTC
 Both are RET mutations
o All in older people except MEN mutations
o Multicentricity and C-cell hyperplasia are features of familial
o Invade locally and metastasize to cervical and mediastinal nodes,
lung, liver, bone
o Gross
 Sporadic –→ unilateral
 Familial –→ Bilateral
o Histo
 Cells in nests, trabeculae
 Stroma containes broad bands of amyloid
o Cytology
 Plasmacytoid or spindle cells
 Cytoplasmic granules
 Granular chromatin
 Amyloid
 Calcitonin IHC
 Wuestions
 Painless cervical lymph node and thyroid mass
o Papillary carcinoma
 Histo of lymphocytes, germinal centers in thyroid
o Hashimoto thyroiditis
 Difficulty swallowing, self limited dz, painful thyroid
o Subacute granulomatous thyroiditis
 Amyloid, basophilic, calcitonin _, mutation in RET
o Medullary carcinoma
 Pt with throid nodule and no thyroid ab
o Pt had radiation to neck
 o Finger like projections in a single thyroid nodule –→ papilla
(fibrovascular core)
o Large clear nuclei that get close together –→ papillary carcinoma
 Macrophages, giant cells, past hx viral illness
o Subacute granulomatous thyroiditis

005 – Thyroid Physiology Overview

 Thyroid is a single layer of cuboidal epithelial cells
o Surround colloid, parafollicular cells produce calcitonin
 Thyroid hormone synthesized and secreted by follicular epithelial cells of
thyroid gland
 To make TH, need dietary
o Tyrosine
o Iodine
 Thyroid hormone synthesis big picture
o Na/I symporter brings Na and I into thyroid cells
o I/Cl exchanger pumps I into colloid
o In colloid
 I + thyroglobulin becomes MIT/DIT by thyroid peroxidase
 Conjugated to Thyroglobulin
o Tyroisine is base of Thyroglobulin
 Thyroid hormone, synthesis, storage, and release
o Synthesis of Thyroglobulin, pushed into colloid
 Happens in RER, golgi
o Na/I cotransport ito basal membrane
o Oxidation of I- to I2 by peroxidase
 Inhibited by PTU
o Organification of I2 to MIT/DIT at apical membrane by peroxidase
o Coupling of MIT/DIT to T3/T4 by peroxidase
o Endocytosis of Thyroglobulin
o Hydrolysis of T3 and T4
 Happens in lysosome
 o T3 and t4 enter circulation
o Deiodination of residual MIT and DIT
o Recycling of I- and thyrosine

o
 Deiodination leads to production of potent hormone T3 and inactive
hormone –→ reverse T3
 Pharm interventions
o Perchlorate/Thiocyanate pertenchnetate
 Inhibit NA/I symporter
o High Iodides
 Inhibit Peroxidase
 Inhibit T3/T4 importer
o PTU
 Inhibits peroxidase
 Activity of thyroid assessed by radioactive iodine uptake (RAIU)
o Extreme stimulation of thyroid gland –→ very fast uptake of RAI
 Then begins to excrete it due to high turnover
o Organification defect
  Low volume uptake
 But fast uptake speed and turnover
 Most Thyroid hormone in body is protein bound and has no biological
activity
o Thyroxibe binding globulin (TBG) binds majority of T4 and lots of T3
o Albumin binds majority of T3 and little T4
o Transthyretin (prealbumin, TBPA) bunds some T4 and little T3
 TSH is best test to assess Thyroid function
o Because changes in TSH can be detected before alterations of levels
of T4, and in bigger magnitude
 Hypothalamic-pituitary-thyroid axis
o In pituitary
 TRH from hypothalamus binds TRH-R in pituitary
 Activates G protein coupled receptor
 Activates PLC
 IP3-Ca++ pathway
 Activates PKC
 TSH secretion from pituitary
o In thyroid
 TSH from Pituitary binds TSH-R
 Activates Gs
 Adenylate Cyclase produces cAMP
 Increased thyroid hormone synthesis
o At level of pituitary
 If increased T3, T4
 ↓ TRH receptors in pituitary
 Increases inactive TSH
 Decreases active TSH
 Key features of Thyroid regulation and fxn
o TSH
 Binds to Gs protein coupled receptor on follicular cells
 Uses AC cAMP second messenger system
  Stimulates thyroid hormone synthesis
 Stimulates iodine uptake and organification
 Promotes thyroid growth
o Thyroid gland
 Can store 2-3 months worth thyroid hormone
 Stored to thyroglobulin
 Produces more T4 than T3
o Thyroid hormone
 Synthesis undernegative feedback from hypothalamic-
pituitary-thyroid axis
 T4 converted to T3 in peripheral tissues
 T3 has better biological activity
 Binds nuclear receptors and modulates gene activity
 Factors affecting thyroid hormone secretion
o Stimulating TH secretion
 TSH
 TSH-R stimulating Igs
 Increased TBG
 Pregnancy
 Increased estradiol
 Increased TBG
 Less free hormone
 Increased TH production
 Increased total TH
o Inhibiting TH secretion
 Iodine deficiency
 Deiodinase deficiency
 Excessive Iodine intake (via wolff chaikoff effect)
 Perchlorate/thiocyanate)
 Inhibit Na/I cotransport
 PTU
 Inhibits peroxidase)
  Decreased TBG
 ↑ free TH
 ↑ negative feedback
 ↓ hormone production
 Thyroid hormone functions
o Growth, maturation of ones and CNS
o –↑ CO2, ↑ ventilation
o –↑ cardiac output
 By upregulation of B1 adrenergic receptors
o –↑ urea output, ↑ renal function
o Basal metabolic rate
 ↑ NAK ATPase
 ↑ O2 consumption
 ↑ Heat
 ↑ BMR
o Metabolism
 ↑ glucose absorption
 ↑ glycogenolysis
 ↑ gluconeogenesis
 ↑ lipolysis
 ↑ protein synthesis and degredation
 Net catabolic effect
 Don’t see an increase in blood glucose because compensatory
increase in insulin
 Thyroid hormone action on CV physiology
o Direct
 ↑ Cardiac muscle heavy chain NAK ATPase
 ↑ B adrenergic sisgnaling via Gs
 ↑ ventricular contractility
 ↓ peripheral vascular resistance
o Indirect
 ↑ heat production and CO2 in tissues
  ↓ Peripeheral vascular resistance
 ↓ Diastolic blood pressure
 Reflex –↑ adrenergic stimulation
 Thyroid hormone increases basal metabolic rate
 Thyroid hormone effect on growth and development
o If treating hypothyroidism after age 4
o Bone and height quickly catch up
o Mental age stays low –→ mental retardation
o Need to treat hypothyroidism ASAP to avoid mental retardation
 Thyroid axis in pregnancy
o TSH
 Normal
 Stimulates TH production
 Slightly lower in pregnant in first trimester due to
stimulatory effects of hCG on thyroid
 Hyperthyroid
 TSH secretion suppressed because of negative feedback
of –↑ TH in circulation
o hCG
 Normal
 hCG synthesized in placenta
 Stimulates TSH-receptor
 Causes mild increase in T4 and fetal T4
 Causes mild decrease in TSH
 Gestational hyperthyroidism
 In women with –↑↑ hCG during normal pregnancy
 Or in pathological pregnancy (molar pregnancy)
 In graves dz, hCH stimulation overshadowed by
stimulatory effect of TSAb
o TSAb
 Not present in healthy people
 Hyperthyroidism (graves dz)
  In graves dz TSAb activates TSH R
 TSAb can pass placenta and cause fetal and neonatal
Graves disease
 Goiter can be seen in hypothyroid, hyperthyroid, and euthyroid states
o Pr imary hyperthyroidism
 Defect in synthesis and release of TH
 ↑ T3, T4
 ↓ TSH, TRH
o Secondary Hyperthyroidism
 Pituitary defect
 ↑ T3,T4, TSH
 ↓ TRH
o Primary hypothyroidism
 Defect in synthesis and release of TH
 ↓ T3, T4
 ↑ TSH, TRH
o Secondary Hypothyrodism
 Pituitary defect
 ↓ T3,T4, TSH
 ↑ TRH
 Physiological effects of thyroid effect
Hypothyroid Hyperthyroid
BMR ↓ ↑
Carbohydrate ↓ Gluconeogenesis ↑ Gluconeogenesis
metabolism ↓ Glycogenolysis ↑ Glycogenolysis
Normal serum glucose Normal serum glucoses
Protein metabolism ↓ Synthesis ↑ Synthesis
↓ Proteolysis ↑ Proteolysis
↑ muscle wasting
Lipid metabolism ↓ Lipogenesis ↑ lipogenesis
↓ Lipolysis ↑ Lipolysis
↑ Serum cholesterol ↓ Serum cholesterol
Thermogenesis ↓ ↑
ANS Normal level of serum ↑ expression of B
catecholamines adrenoreceptors
↑ sensitivity to
catecholamines
Normal serum level of
catecholamines

 Graves dz
o TSAb –→ ↓ TSH, TRH
 Hashimotos
o Destructive thyroid Ab
o –↑ TSH, TRH
 Common causes of hyperthyroidism
o Grave’s Dz
o Toxic Multinodular goiter
o Follicular Adenoma
o Thyroid medication
 DDx of hyperthyroidism
o RAI scan
 Low uptake
 Exogenous thyroid hormone use
 Thyroiditis
o Postpartum, painless, de quervain (viral)
 High uptake or normal
 Graves Dz
 Toxic multinodular goiter
 Toxic adenoma
 Mechanism of hypothyroidism
o Primary thyroid malfunction
 Lack of TH negative feedback on pituitary TSH secretion and
hypothalamic TRH secretion
  ↓ Thyroid hormone, ↑ TSH, TRH
o Pituitary malfunction
 ↓ negative feedback on hypothalamic release of TRH
 ↓ TSH, T3, T4
 ↑ TRH
o Hypothalamic malfunction
 ↓ TRH, TSH, T3, T4

006 – Thyroid Genetics

 Thyroid pathway review
o Thyroglobulin exported into colloid
o Sodium and Iodide symporter
o Iodide –→ basolateral to apical side
o Transported into colloid by Pendrin
o Sodium transports back across basolateral side with ATPase
o Thyroid Peroxidase (TPO) –→ takes Iodide + peroxide and makes
molecular Iodide (I2)
o Iodide + thyroglobulin –→ makes T3 and T4
o Invagination of this part into lysosome –→ thyroglobulin cleaved
o T3 and T4 leave cell on basolateral side
 Congenital hypothyroidism
o Can be transient
o If permanent:
o Primary hypothyroidism
 Thyroid dysgenesis and hypoplasia
 Thyroid hormone dyshormonogenesis
o Secondary Central hypothyroidism
 TSH deficiency
 Often due to congenital hypopituitarism
o Peripheral hypothyroidism
 Thyroid hormone transport, metabolism, action
 Congenital hypothyroidism
 o Asian females
o Usually due to iodine deficiency
o Mostly thyroid dysgenesis and hypoplasia
 Dyshormogenesis possible
o Mostly sporadic
 Thyroid gland dysgenesis
o Syndromic means it has other associated problems
o Non syndromic means just thyroid hypoplasia and hypothyroidism
o Non syndromic –→ TSH receptor problem
 Thyroid hypoplasia, overt hyperthyroidism
o Syndromic (Autosomal Dominant)
 TTF1/NKX2.1
 Mild
 Ataxia, choreoathetosis
 Truncal apraxia
 Mental retardation
 TTF2/FOXE1
 Thyroid Agenesis
 Cleft palate
 Choanal atresia
 Bifid epiglottis
 Spiky hair
 PAX8 transcription factor
 Variable
 ↓ penetrance
 Expressivity
 Thyroid hypoplasia
 AITD
 Gs GNAS1
 TSH resistance
 Short
 Brachydactyly
  Ectopic calcifications
 Non-syndromic Dyshormogensis
o Autosomal recessive
o Normal at birth
o Prolonged jaundice, Feeding problems
o Umbilical hernia, Macroglossia
o Permanent Neurological damage without treatment by 3
 Have newborn screening for Congenital hypothyroidism
o Screen for TSH, and T4
o If normal, stop
o If high, repeat after 1 wwk –→ if TSH still high T4 low –→ treatment
o If TSH high, T4 normal –→ hypothyroid probable
 Do ultrasound of thyroid
 Normal/goiter
o Maternal autoimmune
o Transient congenital hypothyroid
 Thyroid dysgenesis
o With Cleft palate, spiky hair –→ FOXE1 gene
o With muscle hypotonia/pulm sx –→ NKX2-1 gene
o With renal malformation –→ PAX8 gene
o With Heart defect –→ NKX2-5 gene
 Treatment of genetic disease
o Avoidance
o Dietary restriction
o Replacement
o Diversion, inhibition, Depletion
 Question
o What is risk that couple’s baby will be affected if nephew has
thyroiditis (sibling is possibly carrier)
o Incidence is 1/2500 = q squared
 Q=1/50
 2pq = 1/25
 o Chance of child having dz = 1/25 (chance dad is a carrier) *1/2
(chance mom is carrier)*1/4 (chance homozygous recessive) = dz
 Autoimmune Thyroid Disease (AITD)
o Graves Disease (GD)
 Fatigue or muscle weakness
 Thinning skin, fine brittle hair
 Problems getting pregnant
 Weight loss
 ↑ Heart rate
 Heat sensitivity, increased sweating
 Light menstrual flow and less frequent periods
 Frequent bowel movements
o Hashimoto’s Thyroiditis (HT)
 Fatigue
 Dry thin hair
 Problems getting pregnant
 Weight gain
 ↓ Heart rate
 Feeling cold
 Heavy/irregular periods
 Constipation
 Is AITD genetic?
o 33% recurrence risk of siblings
o Sibling ratio lambda = 16.9
 GD = 12
 HT = 28
 Liability threshold
o –↑ incidence of AITD in females
o Lower genetic load needed in females
o Daughters of affected fathers most affected


 GD vs HT (HLA-DRB1*03)
Graves Disease Hashimoto Thyroiditis
Phenotype Hyperthyroidism Hypothyroidism
AutoAb a-TSH-Receptor Thyroid Peroxidase
stimulator (TPO)
Thyroglobulin (Tg)
MHC Susceptibility DRB1 03 (DR3) DRB1 03 (DR3)
MHC protective DRB1 03 (DR3) DRB1 03 (DR3)

 HLA-DRB1*03
o Codes for binding pocket
o Mutation at same site can be protective or susceptible depending on
what the mutation was
 AITD other genetic susceptibility loci
o CTLA-4 (microsatellite)
o CD40
o PTPN 22
o Thyroglobulin
o TSH-$
 AITD environmental factors
o Iodine
o Amiodarone (iodine rich)
o Anti-retroviral therapy
o IFN-alpha
o Infections
 AITD + T1D = APS3v mutation
o Autoimmune polyglandular syndrome 3 variant
o T1D patients with ant-TPO and anti-Tg Ab
 AITD susceptibility
o AITD patients with islet cell antibodies
 T1D susceptibility
 o Age dependent penetrance of T1D patients with Anti-TPO and anti-
TG Ab
 Onset is 15-20 y/o
o Family studies
 T1D first degree relatives
 10% have islet cell Ab
 15% have anti-TPO or Anti-TG
 Familial autoimmune Diabetes
 In female Diabetic probands
 Hypothyroidism seen in 60% of T1D cases
 Hypothyroidism seen in 33% of female relatives of T1D

007 – Pathophysiology Abnormalities of Thyroid Function

 Clinical presentations of Thyroid disease
o Thyroid fxn
 Thyrotoxicosis
 Hypothyroidism
 Euthyroid
o Thyroid gland
 Diffuse multinodular goiter
 Toxic
 Non functioning
 Solitary nodule
 Normal
o Lab abnormality only
 Thyrotoxicosis is high T3 and T4 only
o Don’t know why
 Hyperthyroid = true increased production and secretion of TH
 Regulation of TH production
o TRH from hypothalamus
o TRH –→ ↑ TSH secretion from pituitary
o TSH –→ ↑ Production and secretion of T3 and T4 by thyroid gland
 o T3 and T4 give negative feedback to secretion of TSH
 Directly on pituitary
 Indirectly on HT –→ ↓ TRH –→ ↓ TSH
o T4 converted to T3 in liver and other tissues by deiodinase
o Some T4 and T3 conjugated with glucuronide and sulfate in liver
 For excretion in bile
 Partially hydrolyzed in intestine
o Some T3 and T4 formed in intestine
 May be reabsorbed
 Differential Diagnosis of Thyrotoxicosis
o Exogenous
 Thyroid Supplements
 Levothyroxine
 Iodine
o Endogenous ectopic
 Struma ovarii –→ a teratoma of thyroid tissue in ovaries
 Bony mets from follicular thyroid cancer
o Hormone leakage
 Thyroiditis
 T3 and T4 has a t1/2 of 1 week
 Takes a month to get pt feeling normal again
o Overproduction
 Toxic nodule/multinodular goiter
 Grave’s Dz
 Hashitoxicosis
 Starts with Hashimoto’s dz
o Ab inhibiting TSH release
 Some pt have both stimulating and inhibiting TSH
release
 Depending on which Ab dominated –→ can get
thyrotoxicosis in background of hashimotos
 Hyperthyroidism
 o Clinical hyperthyroidism –→ ↓ TSH, ↑ T3, T4
 Pituitary knows TH is high
o Subclinical hyperthyroidism –→ ↓ TSH, nl T3, T4
 If T3 and T4 have changed by a bit (not outside range)
 But changed enough for pituitary to realize and decrease TSH
release
 Grave’s Dz
o Ab that causes a range of symptoms including hyperthyroidism
o Classic triad
 Hyperthyroidism
 Grave’s opthalmopathy
 Dermatopathy (pretibial myxedema)
o Results from stimulatory TSH-Receptor Ab (TRAB)
 Stimulatory autoantibodies against TSH receptor
o Ab seen
 TSH Receptor Antibodies (TRAB)
 Stimulatory and inhibitory
 Can have both
 Inhibitory TRAB prevalent in Hashimotos
 Some pt can change from Graves to Hashimotos and
back (Hashitoxicosis)
 TPO-Ab –→ Hashimoto’s only
 TG-Ab –→ Hashimotos only
o Regarding levels of T3 and T4
 Can have one or both hormones elevated
o Physical findings on Grave’s Dz
 Thyroid
 Smooth consistency (can be nodular)
 Symmetrical
 Firm, but elastic diffusely
o Becomes very firm if iodide given
 Hear Bruits on auscultation
 o Sign of turbulence due to increased blood flow
 Thrill vibrations felt over thyroid on palpation
 Diffuse goiter found in majority of pt
 Opthalmopathy
 Exopthalmos + periorbital edema
 Widened palpebral fissure (wide gaze)
o Because muscles are overexcited
 Periorbital edema
o Due to increased concentration of GAGs
o Mostly hyaluronic acid
 Proptosis = exopthalmos
 Chemosis
 Conjunctival injection
 Not always symmetrical
 Signs of thyroid hormone excess
o Lid retraction
o Lid lag –→ over contraction of levator palpebrae
muscles of eyelids
o Stare
 Graves optalmopathy is better called Grave’s
orbitopathy
o Due to autoimmune disease of retro-orbital
tissues
 Pathogenesis of opthalmopathy/orbitopathy in Grave’s
o Cellular proliferation, inflammation
o Accumulation of hydrophilic GAGs
o Mostly hyaluronic acid
o Volume of extraocular muscles and retroorbital
connective and adipose tissue is increased
o Temporal relationship
 20% get opthalmopathy before
hyperthyroidism
  40% get opthalmopathy and
hyperthyroidism together
 20% get opthalmopathy after onset of
hyperthyroidism
 20% get opthalmopathy when
hyperthyroidism is treated with RAI
 RAI can trigger Grave’s
opthalmopathy or make it worse
 Rare cases of Grave’s opthalmopathy that are euthyroid
while TRAB +
 Grave’s opthalmopathy Risk factors
o Women more often
o Men more severe
o Smoking
o RAI treatment
o –↑ Age
o Stress
 Grave’s opthalmopathy symptoms
o Irritation of eyes
o –↑ tearing made worse by
 Cold air, wind, bright light
o Retroorbital discomfort/pain
o Blurred vision
o Diplopia
o Loss of vision
 Eye signs of thyroid hormone excess
o Lid retraction, Lid lag, Stare
o Due to sympathetic overactivity
o Mediated by –↑ alpha-adrenergic receptors
o Contraction of levator palpebrae muscles on
eyelids
o Improve once hyperthyroidism is treated
 o Lid lag is when upper lid is slow to follow the
movement of the gaze downward
 Treatment of Grave’s opthalmopathy
o Reversal of hyperthyroidism
 Anti-thyroid medication (methimazole, PTU)
 Surgery –→ thyroidectomy –→ may lead to
disappearance of antibodies (TRAB)
 RAI –→ can worsen Grave’s opthalmopathy
 Avoid
o Symptomatic Tx
 Corticosteroid
 Retroorbitoal radiation
 Orbital decompression surgery
 Eye shades, artificial tears
 Elevation of bed at night
 Dark shades for photophobia
o Workflow of Grave’s orbitopathy treatment
 If very mild –→ no tx needed
 Pill (Methimazole, PTU) workfastest
 RAI can take longer to work –→ worsens
orbitopathy
 Methimazole is first line –→ PTU more toxic
 Cant give Methimazole in 1st trimester of
pregnancy –→ aplasia cutis in baby –→ use
PTU
 PTU has black box warning –→ liver toxicity
 In surgery –→ remove thyroid –→
disappearance of Ab
 If in pregnant –→ watch out if TRAB are
going to baby –→ if they are –→
thyroidectomy to remove Ab
o Grave’s opthalmopathy aggressive treatment
 Steroids
  Rituximab
 External orbital radiation
 Orbital decompression surgery
 Corrective eyelid surgery
 Pretibial Myxedema in Grave’s Dz
 Localized myxedema, thyroid dermatopathy, infiltrative
dermatopathy
 Rare
 Only found in Grave’s hyperthyroidism
 Accumulation of GAGs (hyaluronic acid)
o Secreted by fibroblasts
o Fibroblasts stimulated by cytokines
 Raised hyperpigmented papules
 Violaceous, orange peel textured papules
 More common in pt w/ Graves and Grave’
opthalmopathy
 Rare in pt w/ no thyroid dysfxn or in Hashimoto
 Pretibial myxedema Risks
o Smoking
o Weight gain
o –↑ thyroid hormone
 Indications for tx
o Pruritus, discomfort
 Treatment for pretibial myxedema
o Avoid tobacco
o Weight loss
o Reversal of hyperthyroidism
o Compression stockings to improve lymphedema
o Pharmacology
 Topical steroids
 Pentoxifulline, Rituximab
 Plasmapheresis, IVIG
 Toxic adenoma/Toxic Multinodular Goiter
o Do ultrasound if see goiter
o Give RAI (not cytotoxic) for iodine scan
 Can tell if multinodule, single nodule
 If single nodule –→ Can tell if hot or cold
 Cold –→ neoplasia
 Hot –→ toxic nodule
 Approach to treatment of hyperthyroidism
o Direct at specific etiology
 Reduce synthesis and secretion
 Thionamides
 Surgery
 RAI
 Steroids
 Iodine
 Treat systemic disturbances
 Beta blockers
 Remove hormone from circulation
 Cholestyramine
 Plasmapharesis
o Need to treat
 Increased blood flow
 Tachycardia
 Weight loss
 Hyper-rigidity
 Tremors
 Osteoporosis
o In thyroid storm
 Give steroids for thyrotoxicosis
 Give B blockers to calm down CV disturbance
 Give cholestyramine to remove hormone from circulation (in
bile salts)
 Thionamides
o PTU and Methimaxole both inhibit peroxidase
o Peroxidase inhibits release of newly synthesized TH into system
 Beta blockers
o Propanolol used→ nonselective
o Propanolol at high doses
 Inhibits conversion of T4→ T3
 But slow onset
o Can be given prior to RAI uptake and scan
 Distinguish between thyrotoxicosis and hyperthyroidism
 Do RAI
 No uptake in thyroiditis and isolated thyrotoxicosis
 In true hyperthyroid –→ lots of uptake with RAI
 Can buy time for pt w/ B blockers
 Radioactive Iodine (RAI)
o Potentially worsens opthalmopathy
 Prevent with steroids
o Transient worsening of hyperthyroidism
o Takes months for full effect
o Irreversible
o Radiation
o 10-20% treatment failure
 Surgery
o Good for
 Toxic multinodular goiter
 Graves disease
 Toxic adenoma
o Risk of damaging recurrent laryngeal nerve
 Leads to hoarseness
 Thyroid storm
o Clinical picture
 CNS
 Hyperactivity
 Rapid speech
 Stare (lid retraction)
 Lid lag
 CV
 Tachycardia
 Hyperdynamic precordium
 Systolic hypertension
 Widened pulse pressure
 Other
 Warm and moist skin
 Thin and fine hair
 Tremor
 Hyperreflexia
 Proximal muscle weakness
o Hormone levels do not dictate thyroid storm –→ it is a clinical
diagnosis
 Endocrine DDx includes Pheochromocytoma –→ do 24hr
menenephrines
 Can also look like hypertensive
encephalopathy/meningitis/hypoglycemia
 Thyroiditis
o Thyroid inflammation
o Categorized based on pain
o Painful thyroiditis
 Subacute thyroiditis
 Infectious thyroiditis
 Traumatic thyroiditis
 Radiation thyroiditis
 o Painless thyroiditis
 Painless thyroiditis
 Post-partum thyroiditis
 Drug induced thyroiditis
 Fibrous thyroiditis
 Painful thyroiditis
o Subacute thyroiditis
 AKA Subacute granulomatous thyroiditis = subacute
nonsuppurative thyroiditis = De Quervain thyroiditis
 Viral/post-viral inflammatory process
 Not Ab mediated
 3 phases
 Initial event damages thyroid
 Get –↑ Thyroid hormone in blood
 Body gets rid of thyroid hormones (normal)
 Thyroid remains broken
o If thyroid cells broken –→ no RAI uptake
o If 1 or2 affected spots –→ nodular uptake
o If Ab mediated –→ diffusely increased uptake
o In inflammatory thyroiditis –→ no RAI uptake
 Stages
 Hyperthyroid stage
o 0-4 months
o Inflammation leads to leakage of hormones and
hormone excess
o –↑ T3, T4
o –↓ TSH
o –↓ RAI uptake
 Hypothyroid stage
o 4-7 months
o Hormone levels exhausted
o –↓ T3, T4
 o –↑↑ TSH
o –↑↑ RAI uptake
 Recovery to euthyroid sage
 Treatment of subacute thyroiditis
 B blockers for palpitations, anxiety, tremors
 NSAIDS
 Steroids
 Should improve in 1-2 days
o Infectious thyroiditis
 Acute
 Hematogenous spread in immunocompromised pt
 Spread via fistula from piriform sinus adjacent to larynx
 Sudden neck pain, unilateral pain, fever
 Mass felt
o Unilateral, fluctuant, febrile
 Labs
o TH elevated or nl
 Can do thyroid US or FNA
 Abscess is main complication
 Chronic
 In immunocompromised pt
 Mycobacterial, fungal, pneumocystis
o Radiation Thyroiditis
 Post RAI treatment for Grave’s dz
 5-10 days post treatment
 RAI induced injury and necrosis of follicular cells and
associated inflammation
 Possible transient exacerbation of existing hyperthyroidism
o Traumatic thyroiditis
 Thyroid biopsy or neck surgery
 Car accident
 Transient pain and transient hyperthyroidism
 Painless thyroiditis
o Hashimoto’s thyroiditis
 AKA Chronic Autoimmune thyroiditis
 Intense lymphocytic infiltration of thyroid
 Struma lymphomatosa
o Painless thyroiditis
 AKA Silent thyroiditis = Lymphocytic thyroiditis
 Variation of Hashimoto’s chronic autoimmune thyroiditis
 Caused by
 Hashimotos Or
 Drugs (IFN alpha, IL-2, lithium)
 Transient hyperthyroidism
 Followed by transient hypothyroidism
 Then recovery
o Post-partum thyroiditis
 Occurs within 1 year after giving birth or abortion
 Clinically similar to painless thyroiditis
 ↑ level of thyroid Ab
 ↑ concentration of Ab –→ ↑ chance of permanent
thyroid disease
 Can be more aggressive than painless thyroidits
 If low T3/T4 –→ give hormone
o Drug induced thyroiditis
 IFN-alpha
 Risk is greater in pt who had pre-existing thyroid Ab
 Amiodarone
 Contains Iodine
 Lipophilic
o Concentrates in adipose, cardiac/skeletal muscle
o And concentrates in thyroid
 T1/2 is 100 days
o Toxicity can occur long after drug withdrawal
  Lithium
 Inhibition of TH secretion
 ↓ T3, T4 –→ ↑ TSH
o Body overcomes and secretes correct T3, T4
 New steady state –→ enlarged thyroid gland
 Can result in hypothyroidism or hyperthyroidism
 Tyrosine kinase inhibitors (cancer medication)
 Rare –→ can cause destructive thyroiditis
 Amiodarone induced thyroiditis or thyrotoxicosis
o Amiodarone contains Iodine
o Lipophilic
 Concentrates in adipose, cardiac/skeletal muscle
 And concentrates in thyroid
o T1/2 is 100 days
 Toxicity can occur long after drug withdrawal
o Amiodarone can cause thyroiditis or thyrotoxicosis (AIT)
 Amiodarone induced hypothyroidism
 Via anti-thyroid action iodine
 Especially in pre-existing thyroid disease
 Due to Wolff-Chaikoff effect
 Amiodarone induced thyrotoxicosis 1 (AIT1)
 Increased synthesis of TH
 In pt w/ pre-existing nodular goiter or latent Grave’s
 Occurs early
 Jod-Brasedow effect
 Amiodarone induced thyrotoxicosis 2 (AIT2)
 Destructive thyroiditis
 Release of TH is late
 Due due amiodarone’s toxic effect on thyroid cells
 o Amiodarone induced thyrotoxicosis (hyperthyroidism
 AIT1 –→ ↑ synthesis of TH
 MNG or latent Graves’ disease
 Occurs early
 In iodine insufficient areas
 RAI sacn detectible
 Thyroglobulin is high
 IL-6 is low
 Increased vascularity
 AIT2 –→ Destructive thyroiditis
 Occurs late
 In iodine sufficient areas
 RAI scan undetectable
 Thyroglobulin is low
 IL-6 is high
 Wolff-Chaikoff effect
o In destructive hyperthyroidism
o Thyroid cells try to protect themselves
o Stops iodide from coming in
o Cell remains damaged
o Abnormal thyroid cells can’t escape
 Chronic hypothyroidism
o During initial iodine exposure
 Excess iodine is transported into thyroid by Na/I symporter
 This results in transient inhibition TPO (thyroid peroxidase)
 Leads to transient –↓ synthesized Thyroid hormone
o Adaptation
 A decrease in the expression of Na/I symporters
 Results in reduced iodine transport until
 Intrathyroidal iodine stores return to normal
 This enables TH synthesis to continue
  Abnormal thyroid glands can’t escape chronic
hypoparathyroidism
 Iodine induced Hyperthyroidism –→ Jod-Basedow effect
o Thyrotoxicosis from underlying autonomy in thyroid gland
o Iodine supply increases
 Autonomous areas produce thyroid hormone independent of
normal regulatory mechanisms
 Pt may have subclinical hyperthyroidism before iodine
repletion (grave’s dz or toxic nodular goiter)
o Once you give IV contrast with iodine
 Pt is overloaded with iodine
 Can’t do RAI anymore
 Need to use pills or surgery at that point
 Painless fibrous thyroiditis
o AKA Riedel’s thyroiditis = invasive thyroiditis
o Usually from systemic fibrosing disease
o Extensive fibrosis and macrophage and eosinophil infiltration of
thyroid gland that extends into adjacent tissues
o Need to evaluate for mediastinal/retro-peritoneal fibrosis
o Neck tightness and discomfort
 Diffuse/asymmetric goiter that is very hard, fixed and often
not clearly separated from surrounding tissues
o Fibrosis can also involve
 Parathyroid glands –→ hypoparathyroidism
 Difficult to treat
 Give PTH –→ needto give Ca and Vit D concurrently
 Recurrent laryngeal nerve –→ (hoarseness)
 Trachea –→ compression
 Hypothyroidism
o Congenital –→ cretinism
 Protruding tongue
 Coarse facies
  Umbilical hernia
o Childhood
 Mental retardation
 Short stature
 Deafness
 Myxedema
o Mechanisms
 Slowing of metabolic processes
 Accumulation of matrix substances
o Hypothyroidism on physical exam
 Dry cold scaling skin/hair
 Bradycardia, cardiac enlargement
 Hyporeflexia w/delayed relaxation phase, muscle weakness,
slow speech
 Psych = decreased cognition
 Myxedemetous changes –→ pretibial edema, slow speech,
hoarseness
o Labs
 Clinical –→ ↑ TSH, ↓ T3,T4
 Subclinical –→ ↑ TSH, nl T3, T4
o Types of Acquired hypothyroidism
 Primary
 Autoimmune = Hashimotos
 Iatrogenic
 Infectious
 Environmental (iodine deficiency)
 Secondary
 TSH deficiency
o Can look normal since TSH could be normal for
that pt
 Tertiary
 TRH deficiency
 Primary autoimmune Hashimoto’s hypothyroidism
o Common in iodine sufficient areas
o Clusters in families
o Female
o Pathophysiology
 Cell and Ab-mediated destruction of thyroid tissue
 Cytotoxic T cells AND
 Antibodies
 TPO –→ Thyroid peroxidase
 Tg –→ Thyroglobulin
 TRAB –→ inhibitory
o Clinical presentation
 Hypothyroidism and painless goiter
o Chronic lymphocytic infiltration with Anti-TPO Ab
 Early –→ diffusely enlarged, firm rubbery, nodular
 Possible transient hashitoxicosis
 Late –→ atrophic, fibrotic
o Many phenotypes
 Goiter or no goiter
 See lymphocytic infiltration in thyroid
 Hypothyroidism or nl function
 All pt have high titers of
 TPO Ab
 Tg Ab
 TSH Ab/TRAB
o Clinical
 Gradual thyroid failure due to autoimmune destruction of
gland
 Apoptosis of thyroid epithelial cells
 With or without goiter
 Women get it more often
 Possible transient hyperthyroidism (hashitoxicosis)
 o Autoimmune associations with hashimoto’s dz
 Endocrine Disorders
 T1D
 Adrenal insufficiency (addison’s disease)
 Orchiditis/oophoritis autoimmune
 Hypoparathyroidism
 Nonendocrine disorders
 Pernicious anemia
 SLS
 RA
 ITP
 Temporal arteritis
 Sjogrens
 PBC
 If pt has adrenal insufficiency and you give them thyroid
hormone
 Their TSH is already high
 Levothyroxine can push them over the top
 Make em crash
 Iatrogenic hypothyroidism
o Due to surgical thyroidectomy
 Can be transient or permanent
 Give them thyroid hormone after thyroidectomy
o Radiation
 RAI or
 External neck radiation
 Need to give higher dose of radiation if thyroid is less active –
→ less uptake by thyroid –→ thyroid can come back with a
vengeance
o Exogenous
 Amiodarone, supplements, iodine
 Transient forms of thyroiditis
 o Silent thyroiditis
o Post partum thyroiditis
 Can be transient hyperthyroid followed by transient
hypothyroid
o Post sub total thyroidectomy
 Might recover in a fey months, likely due to TSH-stimulated
cell growth
 Myxedema coma
o Severe untreated end stage hypothyroidism
o Precipitated by
 Illness (MI, CVA, infections)
 Cold exposure
 Medications
o Clinical
 Bradycardia and CHF
 Alveolar hypoventilation –→ (CO2 retention with respiratory
acidosis)
 Hyponatremia, hypoglycemia, hypothermia
 Decreased mental status, obtundation, coma
 Treatment of hypothyroidism
o Can give T4 and T3 or T4
o Never give T3 on its own
o If pt doesn’t feel good after T4, can add a little T3
o Most thyroid supplements have both T3 and t4
o Never use T3 in pregnant women since fetus doesn’t get the benefit
 Only T4 can cross the placenta
o Conversion of T4 to T3 happens outside thyroid
 So no big deal to just give T4
 For dose adjustments
o Check TSH 4 weeks after dose change for primary hypothyroidism
o Check free T4 for secondary or tertiary hypothyroidism
 Not as reliable as TSH
  Drugs affecting Levothyroxine absorption
o Calcium
o Cholestyramine and colestipol
o Sucralfate
o Ferrous sulfate
o Raloxifene
o Ciprofloxacine
o Aluminum
 Drugs that increase thyroid hormone metabolism
o Phenobarbital
o Rifampin
 Increased deiodinatoin of T4 and T3 by stimulation of hepatid
drug metabolizing system
o Phenytoin
o Carbamazepine
 Increase thyroid hormone metabolism and displaces thyroid
hormones from the serum binding proteins
 Mainly TBG

008 – Goiter, Thyroid Nodules, and Thyroid-Function Testing (TFT) +

Application
 TSH is main thyroid function test
 Total T4 = free T4 + T4 bound to TBG
o Used to confirm TSH
 Total T3 = free T3 + T3 bound to TBG
o Used to confirm TSh
 Free T3 and T4
o Used to interpret abnormal total T3 and T4 levels in pt who may have
TBG alterations
 Thyroid Ab
o TPO –→ hypothyroidism
o TG –→ hypothyroidism
 o TRAB –→ hypo or hyper
 What tests to use
o In low index of suspicion
 TSH, free T4
o In high index of suspicion
 TSH, Free, T3,
 Free T4, Thyroid Ab
 TSH is most sensitive
o Evaluated by Radioiummunoassay or immunoassay
 RIA/IMA
 IMA has –↑ sensitivity
o For every change in free T4 –→ get logarithmic response in TSH
o Normal TSH rules out thyroid abnormality except in
 1st trimester pregnancy
 Pt with comorbidities
 Pituitary disease
 Hypothalamic disease
 Certain drugs
 Steroid use
 Dopamine/bromocriptine use
 TSH still remains detectable, (but in true
hyperthyroidism, TSH can be suppressed beneath
detection limit)
 Biotin can also lower TSH and increase T4/T3
 Total T4
o Order to confirm abnormal TSH
o Affected by
 TBG levels
 Drugs that displace T4 from TBG (salicylates, phenytoin, Lasix,
heparin)
 Total T4
o Confirm abnormal TSH
 o Investigate suspected elevated T3 toxicosis when T4 is normal
 To monitor hypothyroidism
o Primary –→ TSH
o Secondary/tertiary –→ Free T4
o Thyroid cancer patients have different treatment goals
o Pregnant patient –→ frequent monitoring
 Estrogen –→ ↑ TBG –→ ↑ total T3, T4, but normal free T3, T4
 Androgens –→ ↓ TBG
 Can get estrogens from OCP or pregnancy
 To monitor hyperthyroidism
o TSH, free T4, T3
o Because TSh might remain subnormal for weeks or months when TH
improves
 Resin T3 uptake test
o Indirect way to measure free T4
o Add radiolabeled T3 tracer to pt serum
o Labeled T3 binds available binding sites on TBG
o Exchange resin is added and the
 Labeled T3 NOT bound to TBG is absorbed into resin
o Result is reported as percent of tracer bound to resin as an uptake
ratio
o Amount of leftover radiolabeled T3 from resin approximates amount
of free T4 (which was on TBG)
o Reported as
 Thyroid hormone biding ration (THBR) or thyroid hormone
binding index (THBI)
 Which is the ratio of T3 resin uptake to the mean of values in
normal subjects
 The mean THBI is by definition 1.00, with a normal range 0.83-
1.16
 Serum free T4 index approximates the free T4
 Serum total x THBI
  Radiolabeled T3 binds unoccupied TBG
 Leftover binds resin
 Normal is 25-35%
 Resin T3 uptake test question
Total T4 T3 Resin Uptake THBI Free T4
Hyperthyroidism High High High
Hypothyroidism Low Low Low
High TBG High Low Normal
Low TBG Low High Normal

o In High TBG
 Free T4 is normal because it is a higher total T4 with a lower
THBI
o In low TBG
 Free T4 is is normal because it is a lower T4 with a higher THBI
 Thyroid hormone transport
o Most T4 and T3 is bound to plasma protein
o TBG = 70%
o Transthyretin = 10%
o Albumin = 15%
 Euthyroid hyperthyroxinemia
o –↑ TBG
 Due to estrogens, hepatitis, drugs
o –↑ Trasthyretin binding
 Paraneoplastic by hepatic and pancreatic tumors
o –↓ T4 to T3 conversion
 Systemic illness, drugs
 Amiodarone, propranolol, steroids, contrast use
 Euthyroid hypothyroxinemia
o –↓ TBG
 Due to androgens, drugs
o –↑ TBG clearance
  Nephrotic syndrome, severe liver disease, loss of protine
o Systemic illness
o Medication
 Phenytoin, carbamazepine
 Diseases and conditions altering TBG levels
o Total T3 and T4 changes while free levels are unchanged
o Increased TBG from
 Pregnancy, estrogen, OCP
 Genetic, drugs
o Decreased TBG from
 Systemic illness
 Steroid use
 Androgens
 Nephrotic syndrome
 Liver failure
 Malnutrition
 Sick euthyroid syndrome
o Transient acquired central hypothyroidism
o Don’t check TFTs in a critically ill patient unless strong suspicion of
thyroid problem
o TSH is not enough
o In sick pt
 More T4 converted to reverse T3
 Reverse T3 is inactive
 Sick euthyroid
o Increased reverse T3 (rT3) in nonthyroidal illness
o Labs
 ↓ T3
 ↑ rT3
 ↓ TSH
 ↓ T4
o T4 converted to T3 by D1/D2 5’ deiodinase
o T4 converted to rT3 by D3 5 deiodinase
 o In sick euthyroid syndrome
 D3 is increased –→ ↑ rT3 formed
 Inhibition of D1/D2 5’ deiodinase
o T4 levels in sick euthyroid syndrome
 ↓TBG –→ ↓ total T4
 Free T4 not reliable
o –↓ TSH in sick euthyroid
 Pt may get transiently high TSH in recovery
 Thyroid function in pregnancy
o In 1st trimester
 ↓ TSH, ↑ total T4
o In 2nd and 3rd trimester
 Gradual return of TSH toward normal
 Total T4 remains high
o TBG increases in pregnancy –→ ↑ total T4
o hCG from placenta stimulates TSH
o Thyroid adaptation during pregnancy
 Stimulation of the TSH receptor by hCG
 Increase in TBG by week 7
o hCG and thyroid function
 hCG is a glycoprotein
 shares a common alpha subunit with TSH
 hCG peaks at 10-12 weeks
 hCG binds TSH-R –→ more hormone produced
 negative geedback on pituitary –→ ↓ TSH (minor)
 Total T4 and T4 increase due to –↑ TBG
 Free T4 and T3 slightly increase
 TSH reduced
o Increase in TBG
 Estrogen increases production of TBG
 T4 and T4 production increases to maintain normal free T3 and
T4
 High total T3 and T4 in first hald of pregnancy
  Plateau by week 16-20
o Tests in pregnancy
 TSH
 Low in first trimester 0.4-0.5
 Gradual increase in 2nd and 3rd trimester
 Free T4 with trimester specific ranges
 Total T4
 TBG is a thyroid hormone transport protein
o rT3 is inactive thyroid hormone
o Iodine enters follicle by symport
o TRH stimulates pituitary
o Majority of T3 is produced in periphery
 T4 converted to T3 in periphery
 In exogenous levothyroxine use
o –↓ TSH
o –↑ total T4
o –↑ free T4
 In Hypothyroid goiter
o –↑ TSH
o –↓ total T4
o –↓ free T4
 If TSH is high
o Primary hypothyroidism
o Pregnancy is distractor
 In nephrotic problems
o –↓ TBG
o –↓ total T4
o Normal TSH
 Goiter
o Any thyroid enlargement characterized by uniform or selective
(restricted) growth of thyroid tissue)
o Can present
  Asymptomatic
 Thyroid dysfnxn
 Obstructive problems
o History
 Fam hx MEN2A/2B
 MEN1
o Parathyroid, pituitary, GI
 MEN2A
o Medullary thyroid carcinoma, parathyroid
hyperplasia, pheochromocytoma
 MEN2B
o Medullary thyroid carcinoma,
pheochromocytoma, neuromas
 Hx head and neck radiation
 Obstructive sx
 Dysphagia
 Cough/dyspnea
 Hoarsness due to compression of recurrent laryngeal
nerve
 Mechanical complications of goiters
o Displacement and/or obstruction
 Trachea
 Esophagus
 Jugular vein compression
o Nerve compression
 Horner’s syndrome –→ cervical sympathetic chain
compression
 Phrenic nerve compression
 Hoarseness –→ recurrent laryngeal nerve compression
o Horner syndrome
 Compression of cervical sympathetic chain
  Ptosis (paralysis of Muller’s muscle, innervated by
sympathetic)
 AKA eyelid fall
 Myosis –→ no pupillary dilation unilaterally or bilaterally
 Anhidrosis
o Pemberton maneuver
 Hold patient’s arms up
 Used to exacerbate obstructive sx by forcing thyroid into the
thoracic outlet
 Hold patient arms up for 60 seconds
 Pt gets cyanotic
 Neck veins distended
 Facial flushing
 Inability to swallow
 Thyroid cork –→ thyroid impacted in thoracic outlet
 Workup of goiter
o Do TSH
 If palpable –→ US
 If TSH high –→ do Ab
 If TRAB high –→ do US
o If US suspicious –→ FNA
 If TSH normal –→ do US
 If US suspicious –→ FNA
 If TSH low –→ do RAI uptake
 If cold –→ do US/biopsy
 Id hot –→ do US only
o Thyroid ultrasound findings that indicate FNA
 Hypoechoic
 Microcalcifications
 Tall nodule
 Irregular margins
 Central vascularity
  Incomplete halo
 Enlargement of nodule
o Treatments of nontoxic multinodular goiter
 Surgery
 Rapid decompression
 Risk of vocal cord paralysis
 Risk of hypoparathyroidism
 RAI
 Few SE
 Reduction not immediate
 Risk hyperthyroidism
 Radiation
 Levothyoxine
 Prevents new nodule formation
 Low efficacy
 Adverse bone problems
 Thyroid nodule
o A discrete lesion within the thyroid gland representing an abnormal
focal growth of thyroid cells
o Types
 Benign
 Multinodular goiter/colloid adenoma
 Hashimoto thyroiditis
 Cysts
 Follicular adenomas
o Macrofollicular adenomas
o Microfollicular or cellular adenomas
 Hurthle cell adenomas
 Malignant
 Papillary carcinoma
 Follicular carcinoma
o Minimally or widely invasive
  Medullary carcinoma
 Anaplastic carcinoma
 Primary thyroid lymphoma
 Metastatic carcinoma
 Thyroid carcinoma
o Thyroid follicular epithelial-derived
 Differentiated CA
 Papillary CA majority
 Follicular CA some
 Undifferetiated CA (anaplastic) rare
o Parafollicular C cell tumors
 Neuroendocrine
 Produces calcitonin
 =medullary cancer
 If you do an RAI and the nodule is hot –→ not cancer –→ don’t do FNA
 Thyroid Scintigraphy = thyroid uptake and scan = nuclear thyroid scan = RAI
o Done to evaluate –↓ TSH or to distinguish between hyperthyroidism
and thyrotoxicosis
o Functional nodules (hot nodules) almost always benign
 Biopsy not indicated
 One hot nodule = autonomously functioning adenoma with
suppression of the surrounding thyroid tissue
 Questions
o Painless nodule in euthyroid pt, but TSH is low
 Do thyroid scan
o Fast growing goiter, normal TSH, stains + calcitonin
 Medullary thyroid cancer
o Hyperthyroid pt gets jaundice
 Most probably from PTU (Jaundice is S/E)
009 – Drugs Used in the Treatment of Thyroid Disease
 Overview of synthesis of thyroid hormone
o Need thyroglobulin and iodine
 Thyroglobulin made in follicular cells
 Pushed into follicular colloid
 Tyrosine is on Tg
o Iodine from diet
 Pumped into tyrocyte by Na/I symporter
 Iodide pumped into colloid
 Then oxidized inot iodine
 Then organifies/iodizes the TG with tyrosine
 Then conjugates
 Organification of Thyroid hormone
o Thyroid peroxidase iodizes tyrosine –→ di-iodotyrosine
o Thyroid peroxidase can also make a linkage between DIT and MIT –→
T3 or DIT and DIT –→ T4
o Organification makes DIT and MIT from iodine and Tg
o Coupling makes T3 and T4
 Movement of T3 and T4
o T3and T4 then endocytosed into follicular cell
o Thyroglobulin then lysed so T3 and T4 are on their own
o Thyroid hormones wait in endosome until signal given to release
o When released
o T4 gets iodine taken off by deiodinase to activate T3
 Drugs for Hyperthyroidism
o Thioamides
 Propylthiouracil
 Methimazole
o RAI
o Surgery
o Rapid symprom reliever
 B blockers
 Thyroid storm
o An exaggerated response to thyroid hormone (sympathetic
hyperactivity)
o Pt gets
 Fever, NV, nervousness, palpitations, tachycardia –→
increased b receptors in periphery
 Use cocktail
 Give anti-thyroid drugs and B blockers for symptom relief
 Thioamines –→ thyroid hormone synthesis inhibitors
o PTU and MMI
o Thioamines block the synthesis of thyroid hormones from the thyroid
gland by binding to and inactivating the peroxidase
o Interferes with the incorporation of iodine into tyrosyl residues of
thyroglobulin (iodination)
 They also inhibit the coupling of these iodotyrosyl residues to
form T3 and T4
o Thyroid peroxidase blocked by PTU and MMI
 Decreases new thyroid hormone synthesis
o Deiodinase blocked by PTU
 Less T4 converted to active T3 in periphery
o Despite extra action –→ both have equal efficacy
o MMI is superior to PTU due to
 MMI has better compliance
 MMI reaches euthyroid state faster than PTU
 MMI has better safety profile than PTU
o Use PTU in first trimester of pregnancy and in thyroid storm
 Prefer PTU in thyroid storm since it acts peripherally
 PTU vs MMI
PTU MMI
Serum t1/2 1 hr 4-6 hr
Concentrated in thyroid Yes Yes
Dosing frequency 3-4 times daily 1 time daily (better
compliance)
Transplacental passage Low low

 Regarding the onset of thioamines

o MMI concentrates in thyroid much more than PTU
o MMI/PTU onset of clinical effect takes a long time since only inhibits
synthesis of new T3/T4, takes a month for circulating T3/T4 to calm
down
o MMI reaches euthyroid state faster though –→ but clinical effect still
takes awhile (5 half lives is still >1 month)
 Side effects of PTU
o Black box warning for liver failure
 Need to monitor LFTs regularly
 Fulminant liver failure –→ prefer MMI unless 1st trimester
pregnant or thyroid storm
o Rash, pruritus, urticarial, arthralgia, arthritis, fever, loss of taste, NV,
allergies
o Agranulocytosis
 Agranulocytosis is a severe side effect where decrease in
granulocytes (neutrophils, basophils, eosinophils)
 Numbers down to 500 –→ high risk of infxn
 Don’t monitor for agranulocytosis regularly since it’s sudden
and short lived
 Can miss it if testing for it
 Side effects of MMI
o Rash, pruritus, urticarial, arthralgia, arthritis, fever, loss of taste, NV,
allergies
 o Agranulocytosis
 Agranulocytosis is a severe side effect where decrease in
granulocytes (neutrophils, basophils, eosinophils)
 Numbers down to 500 –→ high risk of infxn
 Don’t monitor for agranulocytosis regularly since it’s sudden
and short lived
 Can miss it if testing for it
 When do we use PTU?
o MMI is first line for hyperthyroidism
o Give PTU in qst trimester of pregnancy
o Or when pt doesn’t tolerate MMI
o Or in pt with life threatening thyrotoxicosis or thyroid storm
 Hyperthyroidism and pregnancy
o Hyperthyroidism can be fatal for fetus and mother
 Fetus –→ prematurity, stillbirth, IUGR, low birth weight,
neonatal hyperthyroidism
 Mother→ eclampsia, miscarriage, placental abruption,
congestive heart failure, thyroid storm
o Onlyuse drugs if moderate to severe hyperthyroidism
 Both category D in pregnancy
 Can have teratogenic effects
o Frequency and severity of teratogenic effects is lower in PTU than
MMI
o MMI has teratogenic effects more severe and more often
 Choanal atresia –→ nasal passage is blocked, esophageal
atresia, tracheoesophageal fistula
o Teratogenic effect most common during first trimester –→ use PTU
here
 Hyperthyroidism and pregnancy pt 2
o Use PTU to treat maternal hyperthyroidism during the 1st trimester
 o Pt taking PTU in the first trimester may continue for the remainder of
pregnancy OR switch back to methimazole at the start of the second
trimester
 B blockers
o Rapid symptom relief
o No intrinsic anti-thyroid activity
o Rapid relief of symptoms (tachycardia, tremor, palpitations, anxiety)
o Useful in symptomatic treatment of thyrotoxicosis/thyroid storm
o B blockers –→ propranolol in high doses can prevent
 Conversion of T4 to T3
o Propanolol –→ non selective
 Atenolol, esmolol, metroprolol –→ B1 selective
o Before you give B blockers
 Need to rule out heart block, heart failure, and asthma before
you give B blockers
 Otherwise –→ can cause bradycardia or bronchoconstriction
 Hypothyroid drugs
 Levothroxine –→ T4
 Liothyronine –→ T3
 Levothyroxine MOA
o Hormone receptors in cytoplasm
o Inactive
o T3 activates them when it binds to receptors
o Takes them to nucleus
o Binds thyroid response element
o Causes nuclear change
 Via histone acetylation –→
 causes transcription –→ gene effect
 Levothyroxine
o Synthetic T4
o T4 absorbtion decreased by
 Aluminum (constipation)
  Cholestyramine, cholestipol
 Bile acid sequestrant –→ less cholesterol
 Calcium
 Sucralfate
 Iron compounds
 Food
o Instructions
 Take drug early in morning, no food
o Levothyroxine monotherapy remains the standard treatment for
hypothyroidism
o Pregnancy category A
o Check thyroid hormone every 4-5 weeks because long t1/2
 Underdose –→ ↑ TSH
 Overdose –→ ↓ TSH
o Liothyronine –→ ↓ compliance due to increased dosing
o Black box warning
 For weight reduction
 Do not use thyroid hormones for weight loss
 In euthyoid patients
 Ineffective for weight loss
 Large doses may cause toxicity
o Levothyroxine underdose
 Bradycardia
 Lethargy
 Constipation
 Fatigue
 Excess sleeping
o Levothyroxine overdose
 Irritability
 Palpitations
 Tachycardia
 Diarrhea
 Tremors
  Insomnia
 Drugs affecting Thyroid gland
o Lithium
 Can cause thyroid dysfunction
 Inhibits coupling of MIT and DIT to T4 and T3
 Inhibits release of T4 and T3
 40-50%
 Lithiuminduced goiter
 No functional impairment
 20% → can cause hypothyroidism
 Evaluate baseline and reavaluete every 6 months
 If thyroid dysfunction fromlithium –→
 Continue lithium
 Fix goiter
o Amiodarone
 High iodine content
 Can cause hyper or hypothyroidism
 Drug has direct and indirect toxic effect on thyroid

010 – Physiology of the Hypothalamus and the Pituitary Gland

 In hypothalamus
o Parvocellular neurons –→ to ant pituitary
 Make releasing/inhibiting hormones
 Transport these down their axons –→
 secrete them into primary capillary plexus
 TRH and other hormones
 Made in parvocellular neurons in hypothalamus
 Released from hypothalamus
 Acts on anterior pituitary
 Has vascular and neural connections
 Portal circulation
 Parvocellular cells go through median eminence
  Hormones transported from hypothalamus through
blood vessels of median eminence –→ ant pituitary
 Hypophysiotropic hormones
 Secreted by parvocellular neurons of the hypothalamus
 Transported by hypothalamic pituitary portal vessls
 Modulate synthesis and release of tropic hormones of
anterior pituitary
 Release is pulsatile
o Prevents downregulation and negative feedback
 Types of hormones
o Releasing –→ stimulate secretion, hyperplasia,
hypertrophy
o Inhibiting –→ statins (somatostatin, growth
hormone inhibiting hormone, Dopamine)
 Key hypophysiotrophic hormones
 TRH
o From paraventricular nuclea
o Controls TSH and prolactin
o Target cell is thyrotroph
 GnRH
o Anterior/medial hypothalamus, preoptic septal
areas
o LH and FSH
o Gonadotrophs
 CRH
o Medial parvocellular portion of paraventricular
nucleus
o ACTH
o Corticotroph
 GHRH
o Arcuate nucleus, close to median eminence
o GH
 o Somatotroph
 Somatostatin or GH inhibiting hormone
o Anterior paraventricular area
o –↓ GH
o Somatotroph
 Dopamine
o Arcuate nucleus
o –↓ Dopamine
o Lactotrophs
o Magnocellular neurons –→ to post pituitary
 Make ADH and Oxytocin
 Produced in hypothalamus
 Stored in posterior pituitary
 Transport these to posterior pituitary to release
 Hormones made in hypothalamus go to post pituitary by direct
axonal transport
 Cellular signaling pathways involved in hypothalamo-pituitary hormone-
mediated effects
o TRH –→ median eminence –→ GpcR receptors in anterior pituitary –
→ thyrotroph –→ ↑ PLC –→ ↑ TSH –→ GpcR in Target organ –→ ↑
AC
o GnRh –→ median eminence –→ GpcR receptors in anterior pituitary
–→ gonadotroph –→ ↑PLC –→ ↑ LH, FSH –→ GpcR in Target organ
–→ ↑ AC
o CRH –→ median eminence –→ GpcR receptors in anterior pituitary –
→ corticotroph –→ ↑ AC –→ ↑ ACTH –→ GpcR in Target organ –→
↑ AC
o Somatostatin –→ median eminence –→ GpcR in anterior pituitary –
→ somatotroph –→ ↓ AC –→ ↓ GH –→ Class 1 cytokine in Target
organ –→ ↓ Kinase activity
 o GHRG –→ median eminence –→ GpcR receptors in anterior pituitary
–→ Somatotroph –→ ↑ AC –→ ↑ GH –→ Class 1 cytokine receptor
in target organ –→ ↑ Kinase activity
o Dopamine –→ median eminence –→ GpcR receptors in anterior
pituitary –→ Lactotroph –→ ↓ Prolactin –→ ↓ AC, ↑ K, ↓ Ca –→ ↑
Kinase activity
Cellular signaling pathways in hypothalamopituitary hormone mediated effects
Moves to MoA in Acts on Effect in Hormone Receptor Target
ant pituitary effect in target organ
pituitary organ effect
TRH Median GpcR Thyrotroph ↑ PLC ↑ TSH GpcR ↑ AC
Eminence
GnRH Median GpcR Gonadotroph ↑ PLC ↑ LH, FSH GpcR ↑ AC
Eminence
CRH Median GpcR Corticotroph ↑ AC ↑ ACTH GpcR ↑ AC
Eminence
Somatostatin Median GpcR Somatotroph ↓ AC ↓ GH Class 1 ↓
Eminence Cytokine Kinase
receptor activity
GHRH Median GpcR Somatotroph ↑ AC ↑ GH Class 1 ↑
Eminence Cytokine Kinase
receptor activity
Dopamine Median GpcR Lactotroph ↓ AC, ↑ ↓ Class 1 ↑
Eminence K+, ↓ Ca++ Prolactin Cytokine Kinase
receptor activity
Anterior Pituitary Hormones and actions
Cell Hormone Chemistry Action
Somatotrope GH Peptide ↑ body growth, ↑ IGF secretion, ↑ lipolysis,
↓ insulin
Corticotrope ACTH Peptide ↑ cortisol, ↑ androgens, trophic for zona
facsciculata and reticularis
Thyrotropes TSH Glycoprotein ↑ T3, T4, trophic for follicular cells
Gonadotropes FSH, LH Glycoprotien ↑ development of ovarian follicles, regulates
spermatogenesis, causes ovulatation and
formation of corpus luteum, ↑ estrogen and
progesterone, ↑ testosterone
Lactotropes/ Prolactin Peptide ↑ breastmilk production and secretion
mammotropes

 Classification of ant pituitary hormones

o Glycoproteins
 TSH, FSH, LH
 Pituitary origin
 Common alpha units
 Share alpha unit with hCG as well
 Unique B units confer specificity
o POMC
 Cleavage gives
 ACTH, B-endorphins, MSH (melanocyte stimulating)
o GH and prolactin
 GH
 Structural and genetic
 Human placental lactogen
 Prolactin
 Growth hormone
o GH axis
 Stimulus
  Exercise, stress, fasting, low plasma glucose, sleep
 Hypothalamus –→ ↑ GHRH secretion and –↓ SST
(somatostatin) secretion
 –↑ plasma GHRH
 –↑ GH secretion in ant pituitary
 –↑ plasma GH
 Goes to liver
 –↑ IGF-1 secretion
o GH actions
 Adipose
 ↓ glucose uptake
 ↑ lipolysis
 Muscle
 ↓ glucose uptake
 ↑ AA uptake
 ↑ protein synthesis
 ↑ IGF-1 from liver
 In chondrocytes
o –↑ AA uptake
o –↑ protein synthesis
o –↑ DNA synthesis
o –↑ chondroitin, collagen
o –↑ cell size
o GH stimulated by
 ↓ glucose
 ↓ FFA
 ↑ arginine
 Fasting
 Estrogen, testosterone
 Exercise, stress, sleep
o GH inhibited by
 ↑ glucose
  ↑ FFA
 Obesity
 Old age
 ↑ SST
 GH.IGF-1 (negative feedback)
 Beta agonists
 Pregnancy
o –↑ GH in adults
 Acromegaly
 ↑ organ size and function
 Organomegaly
 Prolactin
o Under tonic inhibition by HT
o If damage to pituitary stalk –→ all andt pituitary hormones go down
except prolactin
o Prolacting fxn
 Breast differentiation
 Duct proliferation and branching
 Glandular tissue development
 Milk synthesis
 Mammary gland development
 Milk production
o Prolactin stimulated by
 Pregnancy, Breast feeding
 Sleep, stress
 TRH
 Dopamine antagonists
o Prolactin inhibited by
 Dopamine
 Bromocriptine
 Somatostatin
 Prolactin (negative feeback)
 Posterior pituitary hormones
 o Oxytocin and ADH/AVP/Vasopressin
o Produced in magnocellular neurons of hypothalamus
o Travel to posterior pituitary via neuronal axons
o Supraoptic nucleus (SON) –→ makes ADH
o Paraventricular nucles (PVN) –→ makes ADH
 Synthesis of ADH
o In HT
 Prepropressophysin –→ propressophysin
 Propressophysin goes to postpituitary
 Propressophysin cleaved to –→ ADH + Neurphysin II (NPII)
 If problem with NPII –→ get T1DM
 Synthesis of oxytocin in HT
o Prepro-oxyphysin –→ oxyphysin
o Oxyphysin goes to post pituitary
o Oxyphysin cleaved to –→ oxytocin + NP1
 ADH stimulated by –↑ plasma osmolarity
 Oxytocin stimulated by
o Suckling of breast
o Sex
o –↑ estrogen

Key aspects of Post pituitary hormones

Receptor Second Target Effect
Messenger organ/cell
Oxytocin Gq coupled ↑ PLC, ↑ Ca++ Uterus Uterine contraction
Receptor Mammary Milk ejection
epithelial cells
ADH V1R Gq coupled ↑ PLC,↑ Ca++ Smooth muscle Vasoconstriction
receptor cells

V2R Gs coupled ↑ AC, ↑ cAMP Kidney ↑ H2O permeability

receptor collecting ducts
 Oxytocin
o Stimulated by
 Suckling
 Sound of infant
 Dilation of cervix
 Orgasm
o Inhibited by
 Opioids
 Mechanism of water resorption by ADH
o Water deficit
o –↑ ECM osmolarity –→ osmoreceptors
o –↑ ADH secretion by post pituitary
o –↑ plasma ADH
o –↑ H20 permeability in distal tubules and collecting ducts
 By AQP2
 Exclusively in collecting ducts
 Only AQP directly regulated by ADH biding V2R
 Stimulates insertion into luminal membrane
o –↑ H2O reabsorption
o –↓ H2O excreted
 ADH V1R/V2R
o V2 can be activated with less ADH
o V1 is for vasoconstriction, so needs more ADH
o Stmulated by
 ↑ osmolarit
 ↓ ECFvolume
 Angiotensin II
 Pain
 Nausea
 Hypoglycemia
 Opiates
 o ADH inhibited by
 ↓ osmolarit
 Ethanol
 A adrenergic agonists
 ANP
 Diabetes insipidus
o Central Diabetes insipidus
 Failure of ADH secretion
 Due to
 Tumors, Trauma, Surgery
 ↓ ADH secretion –→ V2 doesn’t recognize ADH
 Results in
 Decrease in renal H2O reabsorption –→ polyuria
 ↑ thirst –→ polydipsia
 ↑ serum osmolarit and Na concentration
 ↓ ADH
o Peripheral/nephrogenic diabetes insipidus
 Failure of renal response to ADH
 Due to
 Renal Dz, ADH unresponsive kidney, Drugs (lithium)
 ↓ V2 receptors, or V2R unresponsive to ADH
 Reuslts in
 ↑ ADH
 Signs of central diabetes insipidus
 Syndrome of inappropriate ADH secretion (SIADH)
o Small cell carcinoma of lung
 Secretes ADH
o Excessive ADH secretion
 Water retention
 ↑ blood and ECF volume
 ↓ plasma osmolarity
 Summary
 o Magnocellular neurons in HT produce oxytocin and ADH
 Hormones released from post pituitary into systemic
circulation
o Parvicellular neurons of Htproduce neuropeptides
 Released at meidan eminence
 Transported to ant pituitary
 Regulate release of hormone
o Ant pituitary under feedback regulation by peripheral hormones
o Dopamine inhibits prolactin
o SST inhibits GH
o Connection between HT and PP is neural
 Cell bodies of HT and hormones are secreted from nerve
terminal to PP
 Oxytocin is stimulated by suckling –→ causes lactation
 ADH responsible for osmoregulation
 ↑ water reabsorption in principal cells of kidne
 ADH stimulated by↑ osmolarity and –↓ ECF volume
 ↓ ADH –→ diabetes insipidus
 ↑ ADH –→ SIADH

011 – Hypothalamic and Pituitary Gland Pathology

 Anatomy
o Pituitary sits in sellar region (on sella turcica)
o Closed by dura mater
 Called diaphragm sella
 Empty in slela turcica syndrome
o If something grows in sellar region (adenoma) –→
 compresses optic chiasm
 Vision problems
 Physio
o ADH produced in supraoptic nuclei of HT
o Oxytocin produced in paraventricular nuclei of HT
 o Move by axonal transport of magnocellular neurons
o Neurosecretory hormones since axons secrete into vessel instead of
synapse
 Ant pituitary produces and secretes
o ACTH, GH, prolactin, FSH, LH, TSH
 Development
o Oral ectoderm –→ ant pituitary
o Neuroectoderm –→ post pituitary
o At 4 weeks –→ get rathke’s pouch
 Get infundibular process in enuroectoderm at this time
 Stroma (mesoderm) grows in the middle during this time –→
 Pinches off rathke’s pouch
 Pituitary formed
 Blood supply of pituitary
o Anterior pituitary
 Internal carotid –→ superior hypophyseal artery –→ median
eminence –→ capillary bed –→ portal veins –→ ant pituitary
 Anterior pituitary is fed by portal veins
 Low pressure state
 Can infarct easier
o Post pituitary
 Internal carotid –→ inferior hypophyseal artery
 ↑ pressure –→ no infarct
 Histo of pituitary
o Ant pituitary
 Can see dilated blood vessels in ant pituitary
 Nests of different cells
 A cells
 Acidophils, eosinophilic
 Secrete GH
 Somatotrophs
 B cells
 Basophils
 Secrete ACTH, FSH, LH, TRH
 Coricotrophs, thyrotrophs, Gonadotrophs
 C cells (chromophores)
 Don’t stain well
 Secrete prolactin
 Lactotrophs
o Post pituitary
 Mostly axons from HT
 Pituicytes (glial cells)
 Can see herring bodies
 Pink swelling inclusions
 Due to oxytocin and ADH coming down –→ get swelling
–→ herring bodies
 Stalk effect
o When something is compressing stalk
o All ant pituitaries decrease except prolactin
o This is because dopamine –→ ↓ prolacting
o So –↓ dopamine –→ ↑ prolactin
o If pt has –↑ prolactin
 Give bromocriptine –→ dopamine agonist
o If pt is on haloperidol (dopamine antagonist)
 Haloperidol –→ ↑ prolactin
 Pituitary gland pathology
o Hyperpituitarism
 Due to adenoma
 Hyperplasia
 Carcinoma
o Hypopituitarism
 Ischemic damage
 Apoplexy
 Sheehan syndrome
 Surgery
 Radiation
 Inflammation
o Local mass effect
 Bitemporal hemianopsia
 Anterior pituitary lobe tumors
o Mostly adenomas
o Most common is prolactinoma
 If lesion is in pituitary and pt has –↑ prolactin
 It is a prolactinoma
o Usually only 1 hormone is produced
o If adenoma
 On MRI –→ see protrusion into sella turcica
o Tumor can be ACTH secreting
 Cushing’s disease
o Adenomas can be large and destructive
 Can cause hydrocephalus
 Can cause expanded sella turcica
o Cancer usually due to metastasis
o Pituitary adenoma histo
 Clonal process –→ neoplasia
 Loss of nests
 Looks like solid sheets of monotonous cells
  Can only tell difference by IHC
 Reticulin histo stain
 Reticulin stains lining of nests
 If normal nests –→ normal reticulin
 If nests expanded, but normal architecture –→
hyperplasia
 If loss of nest architecture –→ adenoma
 Prolactinoma
o Pt has Galactorrhea,
 Amenorrhea, ↓ libido, infertility
 Sexual dysfunction, mass effect
o IHC is prolactin
 See calcifications
 See amyloid
o Other causes of –↑ PL
 Pregnant
 Suprasellar lesion (stalk effect)
 Dopamine inhibiting drugs (haloperidol)
 Growth hormone adenoma
o Gigantism pre pubertal
o Acromegaly in adults
 Jaw enlarged
 Hand, feet, head enlarged
 Shoe size getting bigger
o –↑ GH –→ ↑ IGF-1 –→ bone and muscle overgrowth
o Clinical
 HTN
 Heart failure
 Secondary DM
 ↑ GH –→ peripheral insulin resistance –→ secondary
DM
 Osteoproosis/arthritis
  Gonadal dysfuction
 Colorectal cancer
 ACTH adenoma (cushing disease)
o Corticotroph Adenoma
o Cushing Dz is ONLY when ACTH secreting adenoma –→ ↑ cortisol
 Obesity, stria
 HTN, acne
 Diabetes
 Truncal obesity
 Moon face
o Nelson syndrome happens when cushing pt gets adrenalectomy
 Surgery removes adrenals
 Loss of cortisol
 Loss of negative feedback of cortisol to the pituitary leading to
growth of a pre-existing microadenoma
 Presents as a mass,
 No –↑ corstisol because no adrenals
 Get hyperpigmentation from –↑ MSH from –↑ POMC
breakdown
o IHC
 ACTH Ab granules
 Crook’s hyaline change
o Accumulation of keratin in non-neoplastic ACTH producing cells
o This signals hypercortisolemia
 An ACTH producing adenoma
 Ectopic ACTH production
 Adrenal disease
o In a pt with –↑ cortisol
 Cortisol gives negative feedback on ACTH producing cells
 –→ No ACTH
 Ectopic cells (adenoma) starts making ACTH
 Pituitary adenomas
 o Non functioning pituitary adenoma
 Mass effect
o Gonadotroph adenoma
 Sustained ↑ FSH –→ hypogonadism
 Hypogonadism due to presence of negative feedback
o Thyrotroph adenoma
 Hypopituitarism can be from HT or pituitary
 Causes of hypopituitarism
o Pituitary apoplexy
o Sheehan syndrome
o Rathke cleft cyst
o Empty sella turcica syndrome
 Sella turcica empty on MRI
 This is because dura mater got leaky
 Started letting CSF get into sella turcica
 ↑ pressure –→ pushes pituitary against wall
 Compressed pituitary –→ hypopituitarism
o Tumors
o Pituitary surgery or radiation
o TB
o Sarcoidosis
 Pituitary Apoplexy
o Sudden enlargement due to hemorrhage and necrosis of an adenoma
o Clinical
 Headache
 Vision loss
 Acute hypopituitarism
o Occures when underlying pituitary adenoma necroses
o Must have pre-existing underlying pituitary adenoma
 Sheehan syndrome
o Postpartum necrosis of anterior pituitary
o –→ Hypopituitarism
 o During pregnancy
 Enlargement of Pituitary with increased weight
 Lactotroph cell hyperplasia
 Same level of venous circulation
 ↑ risk for infarct
 Agenesis of pituitary and developmental
o Craniofacial abnormalities
o Congenital hypopituitarism
o Associated with hypoplasia of
 Adrenals
 Thyroid
 Gonads
 Metabolic disorders and pituitary
o Amyloid deposits
 With systemic amyloidosis
 Prolactinomas
o Iron overload
 Hemochromatosis
 Blood transfusions
o Hurler’s syndrome (gargoylism)
 Infectious diseases in pituitary
o Acute inflammation
 In meningitis
 Bacterial more common
o Granulomatous inflammation
 Fungal infection
 Mycobacterial
o Sarcoidosis –→ Granulomatous disease
 Langerhans cell histiocytosis
o Clonal proliferation of Langerhans cells
o Pituitary stalk involvement –→ diabetes insipidus
o Kids with multifocal dz more common
 o On histo
 Langerhans cells have clonal proliferation
 seen with eosinophils and lymphocytes
 Langerhans cells have butt cleft, peach emoji
 Langerhans cells express
 S-100 protein
 CD1a
 Languerin
 Birbeck granules on electron microscopy
o Little tennis racket fuckers
 Hypothalamus
o Controls circadian rhythm
o Thirst center, thermostat, hunger center
o Produces oxytocin and ADH
o ADH
 Synthesized in supraoptic nucleus
 Promotes resorption of free water
 Stimulated by
 ↑ osmolarity
 Changes in left atrial distention
 Exervcise
 Stress
 ADH released from axon terminals in the neurohypophysis
 Into the general circulation
 Posterior pituitary syndromes
o ADH deficiency: Central diabetes insipidus
 May be due to neoplasm, head trauma, inflammation, surgery,
radiation
 Clinical
 Polyuria, ↑ thirst, polydipsia
 Urine has very low specific gravity
 Dilute
  ↑ serum osmolality, s↑ serum Na
 Due to excess renal loss of freee water
o SIADH
 ADH excess
 ↑ resorption of free water
 Hyponatremia –→ cerebral edema
 Causes
 Trauma to pituitary
 Small cell carcinoma of lung (neuroendocrine)
o Paraneoplastic syndrome of lung carcinoma
 Other non neoplastic lung disorders
 Rathke’s pouch
o Intermediate pouch
o Rathke’s cleft cyst
 Rathke’s pouch left as remnant
 Accumulates fluid
 Usually subclinical
 Can give rise to neoplasm
 → cranipharyngioma
o Craniopharyngioma
 Arises from neoplastic transformation of Rathke’s epitheliam
 Benign but locally invasive
 On imaging
 Cystic suprasellar mass with calcifications
 2 types
 Adamantinomatous (resembles tooth epithelium)
 Papillary
 On histo
 Islands of squamoid epithlelism
o Adamantinomatous
 Palisading basal cell layer
 Polygonal cells
  Stellate reticulum
 Wet keratin
 Calcifications
 Questions
o Hypersecretion of ADH is associated with
 Water retention
 Dilutional hyponatremia
 Small cell carcinoma of lung
 Inability to dilute urine
o Hyposecretion of ADH is associated with central diabetes insipidus
o 23y/o man with headaches, polyuria, visual problem. Calcified cystic
mass in supracellar and sellar region. Labs have –↑ prolactin, ↑ Na
 Problem is he had a rathke’s cyst –→ craniopharyngioma
 Destroyed the posterior pituitary

012 – Adrenal Physiology

 Adrenal glands
o Zona Glomerulosa –→ aldosterone release (mineralocorticoid)
o Zona Fasciculata –→ Cortisol release (glucocorticoid)
o Zona reticularis –→ Androgens
o Medulla –→ Epinephrine and norepi (catecholamines)
 Review pathway of cholesterol to pregnenolone via desmolase (stimulated
by ACTH) then to other hormones
o Angiotensin II stimulates aldosterone synthase (primary stimulation)
o ACTH strongly stimulates cortisol/glucocorticoid production
 Deficiencies
o 21b hydroxylase deficiency
 Common
 ↑ androgens
 ↓ aldosterone
 ↓ cortisol
 o 17-a hydroxylase deficiency
 ↑ aldosterone
 ↓ cortisol
 ↓ androgens
o 11b hydroxylase deficiency
 ↑ androgens
 ↓ cortisol
 Deoxycorticosterone (DOC) cannot be converted to
aldosterone
 However DOC still has some mineralocorticoid activity
 Steroid transport tin blood
o Cortisol
 75% bound to cortisol binding globulin (transcortin)
 15% bound to albumin
 10% unbound
 Longer half life
o Aldosterone
 42% bound to albumin
 21% bound to transcortin
 37% unbound
 Short half life
 Factors affecting ACTH secretion
o –↑ ACTH secretion
 ↓ blood cortisol
 Waking up, Stress, hypoglycemia, surgery, trauma
 ADH
 Alpha agonists, Beta antagonists
 Serotonin
o –↓ ACTH secretion
 ↑ cortisol
 Opioids
 SST
 CRH and ACTH
o Both trigger AC-cAMP-PKA pathway
o CRH binds GPCR on corticotroph
 ↑ AC –→ ↑ Ca –→ release of preformed ACTH
 CRH also increases gene transcription and synthesis of POMC
(ACTH precursor)
o ACTH binds to melanocortin-2 receptors
 In all 3 layers of adrenal cortex
 ↑ AC
 ↑ conversion of cholesterol –→ pregnenolone
 Glucocorticoids
o Diurnal secretion –→ ↑ in the AM
o Metabolic effects of glucocorticoids
 Catabolic in most organs
 ↑ lipolysis
 ↑ protein metabolism
 Anabolic in liver
 ↑ gluconeogenesis
 Facilitates mobilization of fuel
 Keep normal blood sugar though because of the
compensatory effect of insulin
 Effect on Carbohydrate metabolism
 Only significant when fasting
 Not active in well fed state
 Prolonged elevation on blood glucose
o –↑ gluconeogenesis enzymes
o –↑ supply gluconeogenic AA
o –↓ insulin induced glucose and AA uptake
o –↑ blood glucose
 Permissive ffects on glucagon action
o Anti-inflammatory actions
 Only seen in large pharmaceutical doses
 o In exogenous glucocorticoid therapy
 HPA axis is quiescent
 Need ot taper off so zona fasciculate can slowly get used to
making cortisol again
 If not –→ can get atrophied adrenals –→ adrenal insufficiency
–→ hypoglycemic shock
o Glucocorticoids are diabetogenic
 ↑ Hepatic glycogen deposition
 ↑ peripheral insulin resistance
 ↑ gluconeogenesis
 ↑ FFA production
 Effects of excess of glucocorticoids on body
o CNS
 Depression, psychosis
o Endocrine system
 ↓ LH, FSH, TSH, GH
o Carbohydrate metabolism
 ↑ Hepatic glycogen deposition
 ↑ peripheral insulin resistance
 ↑ gluconeogenesis
 ↑ FFA production
 Diabetes
o Adipose
 Promotes truncal obesity
o Bone
 ↓ formation
 ↓ bone mass and osteoporosis
o Skin/muscle /connective tissue
 Protein catabolism/collagen breakdown
 Skin thinning
 Muscular atrophy
o Eye
 Glaucoma
 o GI tract
 Peptic ulcers
o CV/Renal
 Salt water retention
 HTN
o Growth
 ↓ linear growth
o Immune
 Anti-inflammatory
 ↓ inflammatory cytokines
 ↓ PGE and leukotriene production
 ↓ bradykinin
 ↓ circulating numers of eosinophils, basophils and
lymphocytes –→ redistribution effect
 Autoimmune
 Cortisol binds the mineralocorticoid receptor with high affinity
o To stop this
o 11b hydroxysteroid dehydrogenase converts cortisol –→ cortisone
 Cortisone cant bind mineralocorticoid receptors)
o Happens in tissues with –↑ mineralocorticoid receptors (kidneys)
o Cortisol-cortisone shunt
 11-B hydroxysteroid dehydrogenase 2 (11B HSD2) converts
cortisol to cortisone
 Cortisone has –↓ affinity for Mineralocorticoid receptor
 Active ingredient in licorice is glycyrrhizic acid
 Glycyrrhizic acid gives cortisol free access to
unprotected mineralocorticoid receptor in kidney
 Causes hypokalemia and HTN
 Mineralocorticoids (aldosterone)
o Produced by zona glomerulosa
o 3 ways to stimulate glomerulosa cells of cortex
 Renin
  Hyperkalemia
 Angiotensin II (from –↑ ACTH)
 Regulation of aldosterone release by RAAS
o –↓ plasma volume –→ ↓ afferent systolic pressure
o –↓ Tubular NaCl in nephron and juxtaglomerular cells
o –↑ Renin released
o Angiotensinogen –→ Angiotensin 1
o Angiotensin 1 –→ ACE –→ Angiotensin II
o ACE found in endothelial cells of lungs
 (40%)
o Angiotensin II causes vasoconstriction
o Angiotensin II stimulates formation of aldosterone
o Aldosterone –→ ↑ Na Reabsorption and –↑ K excretion
 Effects of aldosterone
o On principal cells
 ↑ Na reabsorption at lumen (ENaC)
 ↑ K excretion at lumen
 ↑ Na reabsorption at interstitial space (Na/K ATPase)
o On Intercalated Cells
 ↑ H+ excretion at lumen (H+ ATPase)
 ↑ HCO3- reabsorption at interstitium (HCO3/Cl exchanger)
 Adrenal sex steroids
o Dehydroepiandrosterone sulfate (DHEAS) and androstenedione
 Converted to testosterone in peripheral tissues
o Females have 50% of the androgen requirements of males
 Conversion of androgen precursors to estrogens important
after menopause
o Not important in males
 Leydig cells make enough testosterone
o Hypersection of androgens in females
 Causes adrenogenital syndrome
o Function of adrenal androgens in females
  Stimulate growth of pubic and axillary hair
 Stimulate libido
 Hypoadrenalism
o Primary hypoadrenalism
 Syndrome of insufficient aldosterone secretion
 Glomerulosa affected
 Syndrome of insufficient cortisol secretion
 Fasciculate and reticularis affected
 Addison’s disease
 All 3 layers affected
 Hyperadrenalism
o Tertiary
 Hypothalamic excess secretion of CRH
o Secondary
 Pituitary excess of ACTH (Cushing’s disease)
o Primary
 Conn syndrome
 Glomerulosa –→ ↑ aldosterone
 Cushing’s syndrome
 Fasciculata –→ ↑ cortisol
 Adrenogenital syndrome
 Reticularis –→ ↑ androgens
o Ectopic, Iatrogenic
 HPA in Cushing Dz
o First do low dose dexamethasone suppression test
 If no suppression seen –→ we can say there is an excess of
cortisol coming from somewhere
o Then do high dose dexamethasone suppression test
 If suppression seen –→ ACTH dependent problem
 Cushing Disease with pituitary ACTH producing adenoma
 If no suppression seen –→ ACTH independent problem
 Enzyme deficiencies
 Enzyme deficiencies
o 21 hydroxylase deficiency
 Very common
 Converts progesterone –→ 11 deoxycorticosterone
 17a-hydroxypregesterone –→ 11 deoxycortisl
 Consequence
 ↓ cortisol
 ↓ aldosterone
 ↓ Na because of mineralocorticoid (aldosterone)
deficienct
 ↑ virility because –↑ androgens
o 11B hydroxylase deficiency
 Converts 11 deoxycorticosterone –→ coriticosterone
 Converts 11 deoxycortisole –→ cortisol
 Consequence
 ↑ 11 deoxycortisol
 ↑ 11 deoxycorticosterone
 ↑ mineralocorticoid activity
 ↑ Na and water retention
 Congenital adrenal hyperplasia
o CAH is AR
o Genes coding for an Ez needed for cortisol synthesis is defective
o 21 hydroxylase is most common
 Adrenogenital syndrome
 Synthesis of steroids shunted to production of androgens
 ↑ androgens
 ↓ aldosterone, cortisol
o Signs of deficiency of MC and FC
o –↑ Renin, ↑ ATII
 Due to –↓ ECF volume and –↓ BP
 ↑ ACTH –→ hyperplasia of the adrenal cortex
 Question
 o Baby born, XX, large clitoris, electrolytes show ↑ Na, ↓ K
 Pt has 11 B dehydroxylase deficiency
 ↑ deoxycorticosterone
o Baby born, XX, large clitoris, BP is 55/35, skin has decreased turgor
 Pt has –↓ volume, probably –↓ Na
 21 hydroxylase deficiency
 Consequence of altered steroid hormone synthesis
o 21 hydroxylase deficiency
 Hormone
 ↓ Cortisol, ↓ Aldosterone
 ↑↑ DHEA (androgen)
 Labs
 ↓ Na
 Hypoglycemia
 ↑ virility
o 11 b hydroxylase deficiency
 Hormone
 ↓ cortisol, ↓ aldosterone
 ↑ 11 deoxycorticosterone, ↑ 11 deoxycortisol
o Deoxycorticosterone and deoxycortisol have MC
activity (like aldosterone)
 Labs
 ↑ MC activity
 ↑ Na and water retention
 Hypoglycemia
 ↑ virility
 17a hydroxylase deficiency
o Hormones
 ↓ cortisol
 Causes –↑ ACTH –→ hyperplasia of adrenal cortex
 ↑ aldosterone
 Synthesis of steroids shunted –→ ↑ MC (aldosterone)
 o Labs
 ↑ 11 DOC, aldosterone
 Corticosterone partially replaces lost MC
 ↑ 11 DOC –→
 ↓K
 ↑ Na
 ↑ ECF volume
 HTN
Summary of Ez deficiencies
Deficiency GC ACTH MC MC BP Androgens Estrogen
(cortisol) (aldosterone) (11-DOC)
21- ↓ ↑ ↓ ↓ ↓ ↑ (adrenal)
hydroxylase
11B- ↓ ↑ ↓ ↑ ↑ ↑ (adrenal)
hydroxylase
17a- ↓ ↑ ↑ ↑ ↑ ↓ (adrenal, ↓
hydroxylase testicular)

 Adrenal Medulla
o Tyrosine hydroxylase is rate limiting enzyme
o Phenylethanolamine N methyltransferase (PNMT)
 PNMT is an Ez found in adrenal medulla
 Converts Norepi to Epi
 Effects of Epinephrine
o Carbohydrate metabolism
 ↑ glycogenolysis in liver and muscles (fasting effect)
 ↑ glucose output from the liver
 ↑ lactate output from muscles
o Fat metabolism
 ↑ lipolysis
 ↑ ketogenesis
o Protein metabolism
  No effect
 Pheochromocytoma/paraganglioma
o PCC/PGG are benign or malignant tumors of adrenal medulla
o Result in excess production of catecholamines
o Test with 24hr metenephrines
 Summary
o GC –→ ↑ gluconeogenesis
o MC –→ ↑ Na reabsorption, K+ and H+ secretion by kidney
o Addison disease
 Primary adrenocortical insufficiency
o Cushing’s syndrome
 Overproduction of glucocorticoids
o Conn’s syndrome
 Overproduction of mineralocorticoids
o Ez deficiencies –→ Congenital adrenal hyperplasia
o Pheochromocytomas
 Chromaffin cell tumors
o

013 – Pathology of Adrenal Disorders

 Normal Adrenal
o Cortex
 Glomerulosa –→ MC (aldosterone) –→ regulated by RAAS
 Fasciculata –→ GC (cortisol) –→ Regulated by ACTH
 Reticularis –→ Sex steroids (DHEA) –→ regulated by ACTH
o Medulla
 Chromaffin cells –→ Epi, Norepi –→ regulated by direct
innervation of sympathetic system
 Cortex is lipid rich
 Adrenal medulla histo
o Chromaffin cells
o Sustentacular cells (give architecture)
 Adrenal medulla is derived from neural crest cells
o Neural crest cells migrate in 7th week
 Adrenal cortex is derived from adrenal primordium
 Hyperadrenalism has 3 main clinical syndromes
o Cushing syndrome
 ↑ cortisol
o Conn syndrome (hyperaldosteronism)
 ↑ Aldosterone
o Adrenogenital syndrome
 ↑ androgens
 Cushing syndrome types
o Pituitary Cushing Disease
 Tumor in Anterior pituitary –→ ↑ ACTH –→ ↑ cortisol
 Diffuse adrenal hyperplasia
 Bilateral
o Adrenal Cushing syndrome
 Cortisol secreting tumor OR
 Nodular hyperplasia –→ secretes cortisol
 Uni or bilateral
o Paraneoplastic cushing
 Small cell lung cancer (or other nonendocrine cancer)
 Secretes ACTH
 Bilateral adrenal hyperplasia –→ ↑ cortisol
o Iatrogenic cushing syndrome
 Takes steroids
 Bilateral adrenal atrophy
 Endogenous Cushing Syndrome Causes
o –↑ ACTH produced by pituitary
 Cushing Disease
 Pituitary adenoma (corticotroph microadenoma)
 ACTH dependent
  Corticotroph cell hyperplasia –→ Due to –↑ CRH production
by HT
o Primary adrenal (ACTH independent) Cushing
 Adrenal cortical adenoma
 Primary hyperplasia of adrenals
 Macronodular hyperplasia OR
 Pigmented micronodular
o Secretion of ectopic ACTH by neuroendocrine tumor
 Small cell carcinoma of lung
 Medullary thyroid carcinoma
 Pancreatic neuroendocrine
 Carcinoid
o Most common is exogenous
 Cushing Syndrome
o Gross
 If atrophy –→ exogenous
 If bilateral diffuse hyperplasia
 Endogenous, ACTH dependent
 If Unilateral or Bilateral NODULAR hyperplasia
 Primary cortical hyperplasia
 ACTH independent
 If adenoma
 Unilateral yellow mass
 With capsule
 Atrophic contralateral gland
 If carcinoma
 Large
 No capsule
 Atrophic contralateral gland
o Clinical
 HTN, weight gain, truncal obesity, moon facies, striae, proximal
limb weakness, secondary diabetes, osteoporosis
 Gross feature of a cortical adenoma
o Yellow fatty mass is cortical adenoma –→ ↑ Cortisol
 Negative feedback
 Atrophy seen in cortex of SAME GLAND
 Atrophy –→ ↓ lipid composition of affected part of cortex
 Adrenal hyperplasia
o If diffuse
 ACTH dependent problem
 Cushing disease,
 Corticotroph hyperplasia
o If nodular
 ACTH independent problem
 Adrenal cortical adenoma
 Primary adrenal hyperplasia
 Small cell carcinoma of lung
 Primary pigmented Nodular Adrenocortical Disease
o Pituitary – ACTH – Independent hypercortisol
o Caused by primary bilateral nodular hyperplasia
 Adrenal nodules are pigmented
 Pigment is lipofuscin
o Path
 Moderately –↑ cortisol without diurnal rhythm
 Not cushingoid
 Diabetes, HTN, fatigue
 ↓/undetectable ACTH
 Bilateral adrenalectomy
o Can be familial
 Carney’s complex –→ AD
 PRKAR1A, PDE11A, PDE8B
o Carney’s complex
 Cutaneous abnormalities
 Lentigenes, blue nevi, myxomas
  Cadiac myxoma
 Tumors of testes
 Primary Pigmented Nodular Adrenocortical Disease (PPNAD)
o Gross
 PPNAD shows brown pigmented adrenals
o Histo
 Shows nodules with lipofuscin pigment
 Primary Hyperaldosteronism
o –↑ aldosterone –→ ↓ Renin
o Caused by
 Bilateral idiopathic hyperaldosteronism
 Bilateral nodular hyperplasia
 KCNJ5 mutation
 Adrenocortical neoplasm
 Conn syndrome
 Single cortical adenoma
 KCNJ5 muttation
 Familial hyperaldosteronism
 Fusion of CYP11B1 and 11B2 fusion
 B1 = ACTH regulated hydrolase
 B2 = aldosterone synthase
 Leads to an ACTH sensitive aldosterone synthase
 Can treat with steroids –→ ↓ ACTH –→ ↓ aldosterone
o Fxn of aldosterone
 K moves from bloodstream into tubule and excretedin kidney
 Na reabsorbed from tubular urine back into bloodstream –→
HTN
 Conn syndrome
o Primary cortical adenoma –→ secretes –↑ aldosterone
o On histo
 SPIRINOLACTONE BODIES
 Seen when pt is treated with spironolactone for HTN
 Secondary Hyperaldosteronism
o Activation of RAAS –→ ↑ renin –→ ↑ Aldosterone
o Caused by
 ↓ renal perfusion
 Renal artery stenosis
 Arteriolar nephrosclerosis
 Arterial hypovolema and edema
 CHF
 Cirrhosis
 Nephrotic syndrome
 Pregnancy
 Estrogens –→ ↑ renin
o Clinical
 HTN with –↓ K
 Left ventricular hypertrophy, Stroke, MI
 Weakness, paresthesias due to –↓ K
 Hyperaldosteronism is most common cause of secondary HTN
 Congenital Adrenal Hyperplasia –→ Adrenogenital syndromes
o AR, Ambiguous genitalia
o Defect in synthesis of cortisol –→ shunt
o ↓ cortisol –→ ↑ ACTH –→ ↑ Bilateral adrenocortical hyperplasia
 Hyperplasia –→ ↑ precursors –→ ↑ androgen synthesis
o 21 hydroxylase deficiency most common
 ↓ aldosterone, ↓ cortisol, ↑ androgens
 Hyperplastic adrenal
 ↑ ACTH
 In females
 Clitoral hypertrophy, oliomenorrhea, hirsutism, acne
 In males
 Precocious pubery, oligospermia
 Severe forms
 –↓ Na, Hypotension, dehydration
 o 11B hydroxylase deficiency
 ↓ cortisol, ↓ aldosterone
 ↑ Androgens
 ↑ ACTH
 ↑ 11-DOC (deoxycorticosterone)
 11-DOC has mineralocorticoid (aldosterone-like) activity
 Normal BP due to 11-DOC
 Same male/female specific problems
o 17a hydroxylase deficiency
 ↓ cortisol, ↓ androgens
 ↑ aldosterone
 ↑ ACTH
 Ambiguous genitalia in genetic males
 Girls look like girls
 Boys look like girls
 ↑ altosterone –→ HTN
 Hypoadrenalism
o Primary acute adrenocortical insufficiency (adrenal crisis)
 Stress in pt with underlying chronic adrenal insufficiency
 Sudden withdrawal of steroids
 Massive adrenal hemorrhage (Waterhouse Friderichsen )
o Primarychronic adrenocortical insufficiency (Addison disease)
o Secondary due to a deficiency of ACTH
 Pituitary apoplexy (necrosis of adenomas)
 Sheehan syndrome (postpartum infarction of pituitary)
 Waterhouse Friderichsen syndrome
o Acute adrenocortical insufficiency with bilateral adrenal hemorrhage
o Sepsis caused by Neisseria meningitides
o DIC with hypotension –→ shock
o Reason for adrenal hemorrhage
 Bacterial seeding of small vessels in the adrenal
 DIC
  Endotoxin-induced vasculitis
 Hypersensitivity vasculitis
o Histo
 Shows lots of RBCs
o Waterhouse friderichsen syndrome
 Pt shows purpuric rash
 ↑ risk in asplenic pt
 Due to lack of protection from encapsulated organisms
 Primary chronic adrenocortical Insufficiency –→ Addison Disease
o May be due to
 Autoimmune adrenilatis
 TB
 Caseating granulomatous inflammation
 AIDS
 Metastatic Tumor
 Mets from lung –→ hypoadrenalism
 Amyloidosis
 Sarcoidosis
 Hemochromatosis
o Autoimmune adrenalitis
 Gland becomes atrophic and fibrous
 On histo
 See lymphocytes, plasma cells, and histiocytes
 Isolated or Autoimmune polyendocrine syndromes (APS)
 Autoimmune polyendocrine syndrome 1 (APS1)
 Mutation in AIRE1 gene (autoimmune regulator gene)
o Used for thymic regulation
 Chronic mucocutaneous candidiasis
 Ectodermal dystrophy
o Vitiligo, alopecia
 Autoimmune adrenalitis, autoimmune
hypoparathyroidism
  Autoimmune polyendocrine syndrome 2 (APS2)
 More frequent than APS1
 Women
 Adrenal insufficiency
 Autoimmune thyroiditis
 T1DM
 Secondary Adrenocortical Insufficiency
o Any disorder of the hypothalamus and pituitary that decreases the
output of ACTH
 Metastases, infection, Infarction, irradiation, Prolonged
exogenous glucocorticoids
o Gross
 Small adrenals
 Thin cortex
 Normal medulla
 Chronic hypoadrenalism
o Clinical manifestations when 90% of adrenal is compromised
o Progressive weakness and easy fatigability
o GI disturbances
 Anorexia, NV, weight loss
o –↑ POMC –→ ↑ MSH –→ stimulates melanocytes
 Hyperpigmentation
 ONLY IN PRIMARY CHRONIC HYPOADRENALISM (ADDISON’s)
o –↓ Aldosterone
 ↑ K, ↓ Na, ↓ BP, ↓ ECF volume
o –↓ Cortisol –→ hypoglycemia
 From impaired gluconeogenesis
o Stresses (infxn, trauma, surgery)
 Can cause acute adrenal crisis
 Vomiting, Abdominal pain, hypotension, coma, vascular
collapse, death
 Gross view of adrenals
 o Atrophic adrenals
 Due to exogenous steroid use or late stage addison’s
o Hypertrophic
 Due to ACTH dependent cushing
 Adrenal neoplasma
o Adrenocortical Adenoma
 Well circumscribed yellow mass
 Encapsulated
 Non functional usually
 Adenomas
 Cushing Syndrome or Conn Syndrome
 Carcinomas
 Virilizing neoplasm
 Adrenocortical Adenoma on histo
 Interface, looks like fasciculations
o Adrenocortical carcinomas
 Rare
 Genetic syndromes
 Li-Fraumeni, Beckwith Wiedemann
 Functional
 Gross
 Large and invasive
 Hemorrhage, cystrs, necrosis seen
 Histo
 Varies, necrosis seen
 Invades adrenal veins
 Mets common
o Lymph nodes and hematogenous
o Adrenal medulla –→ pheochromocytoma
 Neoplasm with chromaffin cell differentiation
 Produces catecholamines
 Causes HTN
 o Sustained or paroxysmal HTN
 Labs
 ↑ 24 hr metenephrines
 Gross
 Centered in medulla
 Grey-tan
 May have hemorrhage, necrosis, or cysts
 Tests
 Chromaffin reaction to chromic salts
 Zenker solution is Brown
 Pheochromocytoma histology
 Basophilic cells
 Nested (zellballen)
 Trabecular
 Solid
 Bland to pleomorphic
 Because benign tumors be histologically identical to malignant
tumors to diagnose a malignant pheochromocytoma
 A metastases need to be present
 Nests cell balling pattern
 Basophilic sheets
 Pheochromocytoma IHC
 Chromogranin +
 Synaptophysin +
 Adrenal medulla neuroblastoma
o Kids < 5y/o
o Derived form neural crest cells
o Can occur anywhere in SNS
o More commonly intra-abdominal
o Adrenal medulla
o Prognosis based on
 Amplification of MYC oncogene
 o On histo
 See homer wright rosettes
 Congenital anomalies
o Adrenal cytomegaly
 Large polypoid adrenocortical cell
 Prematurity
 Rh incompatibility
 Rubella
 Lupus
 On histo
 Big cells with inclusions
 DDx
 CMV
 Beckwith Wiedemann Syndrome
o Adrenal hyperplasia + cytomegaly
o Beckwith Wiedemann syndrome
 11p15.5 mutaiton
 Triad
 Visceromegaly
 Omphalocy
 Macroglossia
 Unilateral enlargement of organs
 Macrosomia/hemihypertrophy
 Adrenocortical hyperplasia + cytomegaly
 Neonatal hypoglycemia
 ↑ rsk for
 Wilms tumor
 Adrenocortical carcinoma
o Adrenal fusion (butterfly adrenals)
 Associated with
 Spina bifida
 Myelomeningocele
  Adrenal fusion associated with cornelia de lange
syndrome
o Developmental delay
o Short
o Upturned nose
o Limb problems
o Synophrys/unibrow
 Ectopic adrenal tissue
 In retroperitoneum
 In spermatic cord
 In inguinal hernia sacs
o Wolman disease
 Rare lysosomal storage disorder
 AR
 Deficiency in lysosomal acid lipase
 Cholesterol esters and TG accumulate in tissues
 Fatty liver
 Adrenal cortex
 Necrosis, calcification and fibrosis seen
o Congenital adrenal Hypoplasia
 ↓ Na, ↑ K, Dehydration, hypotension, hypoglycemia
 Small adrenal glands
 Can be sporadic, AR, OR
 XLR
 Mutation in DAX1 gene
 Hypogonadotropic hypogonadism
 ↓ FSH, LH
 Glycerol kinase deficiency
 DMD
 Questions
o What distinguishes primary hyperaldosteronism from secondary
hyperaldosteronism? –→ ↓ Renin
 o Primary adrenocortical deficiency (Addison’s dz) is most commonly
caused by
 Autoimmune
o Characteristics associated with Pheochromocytoma include
 Chromaffin cell differentiation
 Episodic HTN
 Urinary excretion of catecholamines
 Components of MEN syndromes
o Beckwith Widemann syndrome
 Causes hypoglycemia in newborns
 Macroglosia
 Hemihypertrophy
 Cytomegaly
 ↑ risk
 Wilms tumor
 Adrenocortical carcinoma
o Adrenal mass in hypertensive pt w/ ↑ Na, ↓ K
 Conn Syndrome
o Septic pt w/ DIC, purpura, hemorrhagic adrenal cortices
 Waterhous friedrichsen syndrome
 Most common microorganism is Neisseria

014 – Adrenal Genetics

 Multiple Endocrine Neoplasia
o AD, high penetrance
o Multiple tumors in a single endocrine organ
o Or tumors in multiple different endocrine organs
o 3 types: MEN1, MEN2A, MEN2B
o MEN1 = MEN gene
 PPP
 Pituitary Adenoma
 Parathyroid Hyperplasia
  Pancreatic tumors
 Tumors cause hormone overproduction in pituitary gland,
parathyroid gland, and pancreas
 Hyperparathyroidism
 Disrupts the normal blood Ca balance
 Causes kidney stones
 Thinning bones
 HTN
 NV, weakness, fatigue
o MEN2A = RET gene
 PMP
 Parathyroid hyperplasia
 Medullary thyroid carcinoma
 Pheochromocytoma
 Get hyperparathyroidism as well
o MEN2B = RET gene
 MMMP
 Medullary thyroid carcinoma
 Mucosal neuroma
 Marfanoid
 Pheochromocytoma
o Multiple endocrine neoplasia
 MEN1 = Wemer syndrome
o PPP
 Pituitary adenoma
 Parathyroid Hyperplasia
 Pancreatic neuroendocrine tumor
o MEN1 Gene at 11q13
 Menin
 Tumor suppressor
 Scaffold protein
 Loss of function mutation
 o MEN1 inherited AR
 Gene is technically AD at gene level
 But need 1 independent sporadic mutation to give rise to
tumor
 2nd mutation is sporadic –→ can be different cancers in a single
family
 After 2nd hit –→ clonal proliferation of cells with
nonfunctional MEN1
 Diff organs hit –→ pleiotropy
o Loss of heterozygosity in MEN1
 Genetic MEN1
 Germline 1st hit
 Somatic 2nd hit
 Bilateral expression
 Early onset
 Clonal proliferation
 Sporadic endocrine neoplasia
 Somatic 1st hit (of MEN1 gene)
o Proliferation of ½ wt cells, ½ KO cells
 Somatic 2nd hit
o Clonal proliferation
 Late age of onset
 MEN 2
o AD, high penetrance
o RET gene affected
o MEN2A = PMP
 Cysteine transmembrane domain affected
 Parathyroid hyperplasia
 Medullary thyroid carcinoma
 Pheochromocytoma (common)
o FMTC
 Mildest, Medullary thyroid carcinoma
 o MEN2B = MMMP
 Tyrosine kinase affected
 Medullary thyroid carcinoma
 Mucosal neuromas
 Marfanoid
 Pheochromocytomas
 Rare, aggressive
 Bumpy lips
MEN1 vs 2A vs 2B
MEN1 MEN2A, MEN2B
Clinical PPP = Pituitary MEN2A = PMP = Parathyroid Hyperplasia, Medullary
adenoma, Parathyroid thyroid carcinoma, Pheochromocytoma
hyperplasia, Pancreatic MEN2B = MMMP = Medullary thyroid carcinoma, Mucosa
Tumors neuromas, Marfanoid, Pheochromocytomas
Gene Menin RET
Mutation Loss of function Gain of Function
Inheritance AR AD
pattern
Cancer Gene Tumor suppressor Proto-oncogene
type
Tumor Loss of Heterozygous
genotype heterozygosity
Mutation Inactivation Constitutive Activation
consequence

 Hereditary Pheochromocytoma/Paraganglioma
o PCC/PGL
o Tumors of ANS
o Cause
 Mass effect, ↑ catecholaimes
 HTN, stroke
 Headaches, palpitations, diaphoresis, anxiety
o Sporadic –→ high altitudes
 o Tumor syndromes –→ NF1, von Hippel Lindau, MEN2
o If by single trait
 Multiple tumors, bilateral, early onset
o Defect in
 Mitochondrial complex II
 Succinate dehydrogenase
 SDHA, B, C, D, AF2
 Signaling by HIF (hypoxia inducing factor)
o Parent of origin effect in PCC/PGG
 Germline mutation in SDHD or SDHAF2
 Mutation in other, wt allele –→ loss of heterozygosity
 Loss of tumor suppressor gene (H19) on chromosome 11
 H19 is paternally silenced (imprinted and inactive)
 H19 is maternally active
o SDHD defects
 Missense, truncating
o For pt with genetic mutation/at risk,
 Screen w/
 BP, 24 hr metenephrines, abdo CT, MRI of skull base
 X-Linked Adrenoleukodystrophy (X-ALD)
o In boys
 ADHD
 Vision loss
 Incoordination
o In adult men
 Gait disorders
 Sexual dysfunction
o All males
 Primary adrenocortical insufficiency
o Older men
 Paraparesis
 Abnormalities of sphincter control
 o X-ALD genetics
 ABCD1 gene –→ ADLP
 On Xq28
 Defect in peroxisomal B-oxidation of VLCF
 Accumulation of VLCFA (C24:0, C26:0)
o X-ALD different phenotypes
 Cerebral inflammatory
 Common in kids
 Rapid
 ADHD/ white matter lesions
 Adrenomyeloneuropathy
 Adults
 Non-inflammatory distal axonopathy
 Addison only
 Primary adrenocortical insufficiency
o X-ALD is
 Common peroxisomal disorder
 Common monogenic demyelinating disorder
 XLR
o Treat w/
 Lorenzo’s oil (eruric and oleic acids)
 Hematopoietic stem cell therapy

015 – Pediatric Endocrine Genetics

 Williams Syndrome
o Elfin facies, short
o Intelligence strengths
 Auditory, verbal
o Intellectual weakness
 Special and motor
o Elastin arteriopathy, HTN,hypercalcemia
o Can be AD or sporadic
 o Caused by hemizygosity of chr7q11
 Microdeletion
 Cannot see on karyotype
 Test w/FISH
o Ch 7q11 critical region
 Contiguous gene syndrome
 Different genes deleted on this continuum –→ give different
phenotypes
o Detect deletions w/FISH
 22q11.2 deletion syndrome
o AKA di-george/velocardiofacial/shprintzen/CATCH22
o Hypocalcemia due to hpoparathyroidism
o CATCH-22
 Cardiac defects
 Abnormal facies
 Thymic hypoplasia
 Cleft palate
 Hypocalcemia from hypoparathyroidism
 22q11 microdeletion
o Conotruncal anomaly –→ face
 Wide set eyes
 Narrow eyes
 Small mouth
 Nose divided into 2 parts
o Deletion seen in
 DGCR critical region
 Mostly de novo
 Can be AD deletion of TBX1
 T-box transcription factor
 Regulates transcription in development
 Heterozygosity is responsible for 5 phenotypes
o Cardiac abnormalities
 o Abnormal facies
o Thymic hypoplasia
o Cleft palate/velopharyngeal insufficiency
o Hypocalcemia form hypoparathyroidism
 Test for 22q11.2 with FISH
o DGCR (DiGeorge Critical Region) testing
 TUFLE-1 and N25 are part of critical region
 Use to determine if 22q positive or if there is deletion
 Testing regions are
 LCR-A, B, C, D
 Match up with controls to detect recombination and loss
of genes
 ARSA and SHANK3 are controles
 TUFLE-1 is target for region probe
 Imprinting syndromes
o Beckwith Widemann
o Silver Russell Syndromes
o CpG island with methylation silencing
 Beckwith Wiedemann
o Sporadic
o Phenotype
 Overgrowth
 Macroglossia
 Visceromegaly
 Wilm’s tumor and hepatobalstoma
 Hemihyperplasia
 Adrenocortical cytomegaly
 Silver Russell syndrome
o Locus heterogeneit (ch 11, 7 etc..)
o Phenotype
 Dwarfism
 Failure to thrive, feeding problem
  Body asymmetry
 5th finger clinodactyly
 Hemihypoplasia
 Triangle face
 Chromosome 11p15.5 imprinted region
o In normal pt, methylation controls growth and cell proliferation
o ICR1 methylated so CTCF doesn’t bind
 If ICR1 methylated
 No CTCF –→ ↑ IGF2→ ↑ growth
 If ICR1 not methylated
 No CTCF –→ ↓ IGF2 –→ ↓ Growth
 ICR1 normally methylated on paternal gene –→ ↑ IGF2 –→
growth
 ICR1 normally not methylated on maternal gene –→ ↓ IGF 2 –
→ no growth
o ICR2 methylated to –↑ CDKN1C expression –→ ↓ cell division
 ICR 2 normally not methylated in paternal gene
 ↓ CDKN1C –→ ↑ cell division
 ICR 2 normally methylated in maternal gene
 ↑ CDKN1C –→ ↓ cell division
o Gene functions in parents
 From paternal allele
 ICR1 region
o Get IGF2 –→ growth
 ICR2 region
o KCNQ1OT1 –→ ↓ CDKN1C –→↑ Cell proliferation
 From maternal allele
 ICR1 region
o Get H19 –→ tumor suppressor
 ICR2 region
o Get CDKN1C –→ ↓ Cell proliferation
 o In Beckwith Widemann syndrome
 Loss of methylation at ICR2
 ↓ CDKN1C on maternal gene –→ ↑ cell division –→ acts
like paternal gene
 Paternal uniparental disomy
 ↑ IGF2, ↑ cell division
 Gain of methylation at ICR1
 Maternal gene –→ ↑ IGF2 –→ ↑ growth
 Maternal CDKN1C mutation
 ↑ cell division
o In Silver Russel Syndrome
 Loss of methylation at ICR1
 On paternal gene –→ ↓ IGF2 –→ ↓ growth
 Maternal disomy of chromosome 7
 ↓ growth
 Beckwith Widemann vs Silver Russel syndrome
BWS SRS
- Overgrowth syndrome - Failure to thrive
- Sporadic - Sporadic
- Familial = AD - Familial = AD
- Paternal Uniparental disomy at - ↑ maternal 11p15.5
chromosome 11 - ↓ methylation at ICR1
- ↑ Paternal 11p15.5 - Maternal uniparental disomy
- ↑ methylation at ICR1 at chromosome 11
- ↓ methylation at ICR2 - IGF2 silencing
- Maternal CKN1C mutation - Active CDKN1C
- Biallelic IGF2 expression
- Silenced CDKN1c
016 – Adrenal Pharmacology
 Effects of glucocorticoids
o Endogenous glucocorticoids = cortisol
 ↑ blood sugar
 ↑ gluconeogenesis –→ making glucose form muscle AA –→
muscle wasting and weakness
 ↑ lipolysis in periphery –→ fat goes to liver and truncal obesity
 Buffalo hump
 Moon facies
 Protuberant abdomen
 If prediabetic pt on glucocorticoids –→ worsens glucose profile
 Control with fiabetic drugs
o Cortisol important for fetal lung development
 Premature babies have –↓ surfactant –→ ↑ surface tension
 Surfactant made by type 2 pneumocytes
 If pt at risk for preterm labor → give mother steroid injection
betamethasone/dexamethasone 24-48 hours before expected
labor
o Cortisol in skin → inhibits collagen synthesis
 At physiologic levels → no major inhibition of collagen
synthesis
 At high levels from exogenous steroid → inhibits collagen
synthesis → thin fragile skin → purple stria
 Lose flexibility→ easy bruising
 If giving a pt corticosteroid cream for psoriasis or contact
dermatitis → still get skin changes (localized)
 If PO steroids → get skin changes as well, but diffuse
o Main indication these days for glucocorticoids are for effect on
immune system
 Immunosuppression
 Inhibits lymphocytes, basophils, eosinophils
 All cells go ↓ in number
  Induces apoptosis in affected WBCs → redistribution of
lymphocytes
o Used as part of anti-cancer therapy for
hematological malignancies
o Decreases # of WBCs by induction of apoptosis
 Anti-inflammatory (due to PLA suppression)
 Inhibition of phospholipase A2 (normally cleaves
arachidonic acid)
 Inhibition of prostaglandin and leukotriene metabolite
release
 When Arachidonic acid cleaved and free floating → COX
and LOX can cleave it to prostaglandins and leukotrienes
 Anti-allergies
 Stabilization of mast cells → ↓ degranulation of mast
cells
 Decreases release of histamine
o In bone
 Increases Osteoclast activity
 Decreases Ca absorption in GI tract
 Increases Ca excretion in Kidney
 Leads to osteoporosis → GIOP → Glucocorticoid induced
osteoporosis
 Tx with bisphosphonates
o In brain
 Steroids cause euphoria
 Can also cause depression over time
 In bone cancer → also used to increase appetite
 Glucocorticoid MoA
o GC binds intracytoplasmic receptors
o Whole complex foes to nucleus
o Binds DNA –→ alters gene expression
 o –↑ Lipocortin/Annexin –→ inhibits PLA2 –→ ↓ Arachidonic acid
cleavage
 Stabilizes mast cells –→ ↓ histamine release
 ↓ WBCs
 ↓ production and release of cytokines IL-1, IL-6, TNF-a
 Effects
o GC effect –→ ant-inflammatory (AIE)
o MC effect –→ ↑ BP by Na/H2O resorption and K excretion
 PK
o Short acting
 Hydrocortisone
 Cortisone
o Intermediate acting
 Prednisone
 Prednisolone
 Methylprednisolone
 Triamcinolone
o Long acting
 Betamethasone
 Dexamethasone
 Route of administration
o IV/IM/oral –→ get systemic effect
o Inhaled –→ no systemic effect
o Topical –→ no systemic effect
o Intraarticular –→ no systemic effect
 Metabolism
o By phase 1 and phase 2 –→ ↑ t1/2
o Phase 1 –→ 3A4 inhibitors
 Macrolides, erythromycin, clarithromycin, ketoconazole,
antiretrovirals, ritonavir, indinavir
o Phase 2 –→ glucuronic acid conjugation –→ water soluble –→ renal
excretion
 Inhaled steroids
o SE is thrush and hoarseness of voice
o Minimal systemic SE because
 Drug has high 1st pass effect
 Drug has high specificity in lung
o Expect systemic side effects when
 Lower first pass effect (liver disease)
 Drug overuse –→ saturates CYP Ez
 Impaired liver
 Steroid S/E
o Cushings
o Decreased growth in children because
 ↑ glucose –→ negative feedback on pituitary –→ ↓ GH
release
o Glaucoma –→ ↑ Intraocular pressure
o –↑ risk infection
o Osteoporosis
 CNS/Metabolic side effects of steroids
o GC effects
 Increased appetite
 Emotional disturbances
 Ulcer due to –↓ PGE
o MC effects
 HTN
 Peripheral edema
 ↓K
 Suppression of HPA axis
o Due to GC effect
o Systemic steroids
o High dose
o Long use
o Daily use
  Decreases CRH first, then ACTH
 If pt has cushingoid appearance –→ automatically has HPA
suppression
 Taper pt off steroids –→ if suddenly take them off –→
hypoglycemia
 Drugs to inhibit endogenous steroid synthesis
o Ketoconazole most effective
o Mitotantate, metytraprone, aminoglutethimide, mifepristone
o If tumor is in adrenal or pituitary
 Give ketoconazole
 Suppresses most stepes of endogenous MC, GC, and androgen
synthesis
 GC use in pregnancy
o Placenta is capable of metabolizing drugs
o Prednisone is preferred in pregnancy to treat maternal conditions
 Minimizes steroid effect on fetus
o Prednisolone not recommended in pregnant
 Can travel to baby
 Placental enzymes can convert to prednisone (prodrug)

017 – Meet The Patient Hypothalamic Pituitary Adrenal Axis

 L

018 – Meet the Patient Adrenal Part 2

 L

019 – Meet the Patient Functioning, Nonfunctioning Pituitary Adenomas and

Hypopituitarism
 L
020 – Physiology of the Pancreas
 Endocrine pancreas
o Alpha cells –→ Glucagon
o Beta cells –→ insulin, proinsulin, C peptide, amylin
o Delta cells –→ Somatostatin
o F cells –→ Pancreatic polypeptide
o Alpha cells on outside
o Beta cells on inside
 ↓ insulin –→ ↑ glucagon
 ↓ blood glucose –→ ↑ glucagon
 Interactions of hormones to maintain glucose concentration
o Insulin
 ↓ Liver glucose production
 ↑ Adipose and skeletal muscle glucose uptake
o Glucagon
 ↑ liver glucose production
o Epinephrine and norepinephrine
 ↑ liver glucose production
o Glucocorticoids
 ↑ liver glucose production
 ↓ adipose tissue and muscle glucose uptake
o Growth Hormone
 ↑ liver glucose production
 ↓ adipose tissue and muscle glucose uptake
 After ingestion of a carb rich meal
o –↑ insulin
o –↓ glucagon
 Maintenance of blood glucose by glucagon and insulin
o Eat food –→ ↑ blood glucose
o –↑ insulin
 Adipose, skeletal muscle glucose uptake –↑
 Liver –↑ glycogenesis, ↓ gluconeogenesis
 o Blood glucose –↓ to normal levels
o At night
 ↓ blood glucose
o –↑ glucagon
o Liver
 –↑ glycogenolysis, gluconeogenesis
o Blood glucose –↑ to nl levels
 Effect of insulin and glucagon on hepatic glucose metabolism
o In hepatic glycogenolysis
 Insulin
 ↑ Glycogen synthase
o ↑ Glucose-1-P –→ Glycogen
 Glucagon
 ↑ Glycogen phosphorylase, ↓ Glycogen synthase
o Glycogen –→ ↑ Glucose-1-P


o In hepatic glycolysis
 Insulin
 ↑ Glucokinase
o Glucose –→ ↑ G6P
 ↑ Pyruvate Kinase
o Phosphoenolpyruvate –→ ↑ Pyruvate
 Glucagon
 ↓ Glucokinase
o ↓ Glucose –→ G6P
 (↑ glucose, ↓ G6P)
  ↓ Phosphofructokinase
o –↓ F6P –→ F1,6BP
 (↑ F6P, ↓ F1,6BP)
 ↓ Pyruvate Kinase
o –↓ Phosphoenolpyruvate –→ Pyruvate
 (↑ PEP, ↓ pyruvate)


o On hepatic gluconeogenesis
 Insulin
 ↓ PEP Carboxykinase
o –↓ Oxaloacetate –→ PEP
 (↑OAA, ↓ PEP)
 ↓ Glucose 6 phosphatase
o –↓ G6P –→ Glucose
 (↑ G6P, ↓ Glucose)
 Glucagon
 ↑ PEP Carboxykinase
o –↑ Oxaloacetate –→ PEP
 (↓OAA, ↑ PEP)
  ↑ F1,6BP –→ F6P
o –↑ F6P
 ↑ Glucose 6 phosphatase
o –↓ G6P –→ Glucose
 (↓ G6P, ↑ Glucose)


 Nutritional state effect on insulin and glucagon secretion
o After large meal –→ I/G –→ 70
o IV glucose –→ I/G –→ 25
o Small meal –→ I/G –→ 7
o Overnight fast –→ I/G –→ 2.3
o Low carb diet –→ I/G –→ 1.8
o Starvation –→ IG –→ 0.4
 Mechanism of release and cellular action on Insulin
o T1/2 of insulin = 5 min
o T1/2 C peptide = 30 min
 Use C peptide to measure insulin activity
 Mechanism of release of insulin in response to hyperglycemia
o Glucose enters B cell by GLUT2
o Glycolysis –→ ↑ ATP
 o ATP closes ATP sensitive K channel
o Depolarization
o Opens VGCaC
o –↑ Ca –→ exocytosis of insulin
 Cellular action of insulin
o Insulin binds alpha subunit of insulin receptor
o Activates tyrosine kinase
o Phosphorylation of enzymes
 ↑ glucose import into cells
 ↑ protein synthesis
 ↑ fat synthesis
 ↑ glycogen synthesis
 Insulin mechanism of cellular action
o Insulin binding Alpha subunit activates
o Receptor tyrosine kinase activity in Beta subunit of the insulin
receptor
o Tyrosine residues of Beta subunit are auto-phosphorylated
o Receptor tyrosine kinase phosphorylates other proteins
o Phosphorylated substrates promote activation of other protein
kinases and phosphatases, leading to
 ↑ glucose euptake
 ↑ glycogen synthesis
 ↑ protein synthesis
 ↑ fat synthesis
 Plasma insulin concentration
o Sudden spike within 5 minutes
 Represents 5% of insulin activity
o Then drops
o Then slowly increases after 20 min for 2-3hr
 Time course for biological actions of insulin
o Rapid (seconds)
 ↑ transport of glucose, AA, and K into insulin sensitive cells
 o Intermediate (minutes)
 ↑ protein synthesis
 ↓ protein degradation
 ↑ glycolytic Ez and glycogen synthase
 ↓ Phyosphorylase and gluconeogenic Ez
o Delayed (hours)
 ↑ mRNA for lipogenic and other Ez
 Regulation of insulin secretion
o Stimulants of insulin release
 Glucose
 AA (leucine)
 Neural: Vagal stimulation, ACh
 Drugs: Sulfonylureas, Meglitinides
o Amplifiers of Glucose-induced Insulin release
 Enteric hormones: GLP-1, GIP, CCK, gastrin, Secretin
 Neural: B adrenergic effect of catecholamines
 Amino acids: Arginine
 Drugs: GLP1 agonists
o Inhibitors of Insulin release
 Neural: a adrenergic effect of catecholamines
 Humoral: Somatostatin
 Drugs: Diazoxide, thiazides, B blockers, clonidine, phenytoin,
vinblastine, colchicine
 Regulation of Insulin secretion
o Increased by
o GLUT-2 –→ ↑ Glucose→ ↑ ATP, NADPH –→ close K channel –→
open VGCaC –→ Insulin granules release
o CCK, ACh –→ bind Gq pcR –→ ↑ IP3, Ca, Insulin release –→ ↑ DAG,
PKC, insulin release
o GLP-1 –→ bind Gs –→ ↑ cAMP –→ ↓PKA –→ insulin release
o Somatostatin –→ bind G1 –→ ↓ cAMP –→ ↓ PKA –→ ↓ insulin
release
 o
 GLUTs
o GLUT 1, 2, 5 normally on surface
o GLUT 4 in center of cells, released when needed
o GLUT-1
 In RBCs and brain blood vessels, some in skeletal muscle and
fat
 Basal uptake of glucose in muscle and fat
o GLUT-2
 Low affinity glucose transporter present in pancreatic B cells,
liver, intestine, kidney
 Glucose sensing system, glucose uptake into B cells and
hepatocytes only when concentration is high
o GLUT-3
 Primarily in neurons
 GLUT-1 and GLUT-3 are crucial in allowing glucose to cross the
BBB and enter neurons
o GLUT-4
  Mostly in muscle and adipose. Sequestered in specialized
storage vesicles that remained inside cell interior under basal
conditions
 Major insulin responsive transporter
o GLUT-5
 Spermatozoa and small intestine
 Predominantly fructose transporter
 Cycling of GLUT-4 through endosomes in insulin-sensitive tissues
o Insulin binds to its receptor in the cell membrane
o Binding causes a signaling cascade
o Promotes recruitment of glucose transporters from an intracellular
pool to the cell membrane
o GLUT-4 increases insulin-mediated uptake of flucose into the cell
o When insulin levels decrease
o GLUT-4 moves from the cell membrane to the intracellular storage
pool
o Vesicles fuse to form an endosome
 Insulin actions
o in serum
 –↓ glucose, FFA, ketoacids, AA, Glycerol,
 ↓ K+
o In muscle
 ↑ glucose entry, glycogen synthesis, AA uptake, protein
synthesis in ribosomes, ketone uptake, K+ uptake
 ↓ protein catabolism, release of gluconeogenic AA
o In liver
 ↓ ketogenesis, gluconeogenesis,
 ↑ Protein synthesis, lipid synthesis, glycogen synthesis,
glycolysis
o In adipose
 ↑ Glucose entry, FA synthesis, glycerol phosphate synthesis,
TG deposition, activation Lipoprotein lipase, K uptake
 ↓ hormone sensitive lipase
 Glucagon
o Stimulated by
 AA (gluconeogenic alanine, serine, glycine, cysteine, threonine)
 CCK, gastrin, cortisol, exercise, infxn, B adrenergic stimulators,
theophylline, acetylcholine
o Inhibited by
 Glucose, somatostatin, secretin, FFA, ketones, insulin,
phenytoin, a adrenergic stimulators, GABA
o Effect on blood levels
 ↑ glucose, FFA, ketoacids, glycerol
 ↓ AA
o Glucagon effect on hepatic glucose metabolism
 Stimulates glycogen phosphorylase –→ breaks down glycogen
 Stimulates G6 phosphatase –→ ↑ glucose
 Inhibits glycogen synthase –→ ↓ glycogen
 Stimulates gluconeogenic Ez –→ ↑ glucose
 Inhibits glycolytic Ez –→ ↓ glucose
o Effects of glucagon on hepatic glucose metabolism
 –↑ G6 phosphatase –→ ↑ glucose
 –↓ glucokinase –→ ↓ glucose entry into glycolytic pathway
 –↑ glycogen phosphorylase –→ ↑ glycogenolysis
 –↓ glycogen synthase –→ ↓ glycogen synthesis
 –↑ PEP carboxykinase –→ ↑ gluconeogenesis
 –↓ phosphofructokinase 2 –→ ↓ kinase –→ ↓ glycolysis
 –↑ fructose 6 phosphatase –→ ↑ phosphorylation –→ ↑
gluconeogenesis
 –↓ pyruvate kinase –→ ↓ glycolysis
 Somatostatin
o Inhibitory
o Endocrine and paracrine
 Inhibits insulin and glucagon
 Acts as GH inhibitory hormone (GHIH)
 ↓ TSH release
  ↓ gastric motility
 ↓ secretion and absorption in GI
o Is a polypeptide
o Secretion is stimulated by
 ↑ blood glucose, AA (arginine and leucine), FA, CCK, glucagon,
B adrenergic activity
 Pancreatic Polypeptide (PP)
o Synthesized by F cells of pancreatic islets
o Fxn
 ↓ exocrine secretion
 ↓ absorption in small intestine
o Stimulated by
 Fasting, hypoglycemia
 Protein rich meals
 Cholinergic stimulation and exercise
 Incretins
o Released from GI cells in response to food intake
o GLP-1
o GIP
o Incretins don’t do any insulin release on their own
o Incretins potentiate Insulin release in response to food
o This is called incretin effect
o GLP-1 effect in humans
 ↑ B cell response
 ↓ B cell workload
 ↑ satiety, ↓ appetite
 ↓ glucagon release from alpha cells
 ↓ glucose output from liver
o Actions of GLP-1 and GIP
 GLP-1 in brain
 ↓ appetite, ↓ food intake
 ↑ neuroprotection
  GLP-1 in heart
 ↑ Cardiac function
 ↑ cardioprotection
 GLP-1 in pancreas
 ↑ B cell survival
 ↑ insulin secretion
 ↑ insulin biosynthesis
 GLP-1 in adipose
 ↓ lipolysis
 ↑ lipogenesis
 ↑ glucose use
 GLP-1 in liver
 ↓ glucose production
 GLP-1 in muscle
 ↑ glucose use
 GLP-1 in stomach
 ↓ gastric emptying
 Overall –→ ↓ plasma glucose
 Insulin Amylin ration = 20/1
 Regulatory actions of amylin
o –↓ glucagon secretion
o Regulates appetite
o Glucose lowering actions are over-ridden during hypoglycemia
 Leads to glucose-dependence of amylin action
o –↓ gastric emptying
o –↓ food intake
o –↓ digestion
o –↓ glucagon secretion Toliver
o –↑ insulin
 Summaries
o Effect of hormones on skeletal muscle


o Effect of hormones on liver


 o Effect of Hormones on adipose

021 – Endocrine Pancreas Pathology

 Pancreas on histo
o B cells –→ insulin secretion, in center –→ 68%
o A cells –→ glucagon –→ 20%
o D cells –→ somatostatin –→ 10%
o PP cells –→ 2%
o B cells
 Dark granules with halo
o A cells
 Dark granules, no halo
o D cells
 No dark cranules
 Diabetes mellitus
o Characterized by hyperglycemia
o Defects in
 Insulin secretion
 Insulin action
 o Long term damage to
 Kidneys, eyes, nerves, blood vessels
o Leading cause of
 End stage renal disease
 Adult blindness
 Nontraumatic lower extremity amputations
o Type 1
 Autoimmune B cell destruction
 Absolute insulin deficiency
o Type 2
 Insulin resistance
 B cell dysfunction
 Secondary diabetes
o Disease of exocrine pancreas
 Pancreatitis, neoplasia, cystic fibrosis, hemochromatosis,
pancreatectomy
o Endocrinopathies (cushing)
o Drugs: glucocorticoid, B adrenergic agonists
o Infections, CMV, coxsackie, rubella
o Gestational DM
 Monogenic Diabetes
o Genetic defects in B cell function
 MODY (Maturity onset Diabetes of the Young)
 Insulin gene –→ neonatal diabetes
 Maternally inherited Diabetes and Deafness
 MIDD –→ mitochondrial DNA mutations
o Defects in insulin action
 Insulin receptor mutations
 T1DM Pathogenesis
o Lack of insulin
o Islet cell destruction due to
 Autoimmunity (T-cell mediated)
  CD4 and CD8 mediated
 Genetic susceptibility
 HLA-D, CTLA4, PTPN22, insulin
 Environmental (virus –→ molecular mimicry, intestinal
dysbiosis)
o Pathogenesis
 Autoreactive T cells to B cell antigens
 CD4 and CD8 T cells
 Autoantiboides
 Insulitis
 Intense lymphocytic infiltrate
 B cell depletion
 Late –→ atrophy and fibrosis
 Stages
 Stage 1 –→ Overt immunologic abnormalities, nl insulin
release
 Stage 2 –→ progressive eloss of insulin release, nl
glucose
 Stage 3 –→ overt diabetes
 If pt is already at stage 3, overt diabetes, no more
insulitis in islets
o Just see less islets
 Type 2 Diabetes Mellitus
o Pathogenesis
 Obesity and other environmental factors
 Genetic, but no HLA association
 Pro-inflammatory state
 Insulin resistance + B cell dysfunction
 Get insulin resistance before hyperglycemia
 Compensatory B cell hyperplasia –→ normoglycemia
 B cell failure early –→ impaired glucose tolerance
 B cell failure late –→ diabetes
 o Pathogenesis from obesity in T2DM
 Central obesity
 ↓ adiponectin –→ ↓ cardioprotection
 ↑ FFA –→ overwhelm oxidative pathways –→ ↑ DAG –→ ↑
insulin resistance
 Pro-inglammatory state
 All this leads to
 Insulin resistance
 B cell compensation by hyperplasia
 B cell failure
 Insulin resistance + B cell dysfunction
 ↑ FFA –→ lipotoxicity
 Chronic hyperglycemia –→ glucotoxicity
 Blunted incretin effect –→ ↓ insulin sensitivity, ↑
gastric emptying
 Amyloid replacement of islets
o Histology in T2DM
 Amyloid deposition around capillaries and B cells
 Amylin amyloid –→ secreted w/insulin
 Mild B cell depletion in early stages
 Advanced stages –→ islet obliteration, fibrosis
 Chronic complications of DM
o Atherosclerosis –→ HTN, MI, CVA,
o Opthalmopathy
 Retinopathy
 Cataracts
 Glaucoma
o Islet cell loss
 Insulitis (T1DM)
 Amyloid (T2DM)
o Nephrosclerosis
 Glomerulosclerosis
  Arteriosclerosis
 Pyelonephritis
o Peripheral vascular disease –→ gangrene, infections
o PNS/ANS neuropathy
 Metabolic pathways involved in pathogenesis of long term complications
o Formation of AGEs
o Activation of PKC
o Disturbance in Polyol pathways –→ PNS damage
o Glucotoxicity –→ ↑ hyperglycemia –→ harmful precursors –→ end
organ damage
 AGEs
o Advanced glycation end products
o Form by non-enzymatic glycosylation of amino groups
o Bind RAGE receptors on T cells, endothelial cells, and smooth muscle
 Pro-inflammatory cytokines –→ TGF-B, VEGF
 ROS in endothelium
 Procoagulant activity of endothelium and macrophages
 Proliferation of vascular smooth muscle cells
 ↑ synthesis of ECM
o AGEs can crossling to ECM proteins
 Decreases removal from body
o –↑↑↑ Atherosclerosis in AGE modified vessels
 Diabetic macrovascular disease
 AGEs cross linke LDLs and deposit in intima at an accelerated
rate
o Diffuse thickening of basement membranes in glomerulus
 Diabetic microangiopathy
 Glomerulosclerosis
 Activation of PKC
o Intracellular hyperglycemia –→ ↑ DAG synthesis
o DAG activates PKC
  PKC –→ ↑ VEGF –→ neovascularization –→ proliferative
diabetic retinopathy
 Excess vascularity in retina
 PKC –→ ↑ TGF-B –→ ↑ deposition of ECM (type IV collagen)
in basement membrane –→ glomerulosclerosis
 Disturbance in polyol pathway
o PNS damage
o Hyperglycemia –→ excess glucose metabolized to sorbitol
 This uses NADPH via Aldose reductase
 NADPH required to generate reduced GSH
 Hyperglycemia –→ ↑ sorbitol –→ ↓ NADPH –→ ↓ GSH –→
susceptibility oxidative stress
o –↑ cell osmolarity –→ free water influx –→ cell injuty
o Important in diabetic neuropathy
 Chronic complications of DM
o Diabetic macrovascular disease
 Atherosclerosis and hyaline arteriosclerosis
 MI, CVA, gangrene
o Diabetic microangiopathy
 Diffuse thickening of basement membranes
 Skin, retina, glomeruli, renal tubules, bowman’s capsule
o Nephropathy
o Ocular complications
 Retinopathy, cataracts, glaucoma
o Neuropathy
 Symmetric peripheral neuropathy affecting sensory and motor
nerves
 ANS neuropathy
 Diabetic nephropathy
o Renal macrovascular disease
 Atherosclerosis, hyaline arteriolosclerosis
o Glomerular lesions
  Capillary basement membrane thickening (microangiopathy)
 Diffuse mesangial sclerosis (↑ mesangial matrix)
 Mesangial cells are cells between capillary loops in
glomerulus
 Nodular glomerulosclerosis (Kimmelstiel-wilson lesion)
 Nodular sclerosis pathogneumonic for T2DM
o Pyelonephritis
 Necrotizing papillitis
 Papillary necrosis
o Hyaline arteriolosclerosis
 Afferent –→ in HTN and elderly
 Efferent hyaline arteriolosclerosis –→ pathogneumonic of
T2DM
 Can do trichrome stain –→ lots of collagen in hyaline
arteriolosclerosis- → stains blue
 Nodularity in arteriolosclerosis means DM
 Can also do PAS stain –→ stains glycosylation (AGEs) pink
o Renal tubules
 Capillary basement membrane thickening
 Nephrosclerosis
 Glomerular lesions + arteriolar lesions –→ ischemia and
scarring
o Diabetic nephropathy
 Pyelonephritis –→ papillary necrosis
 Necrosed papillae seen in medulla
 Ocular complications
o May lead to blindness
o Retinopathy
 Proliferative or nonproliferative
 Hemorrhage
 Exudates
 Neovascularization seen in proliferative retinopathy
  Retinal detachment
o Cataracts
o Glaucoma
 Diabetic neuropathy
o Diabetes causes several types of neuropathy which include
 Distal symmetric polyneuropathy (common)
 Mononeuropathy
 Cranial radiculopathy
 ANS neuropathy
o Distal symmetric polyneuropathy –→ sensorimotor
 Pain, sensory loss, weak reflexes, weakness
o Microangiopathy + direct axonal damage (polyol)
 Pancreatec Neuroendocrine tumors (PanNET)
o Adults
o Anywhere in pancreas or extrapancreatic
 Usually in body
o Metastasizes to liver
o Express neuroendocrine markers
 Synaptophysin, chromogranin
o Can be syndromic
 MEN1, VHL, NF1, TSC
o Can be functional
 Insulinoma –→ ↑ insulin, hypoglycemia, benign
 Gastrinoma –→ ZES, aggressive
o Ki-67=NIB1 IHC stain
 Only stains cells in G0
 Measures approximate amount of mitoses
 Insulinoma
o Most common functioning PanNet
o –↑ insulin –→ hypoglycemia
o 90% benign
o Histo
  Encapsulated, well circumscribed
 Well differentiated B cells
 Can have amyloid deposits due to –↑ insulin secretion
 Insulinoma amyloid = T2DM amyloid
o Metastasizes to the liver
o Stains with chromogranin, synaptophysin
 Gastrinoma
o Neoplasm with G cell differentiation
o Seen in pancreas, peripancreatic tissue, or duodenum
o ZES syndrome
 ↑ gastric acid –→ PUD –→ ulcers in weird places like distal
duodenum
 Diarrhea
o Malignant usually –→ invasive or metastatic
o MEN1 association –→ duodenal wall involvement, multiple tumors
o Stains with chromogranin, synaptophysin
 Glucagonoma
o Perimenopausal women
o Miled DM
o Necrolytic migratory erythema (NME)
 Rash starts in inguinal area –→ travels to limbs
 Rash + new onset diabetes in postmenopausal woman =
glucagonoma
o Glossitis, alopecia, onycholysis
o Weight loss, depression, diarrhea, DVT
o 4 Ds
 Diabetes
 Dermatitis (NME)
 DVT
 Depression
o 60-70% have metastatic disease at diagnosis
 Other PanNET tumors
o Somatostatinoma
 Delta cell tumor
 DM, cholelithiasis, steatorrhea, hypocholrhydria
 Dx by –↑ somatostatin in plasma
o VIPoma
 Severe secretory diarrhea
 Hypokalemia, achorhydrria
 Verner-morrison sx
o Pancreatic polypeptide secreting tumors
 Asymptomatic
o Pancreatic carcinoid tumors
 Serotonin carcinoid syndrome
 Questions
o Histo showing amyloid in pancreas
 If tumor –→ insulinoma
 Also seen in T2DM
o 50 y/o man, sexual dysfxn, diarrhea, difficulty urinating, why?
 ANS problems
 Due to sorbitol accumulation from polyol pathway
 Aldose reductase, decreased NADPH
o Histo showing pancreas with lymphocytic infiltrate
 CD4, CD8 insulinitis
 No major sx at this time since pancreatic B cells still present
 Early on in course for T1DM
o 30 y/o woman with low volume watery diarrhea, midepigastric pain,
ulcers that don’t respond to treatment
 Gastrinoma
 ZES syndrome
022 – Pre Recorded Drugs used in the treatment of Type 2 Diabetes
 Insulin synthesis
o Synthesized as proinsulin in pancreatic B cells
 Packaged in secretory vesicles by golgi
o Proteolytic cleavage –→ insulin and C peptide
o Test for C peptide (↓ in T1DM, ↑ T2DM)
o Can use to test for B cell failure in T2DM
o Can test for factitious hypoglycemia vs insulinoma
 Insulin receptor
o Tyrosine kinase receptor
o Insulin binds receptor tyrosine kinase
 Kinase activity stimulated
 Tyrosine residues are phosphorylated
 Intracellular proteins bind to phosphor-tyrosine docking sites
 Downstream effect mediated through phosphorylation of
insulin receptor substrates (IRSs)
 Fxn of insulin
o ↑ glucose uptake, ↑ glycolysis
o –↑ glycogen synthesis, ↓ gluconeogenesis
o –↑ lipogenesis, ↓ lipolysis
o –↑ protein synthesis, ↓ proteolysis
o –↑ cell survival
o Activates PIP3 Kinase
 Leads to GLUT-4 translocation to surface of cell
 Goal of insulin therapy
o To mimic physiologic insulin secretion
o Have basal level of secretion and postprandial boosts
 Basal insulin
 Long acting Glargine or detemir
 Intermediate NPH
 Pre prandial insulin
 Rapid acting lispro, aspart, or glulisine
  Short acting regular
 Administration
o IV –→ only regular insulin in emergencies (DKA, Hyperkalemia)
o Subcu –→ rapid or short acting
o Delivery pumps
o Subcu –→ long acting glargine, detemir, or intermediate NPH
 IV regular insulin
o Severe hyperglycemia, hyperkalemia, DKA
o Critical care
o Labor and delivery
o Hyperosmolarstate
o Uncontrolled hyperglycemia due to glucocorticoids
 S/E of insulin
o Hypoglycemia (if don’t eat, exercise, or renal failure –→ ↓ insulin
clearance)
o Hypokalemia
 insulin –→ ↑ Na/K ATPase –→ ↓ Serum K –→ hypokalemia
 Give insulin with dextrose to prevent hypoglycemia
o Lipodystrophy/lipoatrophy at injection site
o Weight gain
o Hypersensitivity
 Hypoglycemia
o Can also be seen in sulfonylureas and meglinitides
o Signs of ANS hyperactivity
 Sympathetic
 Tachycardia, palpitation, sweating, treamor
 Parasympathetic
 Nausea, hunger
o Neurologic Sx
 Irritability, confusion, blurred vision, tiredness, headache,
difficulty speaking, loss of consciousness, seizure, coma
o Tx
  Candy, juice, glucose
 Glucagon injection in severe situation when pt is unresponsive
and cannot eat
 T2DM drug targets
o Liver does gluconeogenesis and glycogenolysis
 Metformin decreases glucogenogensis
o Pancreas secrete insulin
 Try to increase insulin secretion
 Sulfonylureas, meglitinides
o Peripheral glucose uptake
 TZDs to insulin
 Peripheral glucose uptake by insulin sensitivity
o GI glucose absorption
 Acarbose (a glucosidase inhibitors) decrease glucose
absorption from GI tract
 Biguanides –→ metformin
o Monotherapy or combination
o Low risk hypoglycemia
o Does not cause weight gain
o Absorbed in GI
o Not metabolized –→ excreted in kidney
o Contraindicated in renal failure (diabetic nephropathy)
 Monitor GFR (contraindicated in GFR<30)
o Metformin MoA
 Goes into hepatocytes
 Inhibits mitochondrial complex 1 –→ ↓ ATP –→ ↑ AMP
 ↓ ATP –→ ↓ cAMP –→ ↓ PKA activity –→ ↓ Gluconeogensis
 ↑ AMP –→ ↑ AMPK activation –→ ↑ insulin sensitivity
o Metformin fxn
 Increases peripheral uptake of glucose by increasing insulin
sensitivity at skeletal muscle and fat
 ↓ hepatic glucose output
 ↓ glucose absorption from GI tract
  Direct stimulation of glycolysis in tissue
 Increased glucose removal from blood
o Metformin S/E
 Common –→ GI, NV, Flatulence, cramps, diarrhea
 Rare
 Megaloblastic anemia from b12 malabsorption
 Lactic acidosis (MALA)
o Metformin associated lactic acidosis
 Seen in sick pt, renal impairment, CHF, hepatic insufficiency
 Renal failure –→ ↓ excretion of drug
 Hepatic failure –→ ↓ clearance of lactate
 Poor perfusion –→ ↑ fermentation –→ ↑ lactate
 Glycolysis –→ pyruvate –→ oxidative phosphorylation in kreb’s
cycle
 In metformin, oxidative phosphorylation inhibited→
channeled to lactate –→ lactic acidosis
 Insulin release physio
o Glucose enters B cells via GLUT 2
o GLUT 2 has low affinity for glucose –→ imports glucose only when
serum glucose is high
o –↑ ATP in cells
o Binds ATP K channel
o Depolarization of cell
o Opens VGCaC
o –↑ Cell Ca
o –↑ exocytosis of insulin granules
 Insulin secretagogues
o Sulfonylureas (Glyburide, Glipizide, Glimepiride)
 K-ATP channel blockers
 MoA
 Bind SUR1 site on K ATP channel in B cells
 Closes channel –→ ↑ insulin secretion
  Releases insulin regardless of blood concentration
 Metabolized by liver, excreted in urine
 Caution in hepatic or renal insufficiency
 Glyburide caution in renal –→ weak metabolite
 All caution in hepatic
 ↑ risk hypoglycemia
 Hypoglycemic effects present for 12-24 hr
 If elderly pt with hypoglycemia from sulfonylurea use –
→ need to tx for 24 hr
 Minimal transfer across placenta
 Use in pregnant as alternative to insulin
 Sulfonylurea S/E
 Hypoglycemia
 Weight gain
o Non sulfonylurea K-ATP channel blockers (Repaglinide, Nateglinide)
 Binds to K-ATP channel
 Site different from that of sulfonylurea
 Same effect
 Used if pt allergic to sulfa
 Absorbed through GI
 Metabolized in liver –→ excreted in urine
 Caution in hepatic insufficiency and renal impairment
 Shorter acting than sulfonylureas (2-6hr)
 Used to control post-prandial glucose
 S/E
 Hypoglycemia (less than sulfonylureas)
 Weight gain
 Thiazolidinediones (TZDs), Glitazones
o Rosiglitazone, pioglitazone
o PPAR-Y agonists Insulin sensitizer
 PPAR-Y is a nuclear receptor in adipocytes and skeletal muscle
 o TZD glitazone MoA
 TZDs bind PPAR-Y –→ complex with RXR –→ modulate gene
regulation
 ↑ transcription of GLUT-4
 GLUT-4 translocates to surface
 GLUT-4 translocates only when insulin comes and binds
receptor
 ↑ glucose uptake by skeletal muscle and adipose
 Adipose by 30-50%
o Gradual onset of maximal effect over the course of 1-3 months
o Low risk of hypoglycemia
 Because TZDs increase insulin sensitivity, not insulin release
o TZD S/E
 Adipogenesis –→ weight gain
 Kidney –→ sodium and fluid retention
 Leads to peripheral edema
 ↑ appetite
 Major S/E
 CHF due to volume expansion from fluid retention
 Contraindicated in CHF pt
 Osteoporosis
o –↓ osteoblast fxn
o –↑ osteoclast fxn
 A-Glucosidase inhibitors (acarbose
o –↓ glucose uptake in GI
o MoA
 Complex carbs must be broken down in small intestine
 A-Glucosidase is in brush border and breaks down complex
carbs
 Acarbos eis a structural analog of a complex carb
 Competitively blocks the breakdown of complex carbs
 ↓ post prandial glucose
  Given 3x day in relation to meal
 Carbs then broken down in Large Intesitne
 Leads to flatulence and watery diarrhea
o Negligible risk of hypoglycemia and weight gain
o Poor compliance
 Incretin based therapies
o Incretins are GI neuroendocrine hormones (GLP-1, GIP), which are
released in response to a meal
o Incretins are short lived –→ inactivated by DPP4
o Incretins bind B cells, don’t do anything on their own
 Potentiate insulin release in the presence of glucose
o Incretins bind receptors on B cells
 ↑ cAMP in cell –→ ↑ kinase activity –→ ↑ insulin release
o GLP-1 more effective than GIP
o GLP-1 Agonists –→ inhibit DPP4 –→ longer t1/2
o DPP-4 inhibitors –→ ↑ endogenous GLP-1 levels
o Both augment glucose dependent insulin secretion
o Hypoglycemia is rare
o GLP-1 agonists (Exenatide, liraglutide)
 ↑ insulin synthesis, secretion, B cell proliferation, survival
 ↓ gastric emptying, ↑ satiety
 ↑ weight loss
 Contraindicated in
 Gastroparesis
 Pancreatits
o Similar effect in gliptins, but not as effective (saxagliptin, sitagliptin)
 o GLP-1 agonists vs DPP4 inhibitors
GLP-1 Agonists DPP-4 inhibitors
(Exenatide, liraglutide) (Saxagliptin, sitagliptin)
Insulin secretion +++ +
Hypoglycemia Rare Rare
Effect on weight Weight loss Neutral
Administration Sub-Q PO
S/E GI, N/V Well tolerated
Contraindications Hx of pancreatitis, N/A
gastroparesis
 SGLT-2 Inhibitors (canagliflozin, dpagliflozin)
o SGLT2 does glucose reabsorption in proximal tubule
o Gliflozin MoA
 Blocks SGLT-2 pumps
 ↓ reabsorption of glucose
 ↑ urinary excretion of glucose
 ↓ blood glucose
o S/E
 ↑ glucose in urine –→ ↑ bacteria –→ ↑ UTI
 Increased risk of UTI
 ↑ mycotic infections in female
 ↓ blood pressure due to –↓ Na reabsorption from SGLT-2
inhibition
 Moderate weight loss

023 – Pre Recorded Type 2 Diabetes Mellitus

 Types of DM
o T1DM –→ Autoimmune B cell destruction –→ absolute insulin
deficiency
o T2DM –→ Insulin resistance w/B cell dysfunction –→ relative insulin
deficiency
o Genetic defects (MODYs), endocrinopathies and drugs
 o Gestational DM
 T2DM
o 100% MZ concordance, 30% dizygotic
o Strongly familial
o Associated with westernization
o Majority obese
 70% north americans
 100% pima Indians
 30% Chinese/Japanese
o Adipose tissue is heterogeneous
 Visceral abdominal adipose
 More responsive to hormones
 Releases more FFA in response to epinephrine
 Leads to insulin resistance
 Leads to metabolic risk
 Increased waist circumference means increased risk of
co-morbidities
 Subcutaneous adipose
 Metabolically neutral
 Possible mechanisms of why visceral obesity –→ insulin
resistance
 ↑ insulin causes changes in insulin receptor
o –↓ affinity
o –↓ number
o Defects in post receptor signaling
 Release of inhibitory adipokines
o Causes reduced insulin signaling
 ↑ FFAs cause
o Reduced glucose uptake
o –↓ glycolysis
o Ectopic lipid storage in muscle, liver, and B cells
 Inflammatory cells in adipose tissue release cytokines
o Insulin resistance
 Inherited and acquired
 Inherited
 Rare mutations in
o Insulin receptor
o Glucose transporter
o Signaling proteins
 Common forms unidentified
 Acquired
 Inactivity, Overweight
 Aging, Medications
 Hyperglycemia, ↑ FFAs
 Physiologic causes if insulin resistance
 Puberty, pregnancy, aging
 Endocrinopathic causes of insulin resistance
 Cushing’s, acromegaly, pheochromocytoma,
hyperthyroidism, insulinoma, glucagonoma
 Medication causes of insulin resistance
 Steroids, niacin, thiazide diuretics, estrogen, B blockers
o B cells adapt to insulin resistance through
 Hyperplasia compensates for insulin resistance
 Increased insulin secretion –→ normoglycemia
o Acanthosis nigricans
 A sign of –↑ insulin secretion
 Blood sugar may be normal
o Insulin and IGF-1 have some cross activity
 Insulin more specific for insulin receptor
 At high insulin levels
 Insulin can bind IGF-1 receptor
 Leads to growth and IGF-1 response –→ acanthosis
nigricans
o Insulin resistance progression to DM
  B cells can no longer compensate for insulin resistance
 Abnormal B cell function
 Relative insulin deficiency
 Hyperglycemia
 T2DM
o Progression to T2DM
 10 yr before dx –→ insulin resistance
 5 yr before dx –→ compensatory B cell hyperplasia
 B cell burnout
 Fasting glucose increases
 T2DM
 Over time, B cell destruction
 Become insulin dependent
 Plasma glucose rises
 Fasting glucose rises
 Insulin resistance persists
 Insulin secretion decreases
o Diagnosis of Pre-diabetes
 Fasting 100-125
 Glucose tolerance 140-199
 HbA1C 5.7-6.4%
o Diagnosis of diabetes
 Fasting >126
 Glucose tolerance > 200
 HbA1C >6.5
 Sx of T2DM + random plasma glucose >200
 Pre-diabetes
o Impaired fasting glucose
o Elevated fasting glucose
o Impaired glucose tolerance
o Elevated post prandial glucose
o Progresses to T2DM at 10%/yr
 o Diabetes prevention program
 Prediabetics intensive lifestyle vs metformin + diet/exercise vs
placebo + diet/exercise
 Intensive lifestyle had biggest risk reduction
 5-10% weight loss
 Low fat diet + 150 min exercise/week
 Symptoms of T2DM at dx
o Asymptomatic
o Osmotic sx
 Polyuria, polydipsia
 Blurred vision
o Fungal infxn –→ genital
 Latent Autoimmune Diabetes of Adulthood –→ LADA
o 10% adults dx with T2DM are actually T1DM
o More gradual loss of B cells
o Retain some insulin production
o Insidious onset
o Not obese
o Require insulin
 Screening asymptomatic adults for T2DM
o Sedentary
o 1st degree relative with DM
o High risk ethnicity
o PCOS
o Gestational DM or Baby >9ln
o HTN, ↓ LDL, ↑ TG
o HbA1C >5.7, IGT, IFG
o Insulin resistance (acanthosis nigricans)
 Screening asymptomatic children for T2DM
o Test at 10 y/o or puberty if overweight and 2 of the following
 1st or 2nd degree relative w/DM
 High risk ethnicity
  Insulin resistance: Acanthosis nigricans, HTN, dyslipidemia,
PCOS, small for gestational age birthweight
 Maternal hx DM or gestational DM during gestation
 Weight loss is the cornerstone of T2DM treatment
o No optimal nutrient composition
o Low glycemic index foods helpful
o –↑ fiber as general population
o Natural fructose better than sucrose
 T2DM treatments
o Secretagogues –→ Sulfonylurea, meglitinide
 Insulin secretion
o Biguanide –→ metformin
 Inhibits gluconeogenesis
o Incretins –→ GLP-1 agonists –tide, exenatide, liraglutide
 Augment glucose stimulation of insulin release
o DPP4 inhibitors –→ -gliptins, sitagliptin
 Prevent breakdown of GLP-1
o Thiazolidinediones (TZDs) –→ -glitazone, pioglitazone
 ↓ adipose insulin resistance, cause weight gain
o SLT-2 inhibitors –→ -gliflozins, dapagliflozin
 ↑ renal glucose excretion
o A-glucosidase inhibitors –→ acarbose
 ↓ glucose absorption
o Amylin –→ pramlinitide
 ↓ glucagon, slows gastric emptying
 Pathogenesis of T2DM by organ
o Liver –→ ↑ glucose production
o Pancreas –→ ↑ glucagon secretion, ↓ insulin secretion
o Adipose and muscle –→ ↓ glucose uptake
o Intestine –→ GLP-1 deficiency
 Tx of T2DM by organ
o Liver –→ metformin
 o Pancreas –→ Sulfonylureas, meglitiides, GLP-1 agonists, DPP4
antagonist, pramlinitide
o Muscle and lipid –→ TZDs
o Kidney –→ SGLT-2 inhibitor
o Intestine –→ acarbose
 Bariatric surgery shows a DM improvement of 45-97%
o Weight loss –→ ↓ insulin resistance
o Normalized incretin response –→ ↑ post-prandial GLP-1
o –↓ ghrelin production –→ ↓ hunger, ↑ glucose tolerance
 Chronic T2DM
o Progressive B cell fxn loss
o Leads to need for insulin
 Hyperglycemic Hyperosmolar Non-Ketotic Syndrome (HHNKS/HHS)
o Severe hyperglycemia, hyperosmolality
o Dehydration
o No ketosis
o Common in
 Middle aged or elderly T2DM w/
 Renal insufficiency, CHF, severe sickness
 Pneumonia, CVA, MI, Surgery, Burns, dialysis
o Pathogenesis
 Relative insulin deficiency
 Decreased glucose uptake in muscle
 ↑ glucagon
 ↑ hepatic glucose output
 Hyperglycemia
 Osmotic diuresis
 Inability to replace fluids
 Dehydration –→
 Renal failure
 ↓ glucose excretion
 Hyperglycemia
 o Still have enough insulin to suppress ketones
 If acidotic, it’s lactic acidosis
 Not ketoacidosis
o HHS clinical
 Polydipsia, polyuria
 Weakness, weight loss
 Hypotension, tachycardia
 Altered sensorium
 Insidious onset
 Lethargy to coma
 Lethargy when osmolality >300
 Coma when osmolality >330
 Less drinking fluid when lethargic
 Compounds dehydration
o HHNKS treatment
 IV fluids
 IV insulin + Potassium
 Treat underlying problem
 DKS vs HHNKS labs
DKA HHNKS
Glucose >250 >600
pH <7.3 >7.3
HCO3 <15 >20
BUN <25 >30
Osmolality <320 >330
Urine Ketones +++ +1/-
Serum ketones ++ +1/-

 Chronic complications of T2DM

o Macrovascular complications of DM
 Ischemic heart dz
 CVA
  PVD
 Leads to amputation (combined with peripheral
neuropathy and impaired immune response)
 Impotence (combined with autonomic dysfunction)
o –↑ incidence of complications with metabolic syndrome
 Metabolic syndrome
o Insulin resistance –→ diabetes
o Dyslipidemia –→ ↑ VLDL, ↓ HDL
o HTN
o Atherosclerosis
 Underlying factors for Atherosclerosis and DM
Underlying factors Metabolic factors Clinical Outcomes

Insulin resistance HTN, Hyperglycemia Atherosclerosis –→ CVD

Dyslipidemia
Hypertriglyceridemia
Abdominal Obesity ↑ LDL, ↓ HDL T2DM
Hypercoagulability
Inflammation

 Risk of MI in DM
o DM –↑ risk of MI
o DM + past MI –→ ↑↑↑ risk of MI
 DM in pregnancy
o Pre existing –→ T1DM or T2DM
 Effect of –↑ glucose in early gestation
 Fetal malformation
 Miscarriage
 Effect of –↑ glucose in later gestation
 Fetal macrosomia
 Glucose crosses placenta
 Insulin cannot cross placenta
  Fetal insulin production increases in response to –↑
glucose
o Stimulates IGF receptors
o Fetus gets larger
 Effects of DM on pregnant mother
 ↑ retinopathy
 ↓ renal fxn
 Macrosomia induced delivery complications
 Goals of pre-existing DM in pregnancy
 Optimal control before conception
 Aggressive monitoring and control during entire
pregnancy
o Gestational DM
 ↑ insulin resistance in later pregnancy
 Malformations not increased
 Effect on fetus
 Macrosomia
 Effect on mother
 Deliver complications
 ↑ Risk for T2DM –→ 35-60% risk of developing T2DM in
next 10-20 years

024 – Pre Recorded Type 1 Diabetes

 Genetics of T1DM
o Familial clustering
o HLA D3 or D4 association
o MZ twins 50%, siblings 6%
 Natural history of T1DM
o Problem starts before B cell injury
 Virus trigger: coxackie, mumps, rubella
 Breast feeding is protective
 B cell damage starts with T cell infiltration –→ insulinitis
  Cellular T cell autoimmunity
 Humoral autoantibodies –→ marker for damage, do not
mediate damage
 Glucose intolerance
 Loss of insulin response –→ impaired OGTT
 C-peptide loss
 Clinical onset triggered by infection
 Presentation of T1DM
o Due to hyperglycemia
o Polyuria/polydipsia
o Bedwetting ing children
o Blurred vision
 Due to osmotic drag of fluid into lens changes configuration
o Weight loss due to
 Depletion of H2O
 ↓ glycogen, ↓ triglycerides
 Muscle breakdown
o DKA
 DKA
o –↑ glucose production, ↓ glucose utilization, ↑ ketone production
o Hyperglycemia
 Osmotic diuresis
 Volume depletion –→ dehydration
o Hyperketonemia
 Metabolic acidosis
 Kidneys cant excrete ketones fast enough –→ ↓ pH
o Hormone levels in DKA
 ↓ Insulin
 ↑ Glucagon, GH, Cortisol, catecholamines
 Glucagon causes proteolysis in skeletal muscle
o Hyperglycemia in DKA
 ↓ insulin and –↑ glucagon
  ↑ glycogenolysis and gluconeogenesis in liver
 ↑ glucose output from liver
 ↓ glucose uptake in muscle and adipose
o Ketone bodies
 B hydroxybutyric acid most prevalent
 Acetone excreted in lungs –→ fruity odor
 CPT1 catalyzes entrance of FFA + carnitine into hepatic
mitochondrion
 Facilitates FFA –→ ketone bodies
 CPT1 = carnitine palmotyl transferase 1
 Malonyl CoA is the on/off signal to initiate or terminate
ketogenesis in the liver
 Malonyl CoA turns off CPT1
 Insulin suppresses carnitine –→ ↓ FFA breakdown –→
↓ ketones
 Glucagon promotes carnitine –→ ↑ FFA breakdown –→
↑ ketones
 Insulin promotes FA synthesis –→ ↓ FFA –→ ↑ Malonyl
CoA –→ ↓ CPT1 –→ ↓ Ketones
 Glucagon suppresses FA synthesis –→ ↑ FFA –→ ↓
Malonyl CoA –→ ↑ CPT1 –→ ↑ Ketones
 In fed State
 Insulin suppresses carnitine –→ ↓ FFA breakdown –→
↓ ketones
 Insulin promotes FA synthesis –→ ↓ FFA –→ ↑ Malonyl
CoA –→ ↓ CPT1 –→ ↓ Ketones
 In fasting
 Glucagon promotes carnitine –→ ↑ FFA breakdown –→
↑ ketones
 Glucagon suppresses FA synthesis –→ ↑ FFA –→ ↓
Malonyl CoA –→ ↑ CPT1 –→ ↑ Ketones
  In DKA
 No insulin –→ No Malonyl CoA
 Glucagon promotes carnitine –→ ↑ FFA breakdown –→
↑ ketones
 Glucagon suppresses FA synthesis –→ ↑ FFA –→
↓↓↓ Malonyl CoA –→ ↑↑↑ CPT1 –→ ↑↑↑ Ketones
o Pathogenesis of DKA
 Liver –→ ↑ glucose production –→ Hyperglycemia –→ osmotic
diuresis –→ volume depletion
 Peripheral tissue –→ ↓ glucose uptake –→ Hyperglycemia –→
osmotic diuresis –→ volume depletion
 Liver –→ ↑ ketogenesis –→ ketoacidosis –→ ↓ alkali reserve –
→ metabolic acidosis
 Adipose tissue –→ ↑ FFA release –→ ketoacidosis –→ ↓ alkali
reserve –→ metabolic acidosis
o Precipitating factors of DKA
 Poor compliance, infxn, MI, CVA, insulin pump failure
 Can happen in T2DM with severe stress
 Surgery, sepsis, trauma
o DKA clinical
 Hypertonicity
 Polydipsia/polyuria
 Stupor/coma
 Acidosis
 Short onset
 N/V
 Air hunger from acidosis –→ kussmaul breathing
 Signs
 Tachycardia –→ volume contraction/acidosis
 Kussmaul breathing –→ acidosis
 Ileus –→ electrolyte disturbance/acidosis
 Fruity breath –→ ketosis
  Altered sensorium –→ hyperosmolarity
o DKA labs
 Glucose >250
 pH < 7.3
 HCO3 < 15
 Ketones >3+
 Serum Ketones > + at 1:2 dilution
 Hyponatremia/hyperkalemia
o Hyponatremia in DKA
 Na loss from vomiting and diuresis
 Fluid shift into extracellular space due to hyperglycemia
 Correct sodium
 1.6mg/dl for each 100mg/dl glucose above 100
 Dilutional hyponatremia
o Hyperkalemia in DKA
 Total body K is depleted, actually low
 Serum K looks nl or high due to
 Shift from intracellular to extracellular space s in acidosis
and with insulin deficiency
 Early replacement of K is important with insulin
 Insulin causes intracellular K uptake with glucose
o Management of DKA
 Fluid –→ restore volume loss
 Insulin –→ reduce glucose and stop ketogenesis
 Potassium –→ replete losses
o Insulin Therapy in DKA
 Insulin is required
 IV continuous infusion preferred
 Avoid IM or SQ routes since perfusion is compromised
o Complications of Insulin therapy in DKA
 Hypoglycemia
 Hypokalemia
  Cerebral edema
 Mainly in children, possibly caused by fluid replacement,
HCO3 replacement
 Glycemic loads depend on age and condition
o Higher glycemic goals in kids because
o Young child ant give symptoms, cant verbalize
o Higher risk hypoglycemia vs low risk complications before puberty
 Normal glucose Counter-regulation
o At blood sugar 80 –→ ↓ insulin
o At blood sugar 70 –→ ↑ glucagon, epinephrine
o At blood sugar 60 –→ ↑ GH, cortisol,
 neurogenic sx
o At blood sugar 50 –→ cognitive dyfunction
o At blood sugar 40 –→ severe neuroglycopenia
 Signs and sx of hypoglycemia
o Blood sugar 60 –→ neurogenic sx
 Cholinergic –→ sweating, hunger
 Adrenergic (catcholamines) –→ tachycardia, palpitations,
temors, anxiety, weakness, fainting
o Blood sugar 50 –→ Neuroglycopenic
 Headache, fatigue, diplopia, confusion
o Blood sugar 40 –→ severe gypoglycemia
 Seizures, coma death
 Risk factors for hypoglycemia in DM
o Ill timed insulin
o –↓ food intake,
o Gastroparesis
o –↓ endogenous glucose (alcohol)
o –↑ glucose utilization (exercise)
o –↑ insulin sensitivity (weight loss, nighttime)
o –↓ drug clearance (renal failure)
 Protective response to hypoglycemia is impaired in T1DM
o Insulin secretion cannot be suppressed
o Defective counter-regulatory response
 Glucagon response is diminished –→ production decreases
with B cell failure
 Autonomic Dysfunction –→ Impaired sympathoadrenal
response –→ hypoglycemia unawareness
o Hypoglycemia unawareness
 Repeated episodes of hypoglycemia
 ↑ glucose transport to CNS
 Protects brain form hypoglycemia, BUT
 Blunts neurogenic warning signs
 Pt less able to respond to hypoglycemia
o Hypoglycemia in children
 More susceptible
 Lower glycogen stores
 Lower capacity for gluconeogenesis
 ↑ glucose requirement due to development of brain
 Repeated hypoglycemia
 Less of a problem after puberty
 ↑ fat stores
 ↑ insulin resistance
 ↓ glucose demand in brian
 Hypoglycemia
o Whipple’s Triad = hypoglycemia
 –↓ plasma glucose
 Sx hypoglycemia
 Reversal of sx with glucose
o Fasting hypoglycemia
 Hyperinsulinemia
 No hyperinsulinemia
o Postprandial hypoglycemia
 Causes of fasting hypoglycemia with hyperinsulinemia
o Insulinoma –→ associated w/MEN1
o Factitious
o Anti-insulin Ab
 Causes of fasting hypoglycemia with no hyperinsulinemia
o Non-Islet cell tumors –→ IGF-2 production
o Renal failure
o Hepatic failure
o Deficiency in cortisol or GH
 Alcohol in hypoglycemia
o EtOH oxidation –→ ↑ NADH/NAD ratio –→ ↓ gluconeogenesis
o Seen in binge drinking and ↓ food intake
 Causes of post prandial hypoglycemia
o Non-Insulinoma Pancreatogenous hypoglycemia Syndrome (NIPS)
 Post gastric bypass
o Dumping syndrome –→ post gastric bypass
o Reactive hypoglycemia –→ idiopathic
 Evaluation of hypoglycemic episode
o Order serum insulin, C peptide, sulfonylurea screen, ketones
o –↓ ketones in insulinoma
 ↑ insulin –→ ↓ CPT1 –→ ↓ B hydroxybutyrate
o Observe pt w/ no caloric intake for 72 hrs
 Normal –→ nl glucose, low pro insulin, insulin, C peptide, ↑ B
hydroxybutyrate
 Localizaiton of Insulinoma
o Spiral CT or MRI of pancreas
o Transabdominal Ultrasound
o Endoscopic Ultrasound
o Selective arterial Calcium Stimulation Test (SACST)
o Intra operative Ultrasound
025 – Pre Recorded Complications of Diabetes
 Complications of Diabetes
o Microvascular –→ capillary and precapillary arterioles –→ do to
chronic hyperglycemia
 Kidneys
 Eyes
 Peripheral nerves
o Macrovascular –→ accelerated atherosclerosis –→ due to –↑ BP and
lipids
 Heart
 Brain
 Limbs
 Diabetic retinopathy
o Microvascular
o Non proliferative diabetic retinopathy
 Microaneurysms
 Hemorrhages
 Macular edema = Hard cholesterol exudates
 Capillary thrombosis dropout
o Proliferative retinopathy
 Areas of ischemia seen with viable retinal cells
 Lead to release of vascular growth factrs
 VEGF, FGF, TGF-B, IGF-1
o Untreated Proliferative retinopathy
 Vitreous hemorrhage causes vision loss
o Prevention by
 Glucose control
 BP control, quit smoking
o Prevent blindness with regular exam
 Usually asymptomatic
o Can also get cataracts and glaucoma
 Diabetic Nephropathy
o Microvascular
o Pathogenesis
 Hyperglycemia
 Hyperfiltration
 Endothelial injury, Basement membrane thickening, mesangial
cell and ECM expansion, Podocyte loss
 Albuminuria
 Glomerulosclerosis
 Decreased perfusion, filtration, hypertension, nephron loss
 Renal failure
o Hallmark of nephropathy
 Gross proteinuria
 Progression to ESRD
 Renal replacement therapy
 Hemodialysis
 Peritoneal dialysis
 Renal Transplant
o Microalbuminuria
 Urinary albumin –→ predicts renal failure
 Correlates w/↑ BP
 Improves w/ BP control
 ↓ BP –→ slower rate of decline in GFR
 Slowing progression to ESRD
 BP control
 ACE inhibitor or ARB use
 Blood sugar control
 Dietary protein restriction –→ ↓ hyperfiltration
 Diabetic Neuropathy
o Microvascular
o Peripheral neuropathy
 Distal symmetric polyneuropathy
 Stocking glove pattern
 Motor/sensory
 Painful or painless
 Risk for foot ulcers
o Poor sensation –→ pt unaware of injury
o Mechanical changes due to denervation –→
abnormal pressure
o Associated vascular dz –→ poor wound healing
o Can lead to amputation
o Pathogenesis
o Vertical pressure –→ skin callous –→
hematogenous or inflammatory exudate –→ ulcer
 Foot ulcer prevention
o Self foot inspection, no walking barefoot, no
bathroom surgery, examine feet
o Ask tingling in hands or feet
o Ask if pain felt at night
 Tx with ion channel blockers (gabapentin)
 Mononeuropathy
 CN 3, 4 ,6
o Diplopia
o Resolves spontaneousy
 Peroneal neuropathy –→ foot drop
 Lateral femoral cutaneous nerve
o Sensory disturbance
o Numbness, tingling, or burning
o Deep pocket distribution
 o Autonomic Neuropathy
 Gastroparesis –→ ↓ gastric emptying
 N/V, postprandial fullness, erratic blood glucose
 Tx –→ metoclopramide (dopaminergic and cholinergic,
short term use), botulism toxin in pylorus, gastric
electrical stimlation
 Diabetic diarrhea
 Nocturnal watery painless diarrhea
 Multiple possible causes
 Small bowel bacterial overgrowth
 Tx –→ loperamide
 Fecal incontinence, sphincter abnormalities
 Constipation
 Cardiovascular
 Orthostatic hypotension
 Resting tachycardia
o Parasympathetics denervated before
sympathetics
o Vagus slows heart, brake is removed
 Arrhythmia
 GU
 Atonic bladder –→ incomplete emptying
 Overflow incontinence
 Erectile dysfunction
 Retrograde ejaculation
 Diabetic complications of skin
o Candidal infections in intertriginous areas
o Vulvovaginitis
o Necrobiosis lipoidica diabeticorum
 Diabetic complications of bone and joint
o Hand arthropathy
o Carpal tunnel
 o Adhesive capsulitis of shoulder
 Diabetic complications: Infections
o Mucormycosis –→ DKA –→ Rhizopus arrhizus
o Malignant otitis externa –→ pseudomonas
o Emphysematous cholecystitis
o Necrotizing papillitis
 Complication of pyelonephritis
 Macrovascular complications of Diabetes
o CAD
 ↑ in T2DM
 ↑ morbidity and mortality
o CVA
o PVD
o Due to hyperlipidemia, hypercoagulability, HTN, oxidative stress,
inflammation
o HTN and diabetes
 Present in at least 50% of diabetic subjects
 Twice that in non-diabetic people
 ↑ CHD, CVA
 ↑ Retinopathy, nephropathy
 Antihypertensive reduces both microangiopathy and
macroangiopathy
 Dyslipidemia in Diabetes
o Statins effective in reducing risk
o Goals in diabetes with no CVD
 Total cholesterol < 130
 LDL < 100
 HDL >40/50, M/F
 TG <150
 BP <130/80
 o Goals in diabetes with CVD
 Total cholesterol < 100
 LDL < 70
 HDL >40/50, M/F
 TG <150
 Prevalence of Diabetic complicaitons
o T1DM
 ESRD more common than T2DM
 Blindness due to hemorrhage and retinal detachment
 Severe autonomic neuropathy common
 ESRD cause of death
o T2DM
 ESRD in 20%
 Blindness due to Macular edema and ischemia
 MI and CVA cause of death

026 – EBM


027 – Meet the patient Diabetes
 L

028 – Hormonal control of Calcium and Phosphate Metabolism

 Control of Ca and phosphate homeostasis
o PTH
o VitD
o Calcitonin
o Target organs
 Kidneys –→ activate Vit D
 Intestine –→ absorb Vit D
 Bone –→ reservoir of Vit D

 Ca distribution and balance

o 1, 25 OH
 ↑ intestinal absorption of Ca
 ↑ Bone resorption of Ca
 o PTH
 ↑ Bone resorption of Ca
 ↑ Kidney reabsorption of Ca
o Calcitonin
 ↓ Bone resorption of Ca
 Only free ionized Ca is active
o 50% of total Ca is ionized, free and active
o 40% bound ot albumin
o 10% bound to anions
o Only active Ca is regulated
 Effect of acid-base disturbances on plasma protein-binding of Ca and the
ionized Ca concentration in blood
o Albumin has negative binding sites
o During acidosis
 ↑ H+ in serum –→ ↑ H+ bound to albumin –→ ↓ Ca bound to
albumin –→ ↑ Active Ca in serum
o During alkalosis
 ↓ H+ in serum –→ ↓ H+ bound to albumin –→ ↑ Ca bound to
albumin –→ ↓ Active Ca in serum
 Phosphate distribution and balance
o Not bound to anything
o Freely filtered
o Regulated mostly by PTH
 Synthesis of PTH
o N terminal of PTH has all activity
 Regulation of PTH
o Plasma Ca is the major regulator of PTH
 In FHH –→ Ca not being sensed normally in urine –→ PTH still
being exreted at high levels –→ ↑ steady state serum Ca
o –↓ Ca –→ ↑ PTH release + hyperplasia of parathyroid tissue
o PTH does not stimulate osteoclasts directly
 Stimulates osteoblasts –→ stimulate osteoclasts
 o In the kidney
 PTH –→ ↓ reabsorption of phosphate in the proximal tubule
 PTH –→ ↑ Ca reabsorption form ascending loop of henle,
distal tubule, and collecting tubule
 PTH secretion and CaSR
o Ca binds CaSR on Parathyroid Chief cell
o CaSR is Gq –→ PLC –→ DAG/IP2 –→ PKC/Ca –→ ↓ PTH release
o Inhibits PTH synthesis and release
 Regulation of PTH release
o PTH release stimulated by
 ↓ Ca
 ↑ PO4 –→ ↑ PO4 bound to Ca –→ ↓ Ca
 Catecholamines
o PTH release inhibited by
 ↑ Ca
 ↑ 1,25 D –→ nuclear receptor –→ ↓ PTH synthesis
 Hypomagnesemia
 Role of PTH on Ca and PO4 metabolism
o –↑ PTH
o PTH in bone
 ↑ bone resorption –→ ↑ serum Ca
o PTH in kidney
 ↑ 1,25D formation –→ ↑ plasma 1,25 D –→ ↑ intestinal Ca
absorption –→ ↑ serum Ca
 ↑ Ca reabsorption –→ ↓ Ca excretion –→ ↑ Serum Ca
 ↓ Phosphate reabsorption –→ ↑ Urinary excretion of
phosphate –→ ↓ serum PO4
 Signal transduction of PTH and PTHrP
o Has autocrine and paracrine function
o Activates GS –→ AC –→ ↑ cAMP
o Activate Gq –→ PLC → PIP2 –→ DAG/IP3 –→ PKC/Ca from ER
 PTH actions in kidney
 o –↓ Proximal tubule PO4 reabsorption
 Via Na-Pi cotransporter
 Inhibits Na-Pi transporter
 Internalizes and breaks down transporter
 cAMP mediated effect
 ↑ urinary excretion of cAMP
o –↑ 1a hydroxylase activity in proximal tubule
 ↑ 1,25 OH D
o –↑ reabsorption of Ca2 in distal convoluted tubule
 Potentiated by 1,25 OH D
 Potentiates Ca2 ATPase on basolateral side
 ↑ Ca pumped from cell into interstitium
 Synergistic action
 PTH in bone
o Stimulates both bone formation by osteoblasts and bone resorption
by osteoclasts
o PTH mediated osteoclast differentiatieon
 PTH acts on osteoblasts –→ ↑ RANKL expressed –→ ↑
Osteoclast activity
 PTH also –↑ Osteoprotegerin release from osteoblasts –→
Binds RANK to prevent osteoclast activity
 Estrogen –→ ↑ Osteoprotegerin –→ why women get
osteoporosis after menopause
 Effects of PTH on Ca and PO4 metabolism
o –↑ serum Ca and –↓ serum PO4
o –↓ urine Ca and –↑ urine PO4

 Differential Dx of PTH dx
PTH 1,25 D Bone Urine Serum Ca Serum
PO4
Primary ↑ ↑ (PTH ↑ ↑PO4, ↑ ↓
hyperparathyroidism effect on (resorption) ↑Ca due
hydroxylase) to high
 filtered
load
↑ cAMP
in urine
Surgical ↓ ↓ ↓ resorption ↓ PO4 ↓ ↑
hypoparathyroidism ↓ cAMP
Pseudo ↑ ↓ ↓ resorption ↓ PO4 ↓ ↑
hypoparathyroidism due to ↓ cAMP
defective Gs
Humoral ↓ ↑ ↑ ↑ PO4 ↑ ↑
hypercalcemia of ↑ Ca
malignancy (↑ ↑ cAMP
PTHrP)
Chronic renal failure ↑ ↓ Osteomalacia, ↓ PO due ↓ due to ↑ due to
(secondary ↑ resopriton to –↓ –↓ 1,25 –↓ urine
due to –↑ GFR D PO4
PTH

 Chronic renal failure –→ secondary hyperparathyroidism –→ ↓ Vit D

activation
 Formation and hydroxylation of Vit D
o D3 –→ Goes to liver
o Hydroxylated to 25 OH D
o Goes to kidney
 24 hydroxylase –→ 24,25 OH D –→ inactive
 1 a hydroxylase –→ 1, 25 OH D –→ active (calcitriol)
o Stimulates production of 1,25 OH D
 ↓ Vit D
 ↓ Ca
 ↑ PTH
 ↓ Phosphate
o Stimulate production of 24,25 OH D
 ↑ Vit D
 ↑ Ca
 ↑ Phosphate
 Effects of Vit D
o Effect of Vit D on Ca and Phosphate metabolism
 PTH –→ ↑ 1,25 OH D
 In Bone
 Potentiates PTH action –→ ↑ serum Ca
 In intestine
 ↑ Ca absorption –→ ↑ serum Ca
 ↑ phosphate absorption –→ ↑ serum phosphate
 In kidney
 ↑ Ca reabsorption –→ ↓ Ca excretion –→ ↑ serum Ca
 ↑ Phosphate reabsorption –→ ↓ phosphate excretion –
→ ↑ serum phosphate
o Cellular effects of Vit D
 Binds nuclear steroid receptors
o Effects of Vit D on intestinal absorption of Ca
 –↑ TRPV6 Ca channels to absorb Ca from gut
 –↑ calbindin protein to chaperone Ca
o Effects of Vit D on intestinal absorption of Phosphate
 –↑ Na/Pi dual importer
o Effect of Vit D on kidney
 Weak
 –↑ distal tubular reabsorption of Ca
 –↑ proximal tubular reabsorption of phosphate
o Effect of Vit D on bone
 Little effect if lots of serum Ca
 If low serum Ca
 ↑ 1, 25 D –→ ↑ bone resorption by → osteoblasts
show RANK→
 ↓ bone mineralization
 Calcitonin
o Acts on GpcR –→ AC OR PLC
o Secretion is proportional to plasma Ca
 o –↑ Ca –→ ↑ Calcitonin
o –↑ Ca –→ ↓ PTH
o –↓ PTH –→ ↑ Calcitonin
 Effect of calcitonin
o Effect of calcitonin on bones
 ↓ osteoclast activity
 ↑ bone calcification
 ↓ serum Ca
 Long term –→ ↓ number of osteoclasts
o Effects of calcitonin on Kidney
 ↑ urinary excretion of Ca, Phosphate, Na, Cl
 ↓ 1a hydroxylase in kidney –→ ↓ 1, 25 OH D
o Effects of calcitonin on intestine
 ↑ calcitonin –→ ↓ 1,25 OH D –→ ↓ Ca and phosphate
reabsorption
 ↓ gastric motility and gastrin secretion
o Effects of Calcitonin on Ca and phosphate metabolism
 On bone
 ↓ Ca release –→ ↓ serum Ca
 On Kidney
 ↓ Ca reabsorption –→ ↑ urinary ca excretion –→ ↓
plasma Ca
 ↑ Phosphate reabsorption –→ ↑ urinary excretion of
phosphate –→ ↓ plasma phosphate

 Summaries
o Compensation to –↓ Ca
 ↑ PTH –→ ↑ bone resorption –→ ↑ Ca, Phosphate
 ↑ Ca resorption in kidney
 ↑ Phosphate excration in Kidney
 ↑ PTH –→ ↑ 1,25 OH D –→
  ↑ bone resorption –→ ↑ Ca, phosphate
 ↑ GI absorption of Ca, phosphate –→ ↑ Ca, phosphate
o Compensation to↓ serum phosphate
 ↓ FGF-23 –→ ↑ Phosphate reabsorption –→ ↑ serum PO4
 ↑ 1,25 OHD –→
 ↑ bone resorption –→ ↑ Ca, phosphate –→ ↓ PTH
 ↑ GI absorption of Ca, phosphate –→ ↑ Ca, phosphate
–→ ↓ PTH
 ↓ PTH –→ ↓ Ca Reabsorption, ↑ PO4 reabsorption
o Compensation to –↓ 1,25 OH D
 ↓ GI absorption of Ca and PO4 –→ ↓ serum Ca and PO4 –→
↑ PTH
 ↑ PTH –→ ↑ Bone resorption –→ ↑ serum Ca and Pi –→ ↑ Pi
excretion from kidneys
 Leads to
 Hypophosphatemia, ↓ serum Ca and PO4 –→ poor
mineralization

029 – Genetics of Diabetes and Bone Disease

 Diabetes phenotypes
o T1DM
 Classic insulin deficiency
 Non obese
 Ketoacidosis
 Early onset
 Autoantibodies
o T2DM
 Insulin resistance ,
 Obesity
 Later onset
 No Ab
 o Monogenic diabetes
 Early onset
 Non obese
 Hyperglycemia
 DIDMOAD –→ Diabetes insipidus, Diabetes mellitus, Optic
atrophy, and deafness
 Sensorineural deafness, optic atrophy
o Mitochondrial diabetes
 MIDD
 Progressive hyperglycemia
 Sensorineural deafness, optic atrophy, other associated
symptoms
 Later onset
 Type 1 Diabetes
o Autoimmune destruction of Pancreatic B cells
o 90% of T1D kids have MHC II susceptibility haplotypes
o 5% of people with susceptibility haplotypes have T1D
 Need additional factors to develop disease
o 70% of T1D pt have Auto-Ab to GAD
 GAD = Glutamic acid Decarboxylase
o MHC and T1D
 Strongest susceptibility from
 DR3 and 4
 DQ8, DQ2
 Due to linkage disequilibrium
 If 2 genes come close to each other, good chance when
they recombine and cross over –→ all comes together
o Susceptibility genes
 HLA
 Class 1 HLA
o HLA-A24
o HLA-B39
  Other HLA genes
o C4A, C4B, MHC-1 MIC-A, TNF-A
 Non-HLA genes
 VNTR –→ insulin gene promoter
 PTPN22
o Protein tyrosine phosphatase
o Downregulates immune response
o In autoimmunity
 Gain of function mutation
 Affects PTPN22 binding to C-src tyrosine
kinase
 Type 2 Diabetes Mellitus
o GWAS studies show many implicated SNPS
o TCF7L2 and CKAL1 most associated with T2DM
 Monogenic Diabetes
o NIDM –→ Nenonatal Diabetes Mellitus
o MDI –→ Monogenic Diabetes of Infancy
o MODY –→ Maturity Onset Diabetes of the Young
o DIDMOAD –→ Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy,
and Deafness
o MIDD –→ Maternally inherited Diabetes and Deafness
o Insulin and the B cell
 Targets for Monogenic Diabetes
 Glucose kinase –→ MODY
 INS –→ MODY
 WFS1 –→ DIDMOAD
o MIDD –→ Maternally inherited Diabetes Mellitus and Deafness
 Mitochondrally inherited
 Severity depends on degree of heteroplasmy
 Depends on amount of mitochondrial protein gotten from
mother
 Hypophosphatemic Rickets
 o Causes of Rickets
 Sunlight deficiency (phenocopy)
 ↑ skin pigmentation
 ↓ Vit D intake
 Avoidance of milk products
 Malabsorption
 Celiac Dz
 Pancreatic insufficiency
 ↓ synthesis of 25 OH D
 Chronic Liver disease
 Drugs
 Genetics
o Genetic causes of rickets
 Hypophosphatemic Rickets –→ XLD
 Metabolism and gene regulation of Vit D
o Vit D carried by GC to liver
o Vit D hydroxylated to 25 OH D in liver
o Carried by GC to kidneys
o Hydroxylated to 1,25 OH D in kidneys
 ↑ Ca channel TRPV6
 ↑ Phosphate
 ↑ FGF23
 ↑ RANKL
 ↓ PTH
 FDF23 (phosphatoin) and PHEX
o FGF23 is a Vit D counter-regulatory hormone
o FGF23 functions
 ↓ NPT2a Transporters –→ ↑ PO4 excretion
 ↓ 1a hydroxylase –→ ↓ resorption of PO4
o PHEX normally cleaves and inactivates FGF23
o If deficiency in PHEX –→ Hypophosphatemia and Vitamin D resistant
Rickets
  X-Linked Hypophosphatemia
o PHEX gene
o XLD
 Twice as many females as males
 No male to male transmission
o If Father has XLD
 Risk of boy is 0%
 Risk of girl is 100%
 50% risk of child with dz
o If Mother has XLD
 Risk of boy is 50%
 Risk of girl is 50%
 50% risk of child w/dz
 Treatment of Genetic Diseases
o Diabetes
 Insulin → protein replacement
 Sulfonylureas –→ Enhancement of residual function
o Rickets
 Vit D –→ diet specific compensation
 Calcitriol/oral phosphorous –→ pharmacologic disease specific
compensation

030 – Hypercalcemia/Hypocalcemia
 Calcium Homeostasis
o organs
 Bone –→ stores Ca
 Intestine –→ Absorption potentiated by Vit D
 Kidney –→ activation and reabsorption of Vit D
 Parathyroid gland –→ release PTH –→ ↑ serum Ca
 Skin –→ Produce Vit D w/sunlight
o Hormones
 Calcitonin –→ ↓ serum Ca
  Vit D –→ Directs Ca and phosphate metabolism
 PTHrP –→ can cause –↑ Ca in cancer
o Receptors
 CaSR –→ how Ca talks to PTH
 PTH receptor –→ PTHrP binds to PTH receptor and causes
pseudohypophosphatemia
o Enzymes
 25 hydroxylase –→ first OH attached to Vit D in liver
 1a hydroxylase –→ attaches 2nd OH in kidney
 Active Vit D (1,25 OH D) = calcitriol
 24 Hydroxylase –→ upregulated by 1,25 OH D to form inactive
Vit D –→ negative feedback
 Vit D activity
o In Small intestine
 ↑ Ca, PO4 absorption
o In bone
 ↑ Ca, PO4 absorption
o In kidney
 ↓ Ca, PO4 excretion
 Different from PTH
 Hormonal response to hypocalcemia
o –↓ Plasma Ca2 –→ ↑ PTH –→ ↑ 1,25 OH D
o PTH
 ↑ Ca resorption from bone (happens before effect on Kidneys)
 ↑ Ca, PO4 from bone and intestine
 ↑ PO4 excretion in urine
 ↑ Ca reabsorption in urine
 ↑ 1,25 OH D formation in kidney
o –↑ intestinal Ca, PO4 absorption
o 1,25 OH D
 ↑ Ca resorption from bone
 ↑ Ca, PO4 from bone and intestine
 Calcitriol = 1,25 OH D
o Effect on Ca
 ↑ intestinal absorption of Ca
 ↑ bone resorption of Ca
 ↑ renal resorption of Ca in distal convoluted tubule and
collected tubule
o Effect on phosphate
 ↓ renal excretion of PO4
 ↑ intestinal absorption of PO4
o Effects on hormones and Ez
 ↓ PTH production and release
 ↓ 1a hydroxylase –→ ↓ Calcitriol
 ↑ 24 hydroxylase –→ ↑ inactive vit D
 Effect of PTH
o –↑ serum Ca
 ↑ Ca release from bones
 ↑ intestinal Ca absorption
 ↑ reabsorption of Ca from kidney
o Phosphate
 ↓ phosphate reabsorption in kidney
 ↑ serum phosphate by –↑ phosphate release form bone and
–↑ phosphate absorption from intestine
o Calcitriol
 ↑ synthesis of 1a hydroxylase –→ converts 25 OH D to 1, 25
OH D
 ↓ activity of 24, 25 OHD
o If no PTH –→ Vit D can’t become active –→ ↓ Ca absorption
 Calcitonin
o – iCa renal excretion
o –↓ bone resorption by interfering w/osteoclast fxn
 FGF 23
o Secreted by osteoblasts, osteoclasts in response to 1,25 OH D
 o –↑ dietary phosphate load, PTH, and Ca
o –↓ serum phosphate
 ↓ renal phosphate reabsorption
 ↓ intestinal phosphate absorption
o –↓ calcitriol
 ↓ 1a hydroxylase
 ↑ 24 hydroxylase
 Hypercalcemia
o Clinical = stones, bones, groans, and psychiatric overtones
 Stones
 Renal stones, nephrocalcinosis
 Polyuria, polydipsia
 Uremia
 Bones
 Osteitis fibrosa cystica with
o Subperiosteal resorption
o Osteoclastomas
o Bone cysts
 Radiologic osteoporosis, osteomalacia, or rickets
 Arthritis
 Abdominal groans
 Constipation, N/V
 Peptic ulcer, pancreatitis
 Psychiatric overones
 Lethargy, fatigue, depression, memory loss
 Psychoses-paranoia, personality change, confusion,
stupor, coma
 Other
 Muscle weakness, conjunctivitis, HTN, pruritis
o Hypercalcemia = >10.5
 Workup of hypercalcemia
o Ca affected by albumin
  40% of Ca bound to albumin
 Corrected Ca – 0.8(nl albumin-pt albumin) + serum Ca
 Hypercalcemia path
o Can be PTH mediated or non-PTH mediated
o If hypercalcemia + nl or –↑ PTH
 Inappropriately high PTH
 Possible primary hyperparathyroidism OR Familial
Hypocalciuric hypercalcemia (FHH)
 Measure urinary Ca excretion
 If high –→ primary hyperparathyroidism
 If low –→ FHH
o If Hypercalcemia + ↓ PTH –→ appropriate PTH
 Measure PTHrP and Vit D metabolites, if
 ↑ PTHrP –→ scan for cancer
 ↑ 1,25 OH D –→ CXR for lymphoma or sarcoid
 Nl Vit D and PTHrP –→ consider
 TSH –→ if hyperhthyroid
 Vit A –→ bone resorption
 SPEP –→ looking for multiple myeloma
 ↑ 25 OH D –→ check medications and supplements
 Ddx of PTH mediated Hyperparathyroidism
o Sporadic or familial hyperparathyroidism
o FHH
o Usually single parathyroid adenoma
 Hyperparathyroidism
o Primary –→ ↑ PTH –→ ↑ Ca
 Biochemical Dx
 Never try to Dx by a parathyroid scan, except to determine a
surgical target
o Secondary –→ renal stenosis –→ ↓ Ca –→ ↑ PTH
o Tertiary –→ long standing secondary hyperparathyroidism –→
parathyroid hyperplasia –→ autonomous PTH secretion
 Familial Hypocalciuric Hypercalcemia (FHH)
o AD
o Inactivating mutation in CaSR
o –↓ Ca excretion –→ hypercalcemia
o Nl or mildly elevated PTH
o –↑ Ca/Creatinine clearance ratio
o Need to exclude other factors causing hypocalciuria:
 Vit D deficiency, ↓ Ca intake
 Renal insufficiency
 Thiazide diuretics
 Hold on to Ca –→ ↑ Ca
 Opposite of Furosemide/loop diuretics, which waste Ca
 Primary hyperparathyroidism vs FHH
o Primary hyperparathyroidism
 Usually single adenoma
 Symptomatic
 Ca <13
 ↑ urinary Ca
o FHH
 AD
 CaSR gene mutation –→ partial loss of fxn of CaSR –→ shift in
the parathyroid cell Ca set point
 Asymptomatic
 Ca <12
 ↓ urinary Ca
 ↓ Ca/Cr clearance
 Familial hyperparathyroidism
o MEN1 –→ PPP
o MEN2A –→ PMP
o FHH
 Secondary hyperparathyroidism
o From CKD
 o –↓ renal fxn –→ phosphate retention –→ ↓ serum Ca
 ↓ calcitriol –→ ↑ PTH
o –↓ Ca, calcitriol
o –↑ FGF 23
 DDx of primary hyperparathyroidism

o Mimic of FHH –→ Lithium induced hypercalcemia

 ↑ serum Ca,
 ↑ serum PTH
 Non PTH mediated hypercalcemia
o Malignancy
o Vit D intoxication
o Granulomatous Dz
 Hypercalcemia –→ malignancy
o –↑ bone resorption by osteoclasts
 o Ectopic action of PTHrP
 Stimulates expression of RANKL by osteoblasts
 → osteoclast fxn
o –↑ 1a hydroxylase –→ ↑ calcitriol from lymphoproliferative cells or
in macrophages
o Multiple myeloma –→ ↑ IL06, ↑ RANK→
o Osteolytic bone metastases
o Squamous cell lung carcinoma
o Still check PTH if known malignancy –→ primary hyperparathyroidism
is more common in malignancy
 PTHrP
o PTH related peptide
o Similar to PTH, but some differences
 Does not stimulate 1,25 OH D –→ does not –↑ intestinal Ca
absorption
o Results in uncoupling if bone resorption and formation
 → ↑↑ Ca from bone resorption
 Combined with –↓ renal fxn –→
 Striking hypercalcemia of malignancy
o Pathologic role
 Stimulates expression of RANKL by osteoblasts –→ ↑
osteoclast differentiation and fxn
 Vit D toxicity
o Rare, but can lead to hypercalcemia
o –↑↑↑ 25 OH D, but nl to high 1,25 OH D due to regulation
o Calcitriol toxicity possible if pt taking calcitriol
 Granulomatous Dz
o –↑ 1a hydroxylase activity in macrophages –→ ↑ Calcitriol
 Milk-Alkali syndrome
o –↑ intake of milk, Ca carbonate –→ Hypercalcemia
o Metabolic alkalosis
 ↑ Ca reabsorption in distal tubule –→ ↑ hypercalcemia
 o AKI –→ ↓ Ca excretion –→ hypercalcemi
 Hypercalcemia Treatment
o Hydration –→ restore renal fxn
o Calcitonin
o Bisphosphonates
o Furosemide –→ Ca wasting
o Steroids –→ sarcoidosis, MM, lymphoma
 Hypocalcemia
o Correct for albumin –→ total Ca + 0.8(4-serum albumin)
o Clinical
 Neuro –→ paresthesias, Trosseaus (BP), Chovstek (CN VII),
focal or generalized seizures, confusion,
 Cardiac –→ long QT –→ CHF
 Ophto –→ Ca deposits –→ subcapsular cataracts
 Derm –→ Dry flaxy skin, brittle hairs
 How hypocalcemia causes neuromuscular excitability
o –↓ extracellular Ca2 –→ less negative membrane potential –→ cell
more excitable
o Less depolarization required to initiate AP –→ ↑ excitability
o Chvostek sign –→ tap face on CN –→ twitch
o Trosseau –→ put on BP cuff –→ painful carpopedal spasm
 Hypocalcemia types
o Low PTH –→ Hypoparathyroidism
 Parathyroid agenesis –→ genetic
 Parathyroid destruction –→ surgery, autoimmune, infiltration
 Reduced parathyroid fxn –→ ↓ Mg from eclampsia, or
activating CaSR mutations
o High PTH –→ appropriate response
 Vit D deficiency –→ nutritional or renal insufficiency
 PTH resistance –→ pseudohypoparathyroidism
 Drugs –→ Ca chelators, inhibitors of bone resorption
 Misc –→ ↑ phosphate, acute pancreatitis, rhabdomyolisis
  Hungry bone syndrome due to long standing
hyperparathyroidism
o Albumin related hypocalcemia –→ sepsis
 Hypocalcemia due to low PTH
o –↓ PTH, ↓ Ca, ↓ 1, 25 OH D, ↑ phosphate
o Congenital/genetic
 Di George/CATCH22
 AD –→ activating CaSR gene mutation
 AR –→ PTH gene mutation affecting PTH synthesis
o Autoimune
 AIRE
 Activating Ab against CaSR
o Heavy metal deposition
 Hemochromatosis
o Magnesium abnormalities
o Surgical –→ hungry bone syndrome
 Hypocalcemia with high PTH
o Hungry bone syndrome
 Post parathyroidectomy
 Relative decrease in PTH
 Sudden bone remineralization –→ ↓ Ca, phosphate, Mg,
Alkphos
 If pre-existing Vit D deficiency→ might require Ca and Vit D
repletion for a long time
o Pseudo hyperparathyroidism
 Type 1 –→ ↓ urinary cAMP to exogenous PTH mutation
 Mutation of GNAS1 –→ which encodes the a subunit of
GpcR to PTH receptor
 Leads to failure to activate AC –→ no signal transduction
 Organ unresponsive to PTH
  Type 1a = Albright hereditary osteodystrophy
o AD, maternal transmission only
o Round faces, short 4th metacarpal bones
o Obesity, subcu calcification
o PTH resistance at renal tubules
 Hyperphosphatemia, hypocalcemia,
secondary hyperparathyroidism
o Pseudo-pseudohyperparathyroidism –→
paternally transmitted GNAS-1
 AHO phenotype but nl Ca and response to
PTH
 Type 1b
o Hypocalcemia but no phenotypic abnormalities of
AHO
o PTH resistance in kidneys
 Type 1c
o Altered coupling of G protein to PTH Recepter
o Similar to type 1a
 Type 2 –→ No Albright features
 Hypocalcemia, hyperphosphatemia, ↑ PTH
 Nl or –↑ urinary cAMP
 No increase in phosphate excretion
 Hypocalcemia overview in other causes
o CKD –→ ↓ calcitriol formation and –↑ phosphate
o Hyperphosphatemia –→ Ca deposits lead to hypocalcemia
o Tumor lysis syndrome/Rhabdomyolysis –→ hyperphosphatemia
leading to hypocalcemia
o Osteoblastic bone mets –→ Ca deposits around new bone
o Pancreatitis –→ precipitation of Ca soaps in abdomen
o Sepsis/severe illness –→ ↓ PTH secretion and action –→ ↓ calcitriol
formation
o Surgery –→ citrate in transfusions chelate Ca
  Magnesium induced hypocalcemia
o –↓ magnesium –→ PTH resistance or –↓ PTH secretion
o –↑ magnesium –→ ↓ PTH secretion (eclampsia treatment)
 Vit D deficiency
o Measure 25 OH Vit D to assess full stores
o If less than 5 –→ cannot sustain conversion to 1,25 OH D
 Treatment of hypocalcemia
o Acute hypocalcemia
 IV Ca
 Oral supplementation
 Vit D/calcitriol supplementation
o Chronic hypocalcemia
 Oral Ca
 Calcitriol
 Vit D
 Thiazide (risky)
 Recombinant PTH –→ not well tolerated

031 – Parathyroid Pathology

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032 –
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