309 Approach to Endocrine Diseases

ANP from the heart; induce natriuresis in kidney

EPO made in kidney to stimulate erythropoiesis in BM

Leptin - produced by adipose tissue

Cushings Disease impaired inhibition of ACTH but not

completely resistant as evidenced by ACTH suppression
of high dose dexamethasone test

MEN 1 triad of parathyroid, pancreatic islet and pituitary

tumors

MEN 2 predisposed to medullary thyroid CA,

hyperparathyroidism and phrecromocytoma

Activate mutations of LH rc
o McCune Albright syndrome early in
development
o GH secreting tumors and acromegaly
occur only in somatotropes

Hormone resistance defective hormone action

despite increase hormone levels

Cushings syndrome central fat distribution, striae,

proximal muscle weakness, obesity, plethora, hpn,
glucose intolerance

Hypothyroidism mental slowing, fatigue, dry skin

Immuonassays most impt diagnostic tool in

endocrinology; use ab to detect specific hormones

Urinary hormone secretion - assessment of a

hormone that vary within the day.
o 24 hr urinary free cortisol measures
unbound/biologically active hormone

cortisol increase 5 fold between midnight and dawn

reproductive hormones vary during mens

Decrease PTH with hypercalcemia

malignancy/granulomatous disease

ACTH with hypercotisolemia hyperfunctioning

adrenal adenoma

ACTH stimulation test for adrenal insufficiency

Metyrapone inhibition cortisol synthesis

Clomiphene inhibition estrogen feedback

Screening
o Type 2 DM beginning age 45 every 3 years
high risk; FPG 124mg/dl; RPG <200mg/dl
o Hyperlipidemia cholesterol screening every
5 yrs
o Gravess Dse TSH, free T4
o Thyroid nodule/neoplasia PE of thyroid and
FNAB
o PCOS testosterone, DHEAS
o Vit D def 25-OH serum vit D
400 Mechanism of Hormone Action

Classes of Hormones
o Amino acid dopamine, catecholamines, thyroid
hormone
o Small neuropeptide GnRH, TRH, somatostatin,
vasopressin
o Large neuropeptide insulin, PTH, LH
o Steroids estrogen & cortisol
o Vitamin derivative Vit. A & D

Membrane Receptors
o GPCR almost all
o Rc Tyrosine Kinase Insuline
o Cytokine Rc-linked kinase GH, PRL

Hormone precursor
o POMC ACTH
o Pro-glucagon, insulin, PTH

Pro-hormone conversion
o Testosterone dihydrotestosterone
o T4T3
Cholesterol steroid hormones
Stored in secretory granules GnRH, insulin, GH; with
stimulus will be released from the granules
Diffusion as they synthesized steroids stimulated by
StAR protein
Somatostatin - evanescent
TSH long lived
Circulating hormone half-life important to achieve hormone
replacement
o T4 HF:7 days; >1 month to reach steady
state; single daily dose
o T3 HF: 1 day; administered 2-3x a day
o Synthetic glucocorticoids vary

Dexamethasone- longer half-life

greater suppression of ACTH
o Protein hormones short half life <20mins
o PTH short half allows the use of PTH
determination intraoperatively in to confirm
successful removal of adenoma
Hormones in association with serum binding proteins
o Adv: hormonal reservoir, prevent rapid
degradation of unbound hormones, restrict
hormone access to certain sites
o Disadv: Create diagnostic problems
o Liver dse & meds estrogen inc TBG,
salsalate displace T4 from TBG
o For self corrections: except: SHBG dec in
insulin resistance or androgen excess
unbound testosterone leading to hirsutism;
testosterone does not result feedback
correction bec estrogen is the primary
regulator of reproductive axis

Hormone degradation
o 11B-hydroxysteroid dehydrogenase
inactivates glucocorticoids in renal tubular
cells
o Deiodenases convert tT4 to T4 and
inactivates T3
o Cyp26b1 degrades retinoic acid that
prevents promodial germ cells in male to
enter meiosis female ovary

Hormone action through receptors

o Membrane rc bind to peptide hormones
and catecholamines
o Nuclear rc bind to small molecules that can
diffuse such as steroids and vit D.

Functions of hormones
o Growth and differentiation
o Maintenance of homeostasis
o Reproduction

Positive feedback control

o Estrogen mediated mid cycle LH surge
rising estrogen stimulate LH secretion

Paracrine regulation factors released by one cell act

on adjacent cell Ex. Somatostatin secreted by D cells
inhibit insulin secretion from B cells

Autocrine action of factors from which it is produced

Ex. IFG-I acts on many cells from w/c it was produced
like chondrocytes, breasts, and gonadal cells

Hormonal rhythms
o Menstrual cycle 28 days; follicular
maturation & ovulation

Circadian rhythm pituitary hormones

ACTH and cortisol peak early

morning, nadir at night

Cushings increased midnight

cortisol levels

HPA axis susceptible to

suppression by glucocorticoids
administered at night as they blunt
the early morning rise of ACTH

Glucocorticoid replacement: mimic

diurnal pattern; administer large
doses in the AM than in PM
GnRH pulse frequency

Intermittent pulses reqd to

maintain pituitary sensitivity

Continuous exposure causes

pituitary gonadotrope
desensitization

Basis: long acting GnRH

agonists to treat central
precocious puberty or to
decrease hormone levels
in mngt of prostate ca
Integrated markers for hormonal fluctuations:

24 hr urine cortisol

IFG-I - GH action

HbA1C index of long-term bld

glucose control

401 Anterior Pituitary: Physiology of Pituitary Hormones

Table 401e-1

Pituitary Gland
o 600 mg; located within the sella turcica ventral to
diapgragma sella
o bld supply: s/i hypopyseal arteries
o HP portal plexus bld supply of AP
o Inferior hypophyseal art supply posterior
pituitary
o Posterior pituitary innervated by
supraopticohypophyseal and tuberohypophyseal
nerve tracts; so ADH and oxytocin sensitive to
neuronal damage by lesions of pituitary
stalk/hypothalamus

Prolactin
o Analougous to GH and HPL
o Lactotrope hyperplasia pregnancy & lactation
o Transient functional changes in lactotrope
induced by estrogen
o Normal levels:

Men 10-20ug/L

Women 10-25ug/L

Highest secretory peak: REM

Peak serum levels (30ug) 4-6am

Half life: 50mins

o Predominant hormone mechanism: inhibitory

dopamine mediated suppression (D2)

spontaneous hypersecretion of
compressice mass lesion on pituitary
stalk

Dopamine management of
hyperprolactinemic d/o
o Stimulants: TRH, VIP, acute stress
o Inhibitors: glucocorticoids and VIP
o Inc 10 fold pregnancy
o Decline rapidly w/in 2 wks of parturition
o Breastfeeding/sucking PRL remains elevated

Action:

Induce and maintain lactation

Decrease reproductive fxn

Suppress GnRH and

gonadotropin secretion and by
impairing gonal steroidgenesis

Blocks folliculogenesis and

inhibits granulosa cell
aromatase activity
hypoestrogenism and
anovuation

Leutolytic effect: decrease

luteal phase of mens; low
testosterone and
spermatogenesis in men

Suppress sexual drive decrease libido

and reduce fertility
Growth Hormone
o Most abundant AP hormone
o Somatrope cells 50% of total AP cell population
o Stimulant: GHRH discrete spikes, estrogen
o Inhibitor: Somatostatin sets basal tone, chronic
glucocorticoid excess
o IGF-I peripheral target hormone

Liver major source

Hypocaloric states (malnutrition,

cachexia, sepsis) GH resistance, low
IGF-I

Acromegaly high

Injected IGF (100ug/kg)

Approved for GH resistance

syndrome

Cachetic and insulin resistance

o Secretion: pulsatile;

Increase: highest peak levels at night,

sleep onset, execrcise, stress, trauma,
sepsis; chronic malnutrition and
prolonged fasting; IV L-arginine,
dopamine, and apomorphne

Decrease: with age (age rt decline in

lean mass), obesity (IGF-I not decrease:
change in setpoint for FB control);
glucose load
o GH rc agonist (pegvisomant) tx for acromegaly

24 Gh secretion increase in women

and estrogen replacement increased
peripheral GH resistance
o Action:

Antagonize insulin action

Induce protein synthesis,

nitrogen retention, and impairs
glucose tolerance

Stimulates lipolysis

Increase f.a.

Reduced omental fat mass

Enhanced lean body mass

Promotes Na, K, H2O rentention and

Increase phosphate

Stimulate epiphyseal prechondrocyte

differentiation: linear bone growth
ACTH
o 20% of AP cell population
o from POMC precursor
o CRH predominant stimulator of ACTH release
o

Pulsatile and exhibits circadian rhythm; peak:

6am nadir at night
o Increased: stress, exercise, acute illness, and
insulin-induced hypoglycemia
o Action:

maintain metabolic homeostasis and

mediate neuroendocrine response

induce streoidogenesis
Gonadotropins (FSH & LH)
o 10% of AP cells
o with B-subunits (like TSH and HCG) confers
specificity
o Stimulation: GnRH by brain kisspeptin

Secreted in discrete pulses every 60120mins

Pulses prime gonadotropin

responsiveness

Continuous GnRH induces

desensitization
o Estrogen modulates gonadotropin secretion

Chronic estrogen exposure inhibitory

Rising estrogen levels during preovulatory surge positive feedback

o GnRH - Main regulator of LSH and FSH secretion
o Action:

germ cell development

maturation of and steroid hormone

synthesis

FSH regulates ovarian follicle devt;

stimulates ovarian estrogen production;
induce seminiferous tubule devt and
regulates spermatogenesis

LH ovulation and maintenance of

corpus luteum; induces Leydig cell
testosterone synthesis
TSH
o 5% of AP population
o TRH hypothalamic tripeptide; stimulates TSH
secretion and lactotrophe to secrete PRL
o Inhibitor: thyroid hormones, dopamine,
somatostatin, glucocorticoids
o

402 Hypopituitarism
PANHYPOPITUITARISM

Congenital and Developmental Causes

o Pituitary Dysplasia aplastic, hypoplastic pituitary
development; midline craniofacial d/o; birth trauma,
cranial hemorrhage, asphyxia, and breech delivery
o Tissue Specific Factor Mutations Pit 1 and Prop 1
combined GH, prolactin, and TSH deficiencies
o Devtal Hypothalamic Dysfunction:
o Kallman Syndrome - Defective GnRH
synthesis associated with anosmia and
hyposmia due to olfactory bulb dysgenesis;
classically associated with color blindness,
optic atrophy, nerve deafness, cleft palate,
and renal & neuro abnormalities,
cryptorchidism
o Bardet-Biedl Syndrome mental retardation,
renal abnormalities, obesisty, haxadacytyly,
brachydactyl, or syndactyly, Central DI,
retinal degeneration, blind by 30
o Leptin & leptin rc mutations hyperphagia,
obesity, and central hypogonadism
o Prader- Willi Syndrome hypogonadotropic
hypogonadism, hyperphagia-obesity, chronic

muscle hypotonia, MR, adult-onset DM,

somatic defects of skull, eyes, ears, hands
and feet

Acquired Causes
o Hypothalamic infiltration disorders sarcoidosis,
histiocytosis X, amyloidosis, and
hemochromatosis may have DI, growth
retardation if GH secretion in puberty, hypogo2
and hyperprolactinemia
o Inflammatory lesions TB, fungal infxns with
AIDS, granulomas and sarcoidosis may mimic
pituitary adenoma
o Cranial irradiation 50Gy (5000rad) develop
hormone insufficiency and ususally hypothalamic
damage GH deficiency most common
o Lymphocytic Hypophysitis postpartum women;
presents with hyperporlactinemia and MRI
evidence of a prominent pituitary mass that
resembles adenoma with mildly elevated PRL
levels; headache and visual disturbance, ESR
elevated
o Pituitary Apoplexy acute intrapituitary
hemorrgagic vascular events; Sheehans
syndrome hyperplastic enlargement of pituitary
normally during pregnancy increases the risk for
hemorrhage and infarction; endocrine emergency
severe hypoglycemia, hypotension, and
shock, Acute s/sx: severe headache w/ signs of
meningeal irritation, bilateral visual changes,
ophthalmoplegia, and CV collapse and LOC. Tx:
high dose glucocorticoids Sx: severe
ophthalmoplegia and visual deficits
o Empty Sella incidental MRI finding; assoc with
intracranial hypertension; pituitary asses undergo
clinically silent infarction and involution w/c devt
of empty sella by CSF filling the dural herniation;
insidious devt of hypopituitarism

Presentation: GH def TSH ACTH

Laboratory Investigation:

Table 402 -2
o Low free thyroxine, low or N TSH 2nd hypothyroidism
o Low testosterone w/o inc in gonadotropins hypogo

Provocative tests assess pituitary reserve

o GH reserve insulin induced hypogly, arginine,
dopamine, GHRH
o ACTH reserve CRH and synthetic ACTH
(cosyntropin); most reliably assessed by
measuring ACTH and cortisol levels during
insulin induced hypoglycemia but performed
cautiously in pts with adrenal insufficiency
enhanced susceptibility in hypoglycemia and
hypotension
o Administering insulin to induce hypogly CI in
pts with active CAD or seizures

Treatment for Hypopituitarism Table 402-3

o Hormone replacement therapy
o Careful dose adjustment in glucorcorticoids
replacement in acute illness, dental procedures,
trauma and acute hospitalization
DISORDERS OF GROWTH AND DEVELOPMENT

Bone Age delayed in all forms of true GH deficiency or rc

defects

Short stature result of intrinsic or extrinsic factors that

impair growth

Delayed bone age with short stature hormonal or

systemic do

Normal bone age in short child genetic cartilage

dysplasia or growth plate do
GH Deficiency in Children
o Isolated GH deficiency short stature,
micropenis, increased fat, high pitched voice and
hypoglycemia due to unopposed insulin
o Idiopathic GH deficiency diagnosis made after
molecular defects excluded
o GHRH mutations severe proportionate
dwarfism associated with low basal GH levels
that cannot be stimulated
o GH insensitivity Larons Syndrome GH
insensitivity, growth failure, normal or high GH
levels, dec GHBP, low IGF-I levels
o Nutritional short stature caloric deptivation and
malnutrition, uncontrolled DM, CRF produce
cytokines -> exacerbates the block in GH
mediated signal transduction; short stature w/
normal or elevated GH and low IGF-I levels
o Psychosocial short stature emotional and social
deprivation with delayed speech, discordant
hyperphagia
Presentation and Dx
o Family hx
o Short stature evaluated if pts height is >3SD
below the mean for age or if growth rate has
decelerated
o Skeletal maturation measured by radiologic
bone age; based on wrist bone growth failure
o Final height predicted with standardized scales
(Tanner) or add 6.5 cm (boys) or subtract 6.5 cm
(girls) from midparental height
Laboratory Dx: GH secretion pulsatile; provocative test:
increase GH to >7ug/L in children (exercise, insulin
Treatment: recombinant GH (0.02-0.05 mg/kg per day SC
approx. 10cm/year; effective for Turners syndrome and
CRF
o If due to mutations of GH rc: tx with IGF-I
bypasses dysfunctional GH rc
ADULT GH Deficiency
o Usually caused by acquired
hypothalamic/pituitary somatotrope damage
o Sequential order of hormone loss: GH FSH/LH
TSH ACTH
o Presentation: reduced lean body mass, inc fat
mass with intraabdominal visceral fat, and inc
waist-to-hip ratio, hyperlipidemia, L ventricular
dysfunction, hypertension, increased plasma
fibrinogen, dec bone mineral content fractures,
social isolation, depression
o Lab investigation: restricted to the following:

Pituitary sx

Pit/hypothal tumor/granulomas

Hx of cranial irradiation

Radiologic evidence of pituitary lesion

Childhood req for GH replacement

therapy

Low IGF levels

o IGF-I levels useful index of therapeutic
response but not for diagnostic purposes
o Insulin-induced hypoglycemia most validated
test to ADGH

0.05-0.1 U/kg insulin glucose

reduction ~40mg (nueroglycopenic
symptoms) peak GH release at 60
mins and remains elevated up to 2 hrs

Normal: - GH response to hypogly >5

ug/L

AGHD: <3 ug/L

CI: DM, ischemic heart dse, CVD,

epilepsy, elderly
o Treatment: Starting dose 0.1 -0.2 mg/d check
IGH levels after 1 month titrated to 1.25mg/d
(max) check IGF-1 after 6 month if with
response , continue, no response, d/c

CI to therapy: actibe neoplasm,

intracranial hypertension, incontrolled
DM, retinopathy
ACTH DEFICIENCY

Presentation:
o Secondary ACTH (adrenal) def: fatigue,
weakness, anorexia, vomiting, hypoglycemia,
hyperpigmentation, mineralocorticoid def
o Primary ACTH def: no hyperpigmentation, and
mineralocorticoid def

Etiology:
o glucocorticoid withdrawal after tx-assoc.
suppression of HPAdrenal axis.
o Surgical resection of ACTH-secreting pituitary
adenoma

Lab Dx
o Low ACTH levels with low cortisol levels
characteristic diminished ACTH reserve with
ACTH stimulation and insulin-induced
hypoglycemia or testing with metyrapone and
CRH

Tx: Glucocorticoid replacement

o Hydrocotisone replacement: does not exceed
25mg daily
o Prednisone (5mg/morning) longer acting, few
mineralocorticoid effects
o Increased dose with stress and cute illness
GONADOTROPIN DEFICIENCY

Hypogonadism most common presenting feature of adult

hypopituitarism

Presentation:
o Premenipausal: diminished ovarian reserve
oligomenorrhea, amenorrhea, infertility, dec
vaginal secretion, dec libido, breast atrophy
o Men: testicular failure dec libido and potency,
dec muscle mass, reduced body hair, soft testes

Lab Dx:
o Central hypogonadism low gonadotropins, low
sex hormones
o IV GnRH (100ug) stimulates gonadotropes to
secrete LG (peaks w/in 30 mins) and FSH
(plateaus in 60min)
o Normal: LH increase 3fold, FSH inc less
pronounced
o Gonadotropin deficiency: normal response
o Hypothalamic/Pituitary cause: absent reponse
o MRI central hypogonadism

Treatment:
o Males: testosterone IM every 1-4 wks or daily
patches or gels
o hCG or hMG for 12-18 mos restore fertility;
follicular growth and maturation
o pulsatile GnRH therapy: 25-150ng/kg evry 2 hrs
by subq pump for hypothalamic hypogonadism
o premenopausal: cyclic replacement of estrogen
and progesterone
o gonadotropin therapy: ovulation induction

DIABETES INSIPIDUS
Chap 404
403 Anterior Pituitary Tumor Syndromes
Hypothalamic, Pituitary and Other Sellar Masses

Evaluation of Sellar Masses

1. Local Mass Effects
a. Dorsal sellar diaphragm least resistance
to soft tissue expansion
b. Headaches cmmon feature of small
intrasellat tumors
c. Features of Sellar Mass Lesions: Table 4031
2. MRI
a. Pituitary gland height

children 6mm-8mm

pregnaoncy & puberty 10-12mm

adult flat/slightly concave

pregnancy/adolescent convex
( pituitary enlargement)
b. pituitary bright spot high phospholipid
content in posterior pituitary
c. Sellar masses incidental findings

Absence of hormone hypersecretion

monitor with MRI annually

Resection macroadenomas with

invasive and pressure effects
3. Ophthalmologic Evaluation
a. Optic tracts contiguous to expanding pituitary
mass
b. perimetry test visual fields in those with
sellar mass lesions impinging optic chiasm
c. Bitemporal hemianopia compression of
optic chiasm
d. Homonymous hemianopia postchiasmal
compression
e. Monocular temporal field loss prechiasmal
compression
f. Diplopia oculomotor nerve palsy due to
invasion of carvernous sinus
4. Laboratory Investigation
a. Screening Tests for Functional Pituitary
Adenomas
b. Pituitary adenoma suspected in MRI, initial
hormonal evaluation

Basal PRL

IGF-I

24-hr urinary cortisol/overnight oral

dexamethasone (1mg) suppression test

a-FSH and LH

thyroid function test

c. Histiological evaluation after
transphenoidal surgery
5. Treatment
a. Transphenoidal Surgery

Desired surgical approach for pituitary

tumors than transfrontal

Avoids cranial invasion and brain tissue

manipulation

Surgical decompression and resection

for expanding pituitary mass

SE: DI, CN damage, nasal septal

perforation, visual disturbances
b. Radiation

Total of <50Gy (5000 rad) is

given as 180-cGy (180-rad)
divided in 6wks

6.

7.

8.

9.

Sellar Masess: Hypothalamic Lesions

a. Anterior & preoptic regions: Cause
paradoxical vasoconstriction, tachycardia,
hyperthermia
b. Posterior regions: periodic hypothermia
syndrome episodes of <30C, sweathing,
vasodilation, vomiting and bradychardia
c. Ventromedial region: hyperphagia and
obesity
d. Preoptic nuclei damage to osmorc
polydipsia and hypodipsia
e. Cryaniopharnygomas benign, suprasellar
cystic masses that present with headaches,
visual field deficits and hypopituitarism, age
of 20 with sign of inc ICP
Pituitary Adenomas and Hypersecretion Hormones
a. Pituitary Adenomas most common cause
of pituitary hormone hypersecretion and
hyposexretion in adults
b. Benign neoplasms that arise from one of the
5 AP cell types:
c. Classification of Pituitary Adenomas Table
403-3
d. Genetic Syndromes assoc with pituitary
tumors Table 403-4
Hyperprolactinoma
a. Most common pituitary hormone
hypersecretion in both men and women
b. Prolactinomas most common cause of
PRL levels >200ug/L
c. Etiology Table 403-5
d. Presentation:

amenorrhea, galatorrhea, and infertility

hallmarks in women

develops before menarche primary

amenorrhea

hyperestrogenemia vertebral bone

density reduced

men: diminished libido, infertility, and

visual loss

Galactorrhea inaapropriate discharge

of milk; abnormal if > 6 mos after
childbirth, d/c of bf
e. Lab:

Basal, fasting morning PRL levels

assess for hypersecretion

Exclude hypothyroidism excluded by

measuring TSH and T4 levels
f. Tx:

Dopamine agonists

Withdraw drugs causing

hyperprolactenemia

Psych pts: dose titration of neuroleptic

agents

Resolves after thyroid replacement in

hypothyroidism and renal transplant pts
undergoing dialysis

Resection of mass
Prolactinoma
a. Most common pituitary tumor; half of all fxning
pituitary tumors
b. Microadenomas - <1cm; noninvasive; F:M ratio:
1:1
c. Macroadenomas ->1cm; invasive and impinges;
F:M ratio: 20:1
d. Presentation: same with hyperprolatinemia

e.

PR levels > 200ug/L, if less than 100

microadenoma
f. Tx:

Asymptomatic microadenoma no tx;

monitor PRL and MRI

Symptomatic microadenoma
o Medical: Dopamine agonists

Cabergoline (0.5-1.0mf twice

weekly) D2 rc affinity; suppress
PRL for 14 daysafter single oral
dose; SE: headaches, visual d/o;
but less SE than bromocriptine

Bromocriptine (0.625-1.25mg at
bedtime w/ snacks; gradual daily
dose of 2.5mg tid short acting;
preferred in pregnancy; restore
fertility in women with
hyperprolactinemia

SE: constipation, nasal stuffiness,

dry mouth, nightmares, insomnia,
and vertigo
o Mngt Approach with Elevated
Prolactin levels: Fig 403-3
10. Acromegaly
a. Etiology: usually result of somatotrophe
adenoma/pituitary cause -98%
b. GHRH mediated acromegaly most common
cause is chest or abdominal carcinoid tumor
c. Presentation:

GH and IGF-I hypersecretion indolent

clinically diagnosed for 10 yrs or more

Acral bony overgrowth: frontal bossimg,

increased hand and foot size, mandibular
enlargement with prognathism, and widened
space between the lower incisor teeth,

Children: before closure of epiphyseal long

bones: gigantism

Soft tissue swelling

Hyperhidriosis, deep voice, oily skin,

arthopathy, kyphosis, carpal tunnel
syndrome, acanthosis nigricans,
visceromegaly

Most significant impact: CV system CHD,

cardiomyopathy w/ aryhthmia, hpn

Upper airway obstruction with sleep apnea,

DM (GH counteracts insulin), increase colon
polyps and malignancy,
d. Lab: Age matched serum IGF-I are
increased; confirmed by the demonstrating
the failure of GH suppression to <0.4ug/L
w.in 1-2 hr of an OGTT (75g)
e. Tx:
o Surgical resection of GH-secreting
adenomas
o Somatostatin analogues adjuvant tx
for preop shrinkage

Ocreotide acetate SQ 50ug tid to

1500ug/d

SE: GI nausea, abdominal

dscomofrt, fat malabsorption.
Diarrhea, flatulence, suppress
gallbladder contractility leading to
asymptomatic cholesterol gallstone
o GH rc antagonists (Pegvisomant daily
SQ 10-20mg, normalized IGF-I
o Irradiation or rpt sx not responding to
medical therapy

Transphenoidal sx: soft tissue swelling

improves, GH levels return to normal
after 1 hr, IGF-I normal after 3-4 days
o Mngt if Acromegaly approach Fig. 403-5
11. Cushing Syndrome (ACTH-Producing Adenoma)
a. Etiology:

Pituitary corticotrope adenomas - 70% of pts

with endogenous cause of CS

Iatrogenic hypercortisolism most common

cause of cushingoid fechronic cortisol
features
b. Presentation: Typical features of chronic cortisol
excess

Thin skin, central obesity, hpn, plethoric

moon facies, purple striae, easy bruisability,
glucose intolerance, dm, gonodal dysnfxn,
hyperandrogenism, psych disturbances

Hema features: leukocytosis, lymphopenia,

eosinophilia

Immune suppression

Ectopic tumor source: rapid devt of features

of hypercotisolism assoc with skin
hyperpigmentation and sever myopathy, hpn,
hypokalemic alkalosis, glucose intolerance,
edema

Table 403.- 7
c. Lab:

24-hr urone free cortisol (UFC)

failure to suppress after an overnight 1-mg

dexamethasone suppression test cortisol
nadir levels at night elevated midnight
serum samples

Basal ACTH levels distinguish ACTH

independent (adrenal/exogenous
glucocorticoids) from ACTH-dependent
(pituitary ectopic ACTH 8fold higher )

Dynamic testing based on glucocorticoid

feedback or ACTH stimulation in response to
CRH or cortisol reduction

Differentia diagnosis of ACTH-dependent

Cushing Syndrome Table 403-8
d. Treatment

Selective transphenoidal surgery tx of

choice with postop sytomatic ACTH
deficiency low dose cortisol replacement

Pasireotide 600-900ug/d SQ tx for ACTHsecreting pituitary tumors when sx not

useful/successful

Ketoconazole

Mifepristone

Metyrapone 2-4g/d inhibits 11B-hydoxylase

activity and normalizes plasma cortisol

Bilateral adrenalectomy inc morbidity rates

and neccesiates permanent glucocorticoid
and mineralocorticoid replacement; in setting
of corticiotrope adenoma: Nelsons
syndrome rapid pituitary enlargement and
increased pigmentation secondary to high
ACTH; prophylactic radiation therapy

Mngt of Cushings syndrome Fig 403-6

o

404 DISORDERS OF NEUROHYPOPHYSIS

Originate in the supraoptic and paraventricular nuclei

2 hormones:
o AVP acts in renal tubules to reduce water loss
by concentrating the urine

Oxytocin postpartum milk letdown in response

to suckling

DI production of large urine; impairs urinary excretion,

predispose to hyponatremia

Vasopressin
o regulated primarily by the effective osmotic
pressure of body fluids mediated by osmorc w/c
are sensitive to changes in plasma sodium
(280mosmo/L or 135meq?L
o Action: reduce water excretion by promoting
concentration of urine increasing
hydroosmotic permeability of cellsthat line DT
and MCD of kidney
o Water diuresis lack of reabsorption; excretion of
0.2mL/kg per min of maximmaly dilute urine and
SG -1.000 and osmolarity of 50mosmol/L
o Thirst ensure adequate intake to prevent
dehydration
o Oxytocin

Act on mammary ducts to facilitate milk

letdown ; initiate or facilitate labor by
stimulating contraction of uterine sm
muscle
Deficient of AVP Secretion
1. Diabetes Insipidus

Decrease of 75% or more in the secretion or action of

AVP usually results in DI; syndrome characterized by
the production of abnormally large volumes of dilute
urine.

Polyuria urinary frequency, enuresis, nocturia, which

may disturb sleep, slight rise in plasma osmolarity that
stimulates thirst and commensurate increase in fluid
intake (polydipsia)

Etiology: agenesis or irreversible destruction of the

neurohypophysis

Gestational DI primary deficiency of plasma AVP

also can result from increased metabolism by an Nterminal aminopeptidase produced by the placenta

Primary polydipsia secondary deficiencies of AVP

result from inhibition by excessive intake of fluids
o Dipsogenic DI inappropriate thirst caused
by reduction in the set of the osmoregulatory
mechanism Ex. Neurosarcoid, TB meningitis,
MS
o Psychogenic polydipsia not assoc with
thirstl feature of psychosis, OC
o Iatrogenic polydipsia inc fluid intake for its
presumed health benefits
o Nephrogenic DI insensitivity to ADH

Pathophysiology: polyuria dec body water and

increase in plasma osmolarity and Na that stimulates
thirst and inc, water intake

Hypernatremia and dehydration do not develop

unless theres a defect in thirst or fails to inc fluid
intake

Causes of DI: Table 401-1

DDX:
o symptoms of urinary frequency, enuresis,
nocturia and persistent thirst in the absence
of glucosuria collect 24hr urine on ad
libitum fld intake
o volume exceeds 50ml/kg/ per day (3500ml in
a 70kg male) and osmolarity is below
300mosml/L
o Fluid Deprivation test effect on urine
osmolality of injecting 2ug of AVP analogue
o

2.

(desmopressin) pituitary DI/nephrogenic

DI
o Measure basal plasma AVP differentiate
between pituitary, nephrogenic, and primary
polydipsia
o >1pg/ml --) nephrogenic DI
o <1pg/ml MRI differentiate primary and
pituitary DI

present pituitary bright spot

primary polydipsia

absent pituitary bright spot

pituitary DI

Treatment:
o Central DI: DDAVP (desmopressin) acts on
V2 rc to inc urine concn and decrease urine
flow
o Nephrogenic DI: thiazide diuretic, amiloride,
low sodium diet, prostaglandin synthesis
inhibitor (indomethacin) reduce polyuria
and polydipsia
Hyponatremia due to Inappropriate AntidiuresisDecrease
plasma osmolality/sodium below the normal range
a. Types:
o Hypervolemic hyponat CHF, cirrhosis
o Hypovolemic hypnat diarrhea, diuretic abuse
o Euvolemic hyponat excessive intake with defect
in urinary dilution
b. SIADH
o defect in osmoregulation; decrease volume and
inc concn of urine; excess water retention and
expands dilutes body fluids
o symptoms of water intoxication: mild headache,
confusion, anorexia, n/v, coma, convulsion,
edema (hypervolemic)
o inappropriate secretion of AVP
o ectopic: lung cancer
o eutopic: dse & drugs
o exogenous adm: AVP, DDVP, oxytocin
o Increase in body water of 10% and reduces
plasma osmolarity and sodium by approx. 10%
(~28mosmol/L or 14meq/L
o Wt gain of 4kg
c. SIADH diagnosis of exclusion; hyperglycemia
contribution to the reduction in plasma sodium by
measuring plasma osmololarity for a more accurate
estimate of the true effectivity tonicity
o Corrected Pna = measured Pna + (Pglu -90)/36
o Hypotonic hyponat plasma
osmolarity/corrected plasma sodium are below
limits
o Table 404-3
d. Tx:
o Acute asymptomatic SIADH goal: raise
plasma osmolarity and or/plasma sodium at a
rate approx. 1% an hr until they reach
270mosmol/L or 130meq/L infuse hypertonic
saline at a rate of 0.05 ml/kg body wt per minute
o AVP rc2-agonist (Conivaptan) block the antidiuretic effects of AVP and increase urine output;
restrict fluid intake

405 Disorders of the Thyroid Gland

1. Anatomy and Development
a. produce two hormones: T4 and T3
b. 2 lobes connected by isthmus, ant to the trachea
c. 12-20h, highly vascular and soft consistency

d.
e.

2.

3.

4.

5.

6.

7.

parathyroid loc at posterioir pole of the thyroid

thyroid medullary C cells: produce calcitonin Ca
lowering hormone; involve in medullary can
f. TSH regulates increase demand in TSH; most useful
marker of thyroid hormone action; establish the set
point in HPA
g. B-sub unit unique to TSH
h. Thyroid hormones dominant regulator of TSH
production
Thyroid Hormone Synthesis
a. Tg thyroid hormones are derived
b. Steps:

Iodine Metabolism and Transport idodide

uptake is the critical first step in the thyroid
hormone synthesis
o Mutation of pendrin genre Pendrad
syndrome defective organification of
iodine, goiter, and sensorineural
deafness

Organification, Coupling, Storagem and Release

Iodine deficiency
a. prevalent in mountainous regions
b. increased prevalence of goiter
c. severe deficiency: cretinism mental and growth
retardation
d. oversupply of iodine = inc. autoimmine thyroid
dse
TSH Action
a. Regulates thyroid gland fxn through GPCR
b. IGF-I, TGF-B, endothelins
c. Iodine deficiency inc thyroid bld flow and
upregulates NIS more efficient iodine uptake
d. Wolff-Chaikoff effect excess iodide transiently
inhibits thyroid iodide organification
e. Characteristics of T3 and T4: Table 405-2
Abnormalities in Thyroid Hormone Binding Proteins
a. X-linked TBG deficiency -> very low levels of total
T4 and T3, unbound levels are normal, pts
euthyroid and normal
TSH
b. Pregnany/Taking OCP (estrogen) elevated
TBG inc T4 and T3 levels, unbound normal
c. Euthyroid hyoerthyroxinemia inc T4 and T4 but
unbound are norm
d. Salicylates and salsalate displace thyroid
hormones from circuating binding proteins
Deiodenases
a. converts T4 to T3
b. Type 1 thyroid, liver, and kidneys, low affinity to
T4
c. Type 2 higher affinity to T4, pituitary gland,
brown fat, and thyroid- regulate T3
concentrations locally, - impt in levothyroxine
replacement; enhance T4 to T3 conversion
d. Type 3 inactivates T4 to T3 most impt source
of reverse T3m including sick euthyroid
syndrome muscle and liver
Physical Examination
a. Palpate the thyroid
b. UTZ method of choice to determine accurately
thyroid size accurately
c. Bruit/thrill supero/inferolatteraly increased
vascularity such in hyperthyroidism
d. Restrostenal goiter lower borders of thyroid
lobes not felt; venous distention over the neck
and DOB especiallyw hen arms raised
(Pembertons Sign)
e. Central mass above the thyroid --? Extend
tongue thyroglossal cysts move upward

f.

Lymphadenompathy supraclavicalr and cervical

regions
g. Thyroid size, nodularity, consistency tenderness,
fixation
h. UTZ accurate thyroid size
8. Lab Evaluation
a. Measure thyroid hormones
b. TSH logical approach to thyroid testing, tested
first
i. Normal TSH secondary abnormality
ii. Supressed thyroticosis
c. radioimmunoassays for serum total T4 and total
T3 measure free or unbound hormone
d. Thyroid hormone binding ratio (THBR) - derived
from T3 resin uptake
e. Total thyroid hormones increased when TBG is
increased due to estrogens, liver dse, decreased
when TBG binding reduced in androgens,
nephrotic syndrome
f. T4 sufficient to confirm thyrotoxicosis, 2-5% T3
toxicosis still measure T3 if with suppressed
TSH but normal T4
g. Autoimmune thyroid disease detected by
measuring TPO and Tg
h. TRAb (TSH rc antibody) - measure ab that
stimulate TSH-R in Graves Dse
i.
Serum Tg- increase in thyrotoxicosis excpt factitia
self admin of thyroid hormone; increase in
thyroiditis, follow uo if thyroid cancer pts; must be
undetectable in after total thyroidectomy and
radioablation; absence of anti-Tg ab indicate
complete ablation or recurrent ca
j.
Radioiodine uotake & thyroid scanning
i. Graves enlarged gland with increase
uptake
ii. Toxic adenoma focal areas of inc
uptake , suppressed uptake in the
remainder of the gland
iii. Toxic MNG enlarged gland, distorted
architecture increased uptake
(fuxning) and dec uptake (nonfxning)
iv. Thyroiditis low uptake due to follicular
damage and TSH suppression
k. Thydoid scintigraphy
i. Performed if serum TSh levels are
subnormal to determine fxning thyroid
nodules are present
ii. Hot nodules functioning; never
malignant; FNAB not indicated
iii. Cold nodules do not produce thyroid
hormones; likely to be malignant
l.
Thyroidn UTZ

Evaluate thyroid nodular dse; thyroid

nodukes nodule zie
Hypothyroidism

Causes Table 405-6

iodine deficiency common cause of hypothyroidism

worldwide

Hashimotos for areas of iodine sufficiency

Iatorgenic cause tx of hyperthyroidism

Congenital Hypothyroidism
o Prevalence: due to thyroid gland dysgenesis 8085%; common in girls
o Manifestations

Appear normal at birth

Infants: prolonged jaundice, enlarged tongue,

delayed bone formation, umbilical hernia

g.

h.

Adult: tiredness, weakness, dry skin, feeling cold,

weigt gain with poor appetite, dry coarse skin,
puffy hands and feet, bradycardia

Dx & Tx: NBS, measure TSH and T4; 10-15ug/kg

per day, T4 reqts great during the first year for
nomal IQ levels
Autoimmune Hypothyroidsim
o Hashimotos/ Goitrous thyroiditis, atrophic thyroiditis
o Subclinical hypothyroidism minor symptoms
o Overt/clinical hypothyroidism TSH > 10mIU/L
o Prevalence: genetics; chonic exposure to high iodine
diet; mean age of diagnosis: 60y/o
o Hashimotos: Marked lymphocytic infiltration of thyroid
with germinal center formation, atrophy of thyroid
follicles with oxyphil metaplasia
o Atrophic thyroiditis extensive fibrosis, lymphocyte
infiltration less pronounced, thyroid follicles absent;
represents end stage Hashimotos
o HLA-Dr polymorphisms
o Antoboides to TPO and TG useful markers for
thyroid autoimmunity; no effect on fetal thyroid; T-cell
mediated injury
o Antibodies to TSH-R prevent binding of TSH
Asians thyroid atrophy
o Clinical Manifestations: Table 405-6; puffy eyes and
thick skin
o Hashimotos: usually present with goiter irregular
and firm; palpated at pyramidal lobe vestigial
remanant of thyroglyossal duct
o Atrophic thyroiditis/Late stage Hash: dry dec
sweating, thinning of epidermis, and hyperkeratosis of
stratum corneum, skin thickening w/o pitting edema
(mysedema), puffy face with edematous eyelids and
pretibial edema, pallor& yellow-yinged skin
carotene accumulation, brittle nails, fry hair, wt gain
modest and due to fluid retention , dec, libidio,
oligo/amenorrhea, fertility dec, prolactin mod inc--?
Galactorrhea, myocardial comtractility and PR
reduced dec SV and brady, diastolic hpn, cool
extermities blood flow diverted from the skin,
carpal tunnel and entrapment synromes impair
muscle function, stiffness, crmaps, slow relaxation of
tendon reflexes
o Lab Evaluation:

normal TSH secondary cause; pituitary dse

check T4; if low rule out drug effects, euthyroid
syndrome, pituitary tumor

TSh elevated get T4; but T4 inferoir and cannot

detect subclinical hypothy

Establish origin: TPO ab

FNAB confirm the presence of autoimmune

thyroiditis

Evaluation of Hypothyroidsim Fig 405-7

Other causes of hypothyroidism
o Iatrogenic hypothyroidism: first 3-4 months of
radioiodine tx
o Iodine deficiency responsible for endemic goiter and
cretinism in children
o Chronic excess iodine paradozix goiter and
hypothyroidism
Treatment of Hypothyroidism
o Clinical Hypothy:

No residual thyroid fxn: levothyroxine (T4) 100150ug daily before breakfast;

after tx of Graves: lower replacement dose of 75125

adult less 60 y/o with no heart dse: 50-100ung

levo

TSH response measured 2 months after

Effects: slow to appear or relief until 3-6 mos

SE: risk of atrial fibrillation and bone density

Taking >200uf of levo a day with elevated TSH

poor compliance/adherence to tx

T4 long half life miss a dose, can take 2 doses

at once
o Subliclinical Hypothy: biochemical evidence of
hypothyroidism but no apparent clinical features

No recommended tx

Except: Consider in women wish to get pregnant

or TSH below 10mIU/L levo, positive TPO ab,
with heart dse, with suggestive symptoms,
positive TPOab, evidence of heart dse.

Sustained elevation TSH for 3mos before tx is

given

Start low dose: 25-50ug /d

o Special Tx Consideration
Women with high risk of hypothy: must be euthyroid
prior to conception and prganacy maternal
hypothy affect neural devt and cause preterm
delivery.
o Increase levo dose up to 50% with TSH
<2.5mIU/L (1st trim), 3.0mIU/L during
2nd/3rd tri.
Elderly: 20% less thyroxine; those with CAD:
starting dose 12.5-25ug/d emergency surgery
pt must be euthyroid first
Myxedema Coma reduced LOC, assoc with
seizures + hypothyroidism, hypothermia les 23C,
o Precipitating factor: infection, with
precipitating factors such as infection,
drugs, alcohol, MI, GI bleeding, CVA
o Pathogenesis: hypoventilation leading to
hypercapnia and hypoxia
o Tx: single IV bolus 500ug Levo,
continued to 50-100ug/d or via NGT
o Impaired T4 to T3 conversion
liothyronin (T3)
o Supportive therapy: warming,
hydrocortisone (50mg/6hr), remove
precipitating factors antibiotic, ABG,
NSS, glucose,
Thyrotoxicosis

Thyrotoxicosis state of thyroid hormone excess result of

excessive thyroid function

Causes: Primary: Graves, Toxic MNG, Iodine excess (Jod

Basedow Phenomenon

Ophthalmopathy: infiltrtaon of EOM by activated T cells

fibroblast activation muscle swelling

S/Sx: hyperactivity, irritability, lead to fatigue dysphoria,

heat intolerance, sweating, palpitations, fatigue and
weakness weight loss with increased appetite
increased metabolic rate, tachycardia, atrial fib, tremor,
goiter, muscle weakness, lid lag, assoc with hypokalemic
periodic paralysis, sinus tachycardia most common
manifetstaion, directe effect of thyroid hormone on
bones bone resorption (osteopenia)
o Elderly: apathetic thyrotoxicosis: fatige and wt loss
o PE:l diffusely enlarged; no nodulesl thrill/bruit on
inferolateral margins due to increasd vascularity of the
gland
o Lid retraction Graves ophthalmopathy

Most serious manifestation compress optic nerve

papilledema blindness
o Thyroid demopathy/pretibial myxedema shins;
orange skin appearance, noninflamed, indurated
o Thyroid acropachy form of clubbing
Lab Evaluation:
o TSH suppressed, T3 and T4 increased
o 2-5% T3 toxicosis
o T4 toxicosis elevated T4 and normal T3; due to
iodine excess
o Lack features of diffuse goiter and ophtalmopathy:
radionuclide scan Graves high uptake;
thyroiditis, ectopic thyroid tissue, and factititious
thytoxicosis low uptake
o Scintography preferred diagnostic test
o TRAb assess autoimmune activity
o Evalutaion of Thyrotoxicosis Figure 405-9
Treatment;
o Anti-thyroid drugs

PTU, Carbomazole, Methimazole inhibit the fxn of TPO, reducing oxidation

and organification of iodide

PTU inhibits deiodination of T4 to T3;

monitor liver fxn

Carbimazole or methimazole 10-20mg

every 8 or 12hr

PTU 100-200 mg every 6-8 hrs

Throid fxn test reviewed after 4-6wks

Euthyroid 6-8 wks after tx is initiated

SE: rash, fever, arthralgia, hepatitis

(PTU), cholestasis
(methimazole/carbimzole),
agranulocytosis (sorethroat, fever,
mouth ulcers, monitor bld counts)

Propranolol 20-40mg every 6hr

control adrenergic symptoms; useful in
thyrotoxic periodic paralysis; warfarin
atrial fib

Radioidine progressive destruction of

thyroid cells; pretx with antithyroid drugs
for a month to prevent thyrotoxic crisis
to deplete thyroid hormone stores;
carbimazole and methimazole stopped
3-5 days before radionuclide scan
admin; PTU prolonged radiprotetctive
effect stopped longer before
radioiodine is given

Radiation precautions:

avoid close contact with

children and pregnant
transmission of radiation;

2-3 mos full effect -> use

beta blockers to control
symptoms

CI; pregnancy and BF

Can conceive safely 6 mos

post tx

Prednisone 40mg/dl to those

with ophtalmopathy

Subtotal/Near-total thyroidectomy
o Option to those with relapse
after ani-thyroid drugs
o Young - very large
o 3 drops SKKI TID; avoid
thytoxic crisis and reduce
vascularity of gland
o

complication: bleeding,
laryngeal edema,
hypoparathyroidism

Anti-thyroid drugs titrated for pregnant

transplancental passage fetal
hypothy and goiter; PTU given early
gestation prevent fetal aplasia cutis
and choanal atresia with methimazole;
PTU limited to 1st trim converted to
methimazole

BF safe in low dose

Graves children avoid PTU; sx and

radioiodine

Thyrotoxic crisis/thyroid storm life

threatening exacerbation of
hyperthyroidism with fever, delirium,
seizures, coma, vomiting, diarrhea and
hyperthermia; precipitated by acute
illness (stroke, infxn, dka), sx, and
radioiodine tx;
o Management: tx the
precipitating cause
o Large dose PTU 500-1000mg
loading dose and 250 mg every
4 hr orally or by NGT after 1
hr give 5 drops SSKI every 6
hr to block thyroid hormone
synthesis via Wolf-Chaikoff
effect (the delay allows antithyroid drug to prevent excess
iodine from being incorporated
in the new hormone
o Ophthalmopathy: mild or
moderate no tx; avoid
smoking, artificial tears,
uprights leeping position
patches, methyprednisone for
active dse; orbital
decompression
o Demopathy no tx; if
necessary, high potenscy
glucocorticoid

Other causes of thyrotoxicosis

o Destructive thyroiditis short thyrtoxic phase due to
release of preformed hormones and catabolism
of Tg; absnce of true hyperthy; low uptake,
teratomas (struma ovarii)
o TSH-secreting pituitary adenoma increased TSH,
diffuse goiter, increase T4 and T3 levels
Thyroiditis

rare suppurative infection of the thyroid

children and young adults: due to presence of pyriform

sinus

adults: malignancy

S/Sx: thyroid pain, fever, dysphagia, erythema ovary

thyroid, febrile illness, lymphadenopathy

Causes: Bacterial, Viral, Fungal, Parasitic, Amiodarone

ESR and white cell counrl thyroid fxn normal

FNAB PMN

Antibiotics/Culture/ drain abscess

Subacute Thyroiditis

De Quervains thyroiditis, granulomatous thyroiditis, viral

thyroidits

Symptoms mimic phrangitis

Thyroid show patchy inflammatory infiltrate w/ disruption of

thyroid follicles and multinucleated giant cells within some
o

follicles (low uptake) progress to granulomas with

fibrosis thyroid returns to normal (normal uptake)

Disruption phase: release of Tg and thyroid hormones

inT4 and T4, suppressed TSH

S/sx: painful and enlarged thyroid with fever, complains of

sorethroat

Labs and Course: thytoxic (t4 and t4 inc, TSH

suppressed hypothyroid recovery (withdraw thyroxine
replacement)
o Confirmed by increased ESR and radioiodine
uptake
o FNAB distinguish unilateral involvement

Tx: aspirin, glucocorticoids 40-50 mg prednisoe; thyroid

fxn monitoered every 2-4wks
Silent Thyroiditis

Painless thyroiditis or silent thyroiditis

Common is postpartum thyroiditis; common with Type 1

DM

Normal ESR and presence of TPO ab

Thyrotoxic symptoms: no glucocorticoids propranolol

Chronic Thyroiditis
most common cause: Hashimotos thyroiditis firm hard
goiter
Reidels thyroiditis middle aged women; painless hoiter
with compression of trachea, esophagus, neck veins, LN;
hard nontender goiter; FNAB
Sick Euthyroid Syndrome
Low T3 syndrome, normal T4 and TSH
T4 coversion to T3 via peripheral deiodination impaired
leading to increased reverse T3, with decreased clearance
Very sick pts fall in T4 and T3 (low T4 syndrome)
decreased tissue perfusion, muscle, and liver expression
of of type 3 deiodinease
Amiodarone
type 3 antiarrhythmic agents
assoc with high iodine intake; stored in adipose tissue;
persists for more than 6 months
Jod-Basedow phenomenon thyrpid hormone systhesis
excessive as a result of increased iodine exposure
Pregnancy

Increase in Hcg

Estrogen induced rise in TBG

Alterations in immune system

Increased thryroid metab in placenta

Inc urinary iodide excretion

Goiter

Enlarged thyroid gland

Graves goiter results from TSH-R mediated effects of

TSI

Hashimotos lymphocytic infiltration and immune system

induced thyroid enlargement

Nodular dse disordered growth of thyroid cells; with devt

of fibrosis
Diffuse nontoxic (simple) goiter

Diffuse enlargement w/o nodules

Goitrogens

Common in women

Thyroid hormones preserved: asymptomatic

PE: symemetrically endlarged nontender soft gland w/o

nodules (lateral lobe)

Abnormalities in hormone synthesis:

o Iodide transport ( NIS)
o Tg synthesis, organification and coupling (TPO)
o Regeneration of iodide (dehalogenase)

Substernal goiter obstruct thoracic outlet

Pembertons sign faintness w/ facial congestion and
external jugular venous obstruction when arms raised
above the head

Labs
o Iodine def: low t4, normal t3 and TSH, refelecting
enhanced conversion
o Subclinical thyroxicosis: low TSH, normal T3 and
T4 (older pts and undiagnosed graves); elderly
treated to prevent atrial fibr and bone loss
o TPO ab autoimmune
o Low urinary iodine levels (<50ug/L) dx of iodine
def

Tx: Iodine replacement

Nontoxic Multinodular Goiter

Common in women; increase prevalence with age

Hyperplastic response to locally produced gf and

cytokines

Asymptomatic, euthyroid

Lead to compressive symptoms tracheal and venous

congestion: respi distress, plethora

Sudden pain hemorrhage in nodule

Dx: architecture distorted: varying size of nodules

Pembertons

CT/MRI extent of substernal extension or tracheal

narrowing

UTZ identify nodules to be biopsied (>1cm)

Conservative management: levo 50ug daily, contrast

agents avoidedbec risk of inducing Hod-Basedown effect;
Surgery
Toxic Multinodular Goiter
Presence of functional autonomy
With subclinical hyperthyroidism or mild thyrotoxicosis
Pat usually elderly with atrial fib, tachycardia, tremors,
nervousness, wt loss

Low TSH level, T4 normal or minimally increased, T3

elevated to a greater degree

Thyroid scan heterogenous uptake (regions of

increase/decrease uptake)

UTZ: assess the presence of cold nodules dec uptake

if present: FNA

Tx: antithyroid drugs, radioiodine, surgery

Hyperfunctioning Solitary Nodule

Toxic adenoma solitary autonomously functioning thyroid

nodule;

Somatic activating mutations in TSH-R

Mild thyrotoxicosis; subnormal TSH levels, large thyroid

nodule

Thyroid scan definitive diagnosos

Tx: radioablation TOC;

Thyroid Ca

Most common malignancy of the endocrine system

Papillary or follicular thyroid ca curable; good prognosis

Anaplastic thyroid ca poor prognosis; poorly fiffrentiated

and aggressive ca

Common in women but worse in men

Risk factors: childhood neck and head irradiation, large

nodule size (>/= to 4cm), tumor fixation/invasion on lymph
nodes, mets

Unique feat that facilitate mngt:

o Amenable to biopsy by FNA
o Iodine radioisotopes used to diagnose and tc
o Serum markers

Tg for PTC and FTC

Calcitonin- Medullary TC
PTC most common type of thyroid ca; well- differentiated
Follicular common in iodine deficient regions; WD
Thyroid lymphoma arise in background of Hashimotos
MTC MEN syndrome
Tx: Surgery, TSH suppression

406 Disorders of Adrenal Cortex

a. 3 hormones: gluco (cortisol), mineralo (aldosterone),
androgen (DHEAS)
b. anatomy

6-11 grams

above the kidneys

originate in urogenital ridge and separate from ginads

and kidneys by 6th AOG
c. regulatory control of steroidogenesis

gluco and androgens HPA

mineralo RAAS system

hypothalamus produce CRH in response to stress

ACTH released by cortcotrope cells of pituitary;

pivotal regulator of cortisol synthesis; released in
pulsatile fashion that follows a circadian rhythm
(suprachiasmatic nucleus); rise in am prior to
awakening and low levels in the evening

Glucocorticoid excess diagnosed by dexamethsane

suppression test; dexa synthetic glucocorticoid that
suppress CRH and ACTH by binding to gluco rc
therefore downregulation of cortisol synthesis

Dexamethasone test
o Establish Cushingss and ddx of cortisol
excess
o Autonomous(Adrenal nodule) ACTH is
already supressedl dex little effect
o ACTH producing pituitary adenoma dexa
ineffective in low doses but induce
suppression at high doses
o Ectopic source resistant to dexa
suppression

ACTH stimulation
o First line test
o Assess glucocorticoid deficiency
Administer cosyntropin 0.25 mg IV/Im,
collect bld samples at 0,30, 60 min for
cortisol N: >20ug/dl 30-60 min after admin
Insulin tolerance test (ITT)
o Alternative
o Inject insulin to induce hypoglycemia
strong signal that triggers hypothalamic
release and activation of entire HPA axis;
admin reg insulin 0.1U.lg IV & collect bld
samples at 0, 30, 60 120 mins for glucose,
cortisol and GH; then after pt achieved
symptomatic hypogly (glucose <40mg/dl)
give oral or IV glucose; N: cortisol >20ug/dl
and GH >5.1ug/L
o CI: CAD, CVD< seizure
Mineralocorticoid production
o RAAS; release of renin angio I (liver) to
angio II via ACE aldosterone production
and vasoconstriction
o Aldosterone enhance sodium retention and
K excretion; inc arterial perfusion pressure
o Mineralo excess: dec renin; vice versa
o Sodium loading suppress aldosterone;
autonomous mineral exces, absent response
o

e.

Steroid hormone synthesis, metab, and action

o Glomerulosa mineralo
o Fasciculata gluco
o Reticularis androgen
o All require cholesterol
f. Cushings Syndrome

Chronic exposure to excess glucocorticoids

ACTH dependent: cushings dse, pituitary corticotrope

adenoma, ectopic secretion of ACTH by nonpituitary
tumor

ACTH independent: adrenocortical adenoma &

carcinoma, nodular adrenal hyperplasia, McCune
Albright Syndrome polyostotic fibrous dysplasia,
unilateral caf-au-lait spots, precocious puberty

Iatrogenic: admin of endo/exo gluco to treat

inflammatory d/o; most common cause of cushings
syndrome

Primary adrenal cause 10%

Cushings dse pituitary corticotope adenoma; affects

women; prepubertal boys (

Etiology:
o Corticotrope pituitary microadenoma (>1cm
size) 90% of cushings syndrome
o Ectopic ACTH prod carcinoid tumors in the
lung, difficult to locate - small
g. Manifestations

Table 406-2

Wt gain, central obesity, buffalo hump, rounded face,

facial plethora, thin brittle skin, osteopenia,
osteoporos, proximal myopathy (gluteal &upper legs),
weakness, hpn, hypo-K, edema, glucose intolerance,
dec libido, amenorrhrea (cortisol mediated
gonadotropin release, irritability, emotional lability,
anxiety, depression inc susceptibility to infxns,
eosinopenoa, hypercoagulation (DVT and PE
endagered)

Cortisol gluconeogenesis, lipolysis, protein

catabolism; Overcomes ability of 11V-HSD2 o rapidly
inactivate cortisol to cortisone in the
kidneymineralocorticoid excess diastolic hp,
hypoK, edema; Suppress TSH

More specific features: fragility of skin, brusing and

vroad purplish striae, proximal myopathy obvious
when trying to stand

Ectopic ACTH syndrome hyperpigmentation:

stimulatory effects of excess ACTH and POMC on
melanocyte pigment production; rapid progression

Management of pt with suspected Cushings Figure

406-10
o Clinical suspicion
o Screening/ confirmation

24 hr urinry cortisol above normal

(3x)

Dex suppression overnight test:

1mg dexa at 11pm, get plasma
cortisol at 8-9am >50nmoL

Midnight plasma cortosl >130nmol?

L
o Check ACTH

Normal or high >15pg/ml ACTH

dependent

MRI pituitary

CRH test (ACTH

increases >4-% at 1530min + cortisol increase

>20% at 45-50min after

CRH 100ug IV

High dose DEX test

(cortisol suppression
>50% after q6h 2 mg DEX
for 2 days
o Cushings dse:
CRH test and
high dose dex (+)
transphenoidal
sx
o Ectopic ACTH
prod: CRH test
and high dose
DEx negative
do inferioir
petrosal sinus
sampling
(petrosal/peripher
al ACTH ratio >2
at baselin, >3 at
2-5 min after
CRH 100ug IV

If
positive:
transpeh
noidal sx

If
negative
:
bilateral
adrenale
ctomy
Suppressed <5 pg/ml ACTH
independent

Do CT
o If bilateral
micro/macronodul
ar adrenal
hyperplasia or
unilateral adrenal
mass
adrenalectomy

h. Treatment:

See above

Oral agents:
o Metyrapone inhibits cortisol synthesis at the
level of B-hydroxylase; 500mgTID to 6g
o Ketoconazole inhibits the early step of
steroidogenesis 200 mg TID to 1200
o Mitotane adrenolyric agentl low dose for
adrenocortical carcinoma
o Etomidate severe cortisol excess
o After Surgery: HPA remains suppressed
Hydrocortisone
Mineralocorticoid Excess

Conns syndrome aldosterone producing adenoma

a. primary aldosteronism most common cause of
mineralocorticoid excess
b. bilateral micronodular hyperplasia more common
than unilateral
c. somatic mutations in channels and enzymes
responsible for increasing sodium and calcium influx
in glomerulosa prevalent cause of aldosterone
producing adrenal adenomas
d. benign aldosterone producing adenomas - < 2cm dm

e.

Glucose remediable hyperaldosteronism (GRH)

crossover between CYP11B1 and CYP11B2 genes
results in ACTH driven aldosterone prod

Primary Causes:
o Adrenal (Conns) Adenoma
o Bilateral (micronodular) adrenal hyperplasia
o GRH

Clinical Manifestations:
o Potassium depletion and increased Na retention
explansion of extracellular & plasma volume
o Inc ENAC activity hydrogen depletion met
alkalosis
o Direct damage of aldosterone in heart systemic
hpn
o Clinical hallmark of mineralocorticoid excess:
hypokalemic hypertension

Serum Na normal fld retention

peripheral edema

Hypokalemia excacerbated by thiazide

drug tx; muscle weakness,

Alkalosis muscle cramp, tetany

Algorithm for the Management of Pts with Suspected

Mineralocorticoid Excess
o Clinical suspicion

Severe hypertension or hypokalemia,

adrenal mass, fam hx of early-onset hpn
or CV events at <40y/o
o Screening: Measure ARR (aldosterone-renin
ratio) on current Bp meds (stop spironolactone
for 4wks) and w/ hypokalemia corrected

Positive: ARR >750pmol/L and

aldosterone >pmol/L
o Confirmation

Saline infusion test (2L saline over 4hr

IV)

Sodium loading

Fludrocortisone suppression
o CT adrenals

Unilat adrenal mass:

<40yo adrenalectomy

>40yo do adrenal vein

sampling
o if positive:
adrenalectomy
o if negative: MR
antagonists, amiloride

Bilateral adrenal mass - Drug tx

Normal adrenal morphology

Family hx of early onset hpn

Screen for GRH

o If positive: Dexa
0.125-0.5mg/d

Medical tx prior surgery: Spirinolactone or more selective

epleronone (mineralocorticoid rc antagonist: 12.5 to 50mg
bid up to 400mg/d to avoid postsurgical
hypoaldosteronism control bp and normalize K.
Adrenal Insufficiency/Addisons Dse

HP origin most frequent due to excess glucocorticoid tx

Primary adrenal insufficiency most commonly caused by

autoimmune adrenalitis

Secondary adrenal insufficiency consequence of

dysfunction of the HPA due to pituitary or hypothalamic
tumor ortheir tx with surgery or irradiation

s/sx: loss of both gluco and mineralocorticoid secretion

secondary AI only glucocorticoid is deficient bec.

Adrenals intact RAAS works
Adrenal androgen disrupted by both primary and
secondary
HP dses additional manifetsations in thyroid, gonadsm
GH, and prolactin, visual impaitment
Exogenous glucocorticoids abruptly stopped: cushingoid
Chronic adrenal insufficiency nonspecific s/x fatigue;
distinguishing feature: hyperpigmentation in skin exposed
to increased friction or stress
Secondary AI alabaster-like palness due to lack of ACTH
secretion
Hypnatremia char. Biochemical feature in primary AI
due to mineralo def (primary) and diminished inhibition of
ADH release by cortisol lead to SIADH (secondary)
Hyperkalemia 40%
Acute adrenal insufficiency prolonged pd of nonspecific
complaints observed in primary AI due to loss of both
G&M secretion.
Causes of Primary Adrenal Insufficiency:
o Autoimmune polyglandular syndrome (APS1 &
2)
o Autoimmune adrenalitis
o CAH
o Adrenoleukodystrophy
o Drug induced: mitotanem ketoconazole,
o Bilat adrenalectomy
Causes of Secondary AI
o Pituitary tumors endocrine active and inactive
most common; carcinoma-rare
o Pituitary irradiation
o Autoimmune hypophysitis
o Pituitary apoplexy and infiltration
o POMC def
S/Sx:
o Gluco def: TB>fatigue, wt loss, myalgia, joint
pain, fever, slight inc in TSH, hypogly (children),
hyponat (loss of FB inhibition of AVP relase)
o Mineralo def (primary): abdominal pain, n/v,
dizziness, postural hypotension, salt-craving
hyponat, hyperkalemia
o Adrenal androgen def: lack of energy, dry and
itchy, loss of libido and axillary, pubic hair
(women)
Dx: Cosyntropin Test - reliable tool with excellent
predictive diagnostic tool
Algorithm for the Mngt of Pt with Suspected AI
o Clinical suspicion: wt loss, fatigue, postural
hypotension, hyperpigmentation, hyponatremia
o Screening/confirmation:

Plasma cortisol 30-60 min after 250 ug

cosyntropin IM/IV (cortisol post
cosyntropin <500nmoL)

CBC, serum Na, K, Crea, urea, TSH

o DDx

Primary AI (high ACTH, high renin, low

aldosterone) G&M replacement

Check adrenal autoab

If positive:
o Autoiimune adrenalitis
o APS

If negative:
o CXR
o Serum 17OHP
o Adrenal CT

If (+):
adrenal infection (TB)
Infiltration (lymphoma)
Hemorrgae
CAH (17OHP inc)
If (-):
Autoimmune adrenalitis
Adrenoleukodystrophy
(men, VLCFA inc)

Secondary AI (low-normal ACTH,

normal renin, normal aldosterone)
Glucocorticoid replacement
o MRI pituitary

If positive: HP mas
lesion

If neg: hx of
exogenous
glucocorticoid tx,
trauma, consider
isolated ACTH def

Acute AI requires immediate rehydration by saline

infusion at 1L.hr with continuous cardiac monitoring; G
replacement 100 mg hydrocort bolus; M replacement
initiated once hydrocort dose reduced to <50mg bec
higher doses of hydocort stimulates M rc

Glucocorticoid Replacement tx of chronic AI; 15-25mg

hydrocort; prednisone and dexa long acting; not
preferred bec they result in inc gluco exposure

Stress rt dose adjustment in G replacement

Mineralocorticoid replacement: for primary AI initiated at

100-150ug fludrocortisone; measure BP for adequacy of
tx; serum renin and electrolytes measured regularly; renin
not used as monitoring tool in pregnancy bec of
physiologic rise

Adrenal androgen replacement: for women with features

of Androgen def: once daily admin of 25-50mg DHEA,
measured by DHEAS, androstenedione, and testosterone,
shbg 24 hr after the last DHEA dose
Congenital Adrenal Hyperplasia

Measured by the steroids accumulating before the distinct

enzymatic block

Mutataions in CYP21A2 most prevalent cause of CAH

21 hydoxylase deficiency

major: G and M deficiency: classic CAH, neonatal

presentation

minor: G deficiency: simple virilizing, neonatal/childhood

presentation

classic CAH boys; adrenal crisis (salt-wasting)

simple virilizaton: precocious puberty and advance bone

age

Tx:
o hydrocortisone: prevent adrenal crisis
o prednisone: control androgen excess
o dexamethasone: to achieve fertility
o 17OHP useful marker for overtx
o M replacement: renin- regularly monitorer
407 Pheocromocytoma

Catecholamine producing tumors derived from SNS and

PSNS restricted at the adrenals

Mean age of dx: 40yo

Classic rules of ten: 10% bilateral, extra-adrenal and

malignant

Etiology:

Pheochromyctoma: reflects black colored

staining caused by chromaffic oxidation of
catecholamines
o Paraganglioma: catecholamine producing tumors
in the skull base and neck (tumors to all other
sites)
Clinical Features: the great masquerader
o Palpitations, headache, profuse sweating
classic triad + hpn likely diagnosis
o May be asymptomatic for years
o Dominant sign: HPN episodic/sustained
o Catecholamine crisis lead to HF, PE, arythmias,
and intracranial hemorrhage
o Hormone release divergent intervals: anxious,
plae, tachycar, palpitations
Dx:
o Biochemical testing

Catecholamines: epi, NE, dopamine

Elvated plasma and urinary

catecholamines and metanephrines
(leak of O-methylated metabolites)
cornerstone of dx

Urinary test for metanephrines and

cathecholamines widely available and
used for initial evaluation

Refractionated metanephrines &

catecholamines most sensitive

Plasma metanephrines most sensitive

and less susceptible to false positive
eleavtions from stress

Exclude drug rt factors: withdrawal of

levodopa, sympathomimemtics,
diuretics, TCA, alpha and beta blockers

Rpt test or clonidine suppression test

measurement of plasma
normetnephrine 3 hr after oral admin of
300ug clonidine
o Imaging:

T2 weighted MRI with gadolinium

optimal for detecting
pheocrhomocytomas

MIBG scintigraphy, FDG PET selective

uptake for paragangliomas with
hereditary syndromes
Treatment:
o Complete tumor removal ultimate therapeutic
goal
o Preop: Bp must be below 160/90mmhG
o Intraop: Nitroprusside intraophyppertensive
crisis
o Laparoscopy and retroperistoneoscopy
standard approach in pheochromocytoma sx
o Adrenocorticotropic hormone test nexclude
cortisol def when bilateral adrenal cortex sparing
sx
Malignant pheochromycytoma restricted to tumors with
distant mets (lungs, bones, liver)
In preganancy removed by 4-6th month of gestation
Associated syndromes:
o Neurofibromatosis type 1 (NF1) multiple
neurofibromas, caf au lait spots, axillary
freckling of the skin, Lisch nodules of iris
o MEN type 2 best known pheocrhomocytoma
associated syndrome

Men2A MTC, pheo,

hyperparathyroidism
o

Men2B MTC, pheo, mucosal

neuromas, marfanoid habitus, lacks
hyperpara
Von Hippel Lindau syndrome (VHL) predispose
to retinal and cerebellar hamngioblastomas in
brainstem and SC

417 Diabetes Mellitus

a.
Normal
Glucose
Tolerance
Random
blood glucose
concentratiio
n
FPG
<100 mg/dl
2-h OGTT

<140 mg/dl

IGT

100125mg/dl
>140199mg/dl
5.76.4

DM
(Criteria for
Dx)
Symptoms
of DM +
200mg/dl
>126mg/dl
>200mg/dl

HbA1C
<5.6
>6.5
b. Types

Type 1 complete or near total insulin deficiency/ beta cell

destruction; commonly develops before the age of 30 but
any age

Type 2 insulin resistance, impaired insulin secretion,

increased glucose tolerance; preceded by impaired fasting
tolerance

Gestational DM glucose intolerance during preganancyl;

revert to normal postpartum but have substantial risk in
the next 10-20 yrs

Other causes:
o Maturity onset diabetes of the young and
monogenic diabetes early onset of hypergly
<25yo and impaired insulin secretion
o Pancreatic exocrine dse, CF
o Endocrinopathies: acromegaly, Cushings
o Fulminant diabetes rt to virla infections of islets

Type 2 DM rising rapidly due to obesity and reduced

activity levels

Epidemiology
o China highest prevalence of DM
o Scandinavia highest Type 1
o Pacific Islands and ME

FPG and HbA1C screening test for Type 2 DM

recommended

ADA recommends:
o Screening all individuals >45yo evry 3 hrs
o Screening at early age if overweight BMI>25 and
have additional risk factor for DM
o Risk Factors:

Family hx

Obesity

Physical inactivity

Race/ethnicity

Hx of GDM and delivery of >4kg baby

HPN

HDL chole <35 and trigly> 250mg/dl

PCOS

Hx of CVD

Glucose homeostasis balance between hepatic glucose

production and peripheral glucose uptake and utilization

Insulin impt regulator of metabolic equilibrium;

gluconeogenesis, gylcogenolysis, reduced glucose uptake
leading to lipolysis; anabolic hormone; promotes
storage of fat, CHO, CHON

Glucagon secreted by pancreatic alpha cells, stimulates

glycogenolysis and gluconeogenesis

Skelteal ms major portion of postprandial glucose

Brain insulin-independent fashion

Insulin: produced by beta cells; pro-insulin

V-peptide cleared more slowly than insulin; useful

marker of insulin secretion and allows discrimination of
endogenous and exogenous sources of insulin

Glucose key regulator of insulin secretion

Glucose levels 70mg/dl stimulate insulin synthesis

Incretins released from neuroendocrine cells of the GI

tract followed by food ingestion and amplify glucose
stimulated insulin secretion and suppress glucagon
secretion

GLP1 most potent incretin release from L cells of SI,

stimulates insulin secretion only when bld glucose level is
above the fasting levels
Type I DM

Immune beta cell destruction

Common before the age of 20yo

Nonimmune mechanism ketosis prone

Many African American and Asian

Temporal Course:
o With genetic predisposition triggered by
infection initiates autoimmune process
gradual decline in beta cell mass
o Progressive impairment in insulin release when
80% of the beta cell mass destroyed
o Honeymoon phase first 1-2 yrs after onset of
diabetes and insulin reqts

Pathophysiology
o Other islet cell types: spared from autoimmune
destruction

Apha cells glucagon

Delta somatostatin

PP cells pancreatic polypeptide

producing
o Pancreatic islets have infiltration of lymphocytes
(insulitis) beta cells destroyed islets
become atrophic

Environmental Factors
o Triggers of autoimmune process: viral (coxsackie,
rubella, enterovirus), bovine milk CHON,
nitrosourea
Type 2 DM

Insulin resistance and abnormal insulin secretion

Latinos greater insulin resistance

East Asians and South Asians more beta cell

dysfunction

Ketosis prone obese

Ketosis resistant lean

Strong genetic component

Characterized by: impaired insulin secretion, insulin

resistance, excessive hepatic glucose production, and
abnormal fat metab

Obesity - visceral/central evidenced by waist-to-hip ratio

IGT char. elevations in post prandial glucose

Metabolic Abnormalities:
o AbN muscle and fat metabolism

Decreased ability of insulin to act

effectively on target tissues (muscle,
liver, fat)

Rightward shift insulin dose response

curve

Increased hepatic glucose = accounts

for increased FPG levels

Decreased peripheral glucose usage

postprandial hyperglycemia
o Impaired Insulin Secertion

Islet amyloid polypeptide/amylin form

amyloid fibrillar deposit

Chronic hyperglyecemia paradoxically

impairs islet fxn (glucose toxicity)
worsening hyperglycemia

Elevation of free fatty acids (lipotoxicity)

Reduced GLP1 reduced insulin

secretion
o Increased Hepatic Glucose and Lipid Production

Insulin resistance in the liver reflects

failure of hyperinsulinemia to suppress
gluconeogenesis fasting
hyperglycemia and dec glycogen
storage in liver in PP state

Insulin resistance in adipose tissue

lipolysis and free fa flux from adipocytes
are increased increased VLDL and
triglycerides Lipid storage or
steatosis in liver nonalcoholic fatty
liver and abN LFT

Responsible for dyslipidemia in type 2

DM: inc trygly, dec HDL, inc LDL

Mutations in Insulin Rc
o Features: acanthosis nigricans & signs of
hyperandrogenism
o 2 distinct syndromes:

type A: young women, severe

hyperinsulinemia, obesity,
hyperandrogenism

type B: middle aged, severe

hyperinsulinemia, hyperandogenism,
autoimmune

Prevention of Type 2 DM
o Reduce body weight - diet
o Increase physical activity: exercise 30 min/d 5x a
week
o Metformin with high risk of progression, IFG and
IGT, + risk factors
Approach to Patient with DM

History:
o wt, family hx, risk factors
o s/sx: polyuria, polydipsia, wt loss, fatigue,
weakness, blurring of vision, frequent superficial
infections

PE:
o Wt, BMI, BP, foot exam, peripheral pulses, and
insulin injection sites, periodontal dse
o Distal symmetric neuropathy; test of loss of
protective sensation

Classification:
o Type 1: onset before 30yo, lean, insulin as initial
therapy inc risk for autoimmune do and
ketoacidosis
o Type 2: onset after 30yo, obese, not require
insulin initially, with insulin resistance, hpn, cvd,
dyslipidemia, PCOS

Ketosis prone Type 2 present with

diabetic ketoacidosis but lack
autoiimune markers; later tx with OHA

Latent autoimmune diabetes of adult

phenotypic appearance of Type 2 DM do

not have absolute insulin def but have

autoimmune markers (GAD, ICA)
suggestive of Type 1

Lab Assessment: diagnostic criteria and degree of

glycemic control
Diabetes Management
o Overall goals

Eliminate symptoms of hypergly

Reduce long term micro/macrovascular complications

Normal lifestyle
o Symptoms resolve when plas,a glucose is <200mg/dl
o Comprehensive diabetes care

Optimal and individualized glycemic control

Self monitoring of bld glucose (individualized

frequency)

HbA1c testing (2-4 x a yr)

Pt education in DM mngt (annual)

Medical nutrition and mngt (annual)

Eye exam (annual/bi)

Foot exam (1-2 x /yr by doc/ daily by pt)

Annual screening nephropathy

Quarterly BP monitoring

Lipid profile and serum crea (GFR)

Influenza/pneumo/hep b vaccines

Antiplatelet therapy
o Treatment Goals

Glycemic control
o HbA1c <7%
o Preprandial plasma gluc 80-130mg/dl
o Peak PP plasma gluc <180mg/dl

BP <140/90

Lipids
o LDL <100mg.dl
o HDL women >50mg/dl, men >40mg/dl
o Trigly <150mg/dl
o Nutritional recommendations for adults with
diabetes/prediabetes

Wt loss diet: hypocaloric diet

Fat diet: minimal trans fat, Mediterranean style; rich in

monosat

Use glycemic index predict on how much

consumption of a particular food may affect bld
glucose

Fructose preferred over sucrose or starch

Protein: dietary fiber, vegetables, fruits, nonnutrient

sweeteners

Supplements of vitamins not advised

Glycemic index estimate of pp rise in bld gluc when

certain amt in consumed; low glycemic index
preferred

Type 1: goal of MNT is to ooordinate and match the

caloric intake with approp amt of insulin

Type 2: goal: focus on wt loss

o Exercise

ADA recommends 150min/wk Idistributed over at

least 3days) of moderate physical activity w/ no
gaps longer than 2 dyas including resistance
training

Type 1 DM: prone to htper-hypogly during

exercise
o May lead to ketoasis if insulin level is
too low

Avoided by: monitoring flucose

b.d.a exercise

Delay exercise if bld glucose is

<100mg/dl, ingest carbs before
exercise

Monitor glucose during

exercise, ingest carbs

Dec insulin doses before

exercise and inject insulin into
nonexercising area
o Monitoring Glycemic Control

Pts self measurement fo plasma glucose picture of

short term glycemic control

HbA1cC glycemic control prev 2-4 months

Self Monitoring of Blood Glucose standard pf care in

dm mngt; type 1 or type 2 DM taking multiple insulin
inje\ctions each day should routinely measure their
plasma glucose 3/more times per day to estimate and
select mealtime boluses of short acting insulin and
modify ling act insulins

Glycated Hbg (HbA1C) standard method of

assessing long term glycemic control; plasma glucose
consistently elevated increase in nonenzymatic
glycation of hgb; erythrocytes life span 2-3 mos; ADA:
measured at least twice per year; albumin can be
used as alternative indicator of glycemic control when
HbA1c inadequate due to anemia,
hemoglobinopathies; fructosamine glycemic status
over prior 2 wks
Pharmacologic Approach

Individualized; pt approach

Type 1: Goal: design and implement insulin regimens that

mimic physiologic insulin secretion

Insulin regimens:
o Long acting insulins (NPH, glargine, detemir) basal
insulins
o Short acting insulins (regular, aspart, lispro, glulisin)
prandial insulin; inhected before <10min or just after a
meal. Regular insulin 3-45min prior to a meal
o Type 1 DM: require 0.50-1 U/kg per day of insulin into
multiple doses with ~50% of basal insulin
o Generaizations in Glucose Loweing Agents

Insulin secretagoges, biguanides, GLP-1 rc agonists, thiaz

improves glycemic control in a small degree and more
effective than a-glucosidase

Biguanide and thiazo delayed glucose lowering effects by

weeks

Not all agents are effective in Type 2

B, A,GLP1 rc, DPP-IV, thiazo, SLGT2 dont cause

hypogly

Durability of glycemic control slightly less for glyburide

compared to metformine and rosiglitazone
Acute Disorders Rt to Severe Hyperglycemia

Severe hyperglycemia 300 mg/dl

Ketones indicator diabetic ketoacidosis; measured

when glucose is >300mg/dl during concurrent illness,
n/v, abdominal pain

Bld B-hydroxybutyrate measure acetoacetate and

acetone

DKA and HHS both are assoc with absolute/relatve

insulin def, volume depletion, and acid-base
abnormalities
DKA
HHS
Glucose
250-600
600-1200
Na
125-135
135-145
K, Mg, Cl,
Normal
Phosphate
Creatinine
Slightly inc
Moderately inc

Osmolality
Ketones
Bicarb

300-320
++++
<15

330-380
+/Normal to slightly
dec
>7.3
Normal
Normal -slightly inc

Arterial pH
6.8-7-3
Pco2
20-30
Anion gap
Inc
Diabetic Ketoacidosis
a. Symptoms: n.v, thirst, polyuria, abd pain resemble
acute pancreatitis/ruptured viscus, SOB
b. Physical Findings: tachycardia, dehydration, hypotension
due to vol depletion, kaussmauls respiration and fruity
odor breath 2 to met acidosis and inc acetone (classic
signs), lethargy, coma, cerebral edema major
nonmetabolic/ serious complication of DKA common in
children
c. Precipitating events: inadequate insulin admin, infection
(pneumonia, UTI, AGE, sepsis), infarction, cocaine,
pregnancy)
d. Pathophysiology:

both insulin deficiency and glucagon excess necesary

for DKA to develop

dec ratio of insulin to glucagon ratio promotes

gluconeogenesis, glycogenolysis, and ketone body
formation in the liver

cytokines and C-reactive protein markers if inflam

increased

ketosis results form marked inc in free fatty acid

release from adipocytes

hyperglucogonemia alters hepatic metab to favor

ketone body formation thru activation of carnitine
palmitoyltransferase I an enzyme crucial for
regulating fa transport into mitochondria where ketone
conversion occurs.
e. Labs

Chacterized by: hypergly, ketosis and met

acidosis (increased anion gap

Elevated BUN and crea intravascular volume

depletion

B-hydroxybutyrate ketone body three fold great;

but acetotacetate is preferentially detected by
nitroprusside (ketosis detection reagent)
f. Management of DKA

Assess elctrolytes, acid-base status, renal fxn

Replace fluids
o 2-3L 0.9% plain saline over 1-3 hrs
o 0.45% at 250-500ml/hr
o change to 5% glucose and .045% saline at 150250ml/hr when plasma glucose reaches
250mg/dl

Administer short acting insulin IV (0.1 units/kg), then

0.1 units/kg by continuous IV infusion; if initial serum
K is <3.3meq/L, do not administer insulin until K
corrected

Appropriate workup for the precipitating event

Measure capillary glucose e 1-2 hr; measure

electrolytes and anion gap every 4hr for the first 24hrs

Monitor vs, mental stat, i/o every 1-4 hr

Replace K:
o 10meq/L K<5-5.2meq/L, normal ECG, urine
and crea normal
o 40-80meq/L K<3.5 meq or bicarb given
o do not supplement if K>5.2 meq/L until K
corrected.

Glucose goal: 150-250mg/dl and acidosis resolved

Give long acting insulin when pt start eating. Allow for

a 24 hr overlap in insulin and SC insulin injection
Hyperglycemic Hyperosmolar State (HHS)

Elderly with type 2 DM

Several wk hx of polyuria, wt loss and diminisged oral

intake mental confusion

PE: dehydration & hyperosmolality tachycardia,

hypotension, altered mental state

Precipitated by MI, stroke, infection

Pathophysiology: inuslin deficiency and inadequate fld

intake -0> inc hepatic glucose production, osmotic diuresis
exacerbated by inadeqequate fld replacement

Labs: hypergly (1000mg/dl), hyperosmolality (>350), and

prerenal azotemia

Tx:
o Fluid losses and dehydration more pronounced
than DKA
o Fluid replacement
o K repletion
o Insulin
419 DM Complications

Microvascular complications result of chronic

hyperglycemia

4 theories:
o Increased intracellular glucose leads to the formation
of advanced glycosylation end products, which bind to
a cell surface receptor, via the nonenzymatic
glycosylation of intra- and extracellular proteins,
leading to cross-linking of proteins, accelerated
atheroscle- rosis, glomerular dysfunction, endothelial
dysfunction, and altered extracellular matrix
composition.
o Hyperglycemia increases glucose metabolism via the
sorbitol pathway related to the enzyme aldose
reductase
o Hyperglycemia increases the formation of
diacylglycerol, leading to activation of protein kinase
C, which alters the transcription of genes for
fibronectin, type IV collagen, contractile proteins, and
extracellular matrix proteins in endo- thelial cells and
neurons.
o Hyperglycemia increases the flux through the
hexosamine pathway, which generates fructose-6phosphate, a sub- strate for O-linked glycosylation
and proteoglycan production, leading to altered
function by glycosylation of proteins such as
endothelial nitric oxide synthase or by changes in
gene expression of transforming growth factor
(TGF-) or plasminogen activator inhibitor-1.
o Unifying mechanism: hyperglycemia leads to
increased production of ROS

VEG-F increased in retinopathy and dec after laser

TGF-B increase in nephropathy and stimulates BM

production of collagen and fibronectin
OPHTHALMOLOGIC COMPLICATIONS

Retinopathy and Macular edema

2 types of retinopathy:
o nonproliferative appears in late in first or early
in 2nd decade marked by retinal vascular
microaneurysms, blot hemorrhages, and cotton
wool spots; pathophy: loss of retinal pericytes, inc
retinal vasc permeability and alteration in retinal
bld flow; DM>20yrs
o Proliferative hallmark: neovascularization in
response to retinal hypoxemia; formed vessels

near optic nerve.macula vietrous hemorrhage,

fibrosis, and retinal detachment
Macular edema fluorescein angiography and optical
coherence tomography detect
Tx:
o most effective therapy: prevention
o glycemic control and BP control
o Laser preserve vison
Panretinal proliferative retinopathy
Focal macular edema

Renal Complications of DM
DM nephropathy: leading cause of CKD, ESRD
Rt to chronic hyperglycemia
Effects of soluble growth factors (GF, angiotensin II,
endothelin; glomerular hyperfiltrration/hyperperfusion,
increase glomerular capillary pressure
Srtuctural changes in glomerulus: inc ECM, BM
thickeining, mesangial expansion, fibrosis
Smoking accelerates declin in renal fxn
Course
o 1st yrs: glomerular hyperperfusion and renal
hypertrophy; inc GFR;
o 1st 5 yrs: thickening of BM, glomerular
hypertrophy, masangial vol expansion
o 5-10 yrs: albuminuria: microalbumineria 30299mg/dl in 24 hr collection or creatine spt
collection; macroalbuminuria >300mg/24h
o Macroalbuminuria ESRD
Annual microalbuminuria measurement: albumin to
creatinine ratio in spot urine
Tx:
o improved glycemic control, strict BP control and
ACE inhibitor or ARNS
o hemodialysis frequent complications:
hypotension, difficult vascular access, and
progression to retinopathy
o renal transplant preferred byt requires chronic
immunosuppression
o combined pancreas-kidney transplant
nomoglycemia and freedom from diabetes
Neuropathy
due to chronic hyperglycemia
Risk factors: BMI, smoking, CVD, and inc trigly
Polyneuropathy: most common form is distal symmetric
polyneuropathy frequently with distal sensory loss and
pain; senstation of numbness, tingling sensation, and
sharpness, burning pain; neuropathic pain: lower
extremities present at rest and worsens at night; PE:
sensory loss, loss of DTR, abnormal position sense
Diabetic polyradiculopathy- severe disabling pain in the
distribution of one or more nerve roots; intercostal/truncal
pain thorax or abdomen; femoral/lumbr nerve hip
and thigh pain; assoc with diabetic amyotrophy muscle
weakness in hip flexors and extensors
Monneuropathy dysfunction of isolated cranial or
peripheral nerve; pain and weakness in single nerve;
occur at entrapment sites carpal tunnel syndrome; third
cranial nerve -> diplopia
Autonomic neuropathy
o CV: resting tachycardia and orthostatic
hypotension
o Gastroparesis and bladder emptying
abnormalities
o Hyperhidrosis of upper ex and anhidrosis of lower

exn dry cracking feet ulceration

Hypoglycemia unawareness

Tx:
Avoid neurotoxins
Vit B supplementations
Check feet daily; footwear precautions
Painful diabetic neuropathy: duloxetine &
pregabalin
GASTROINTESTINAL/GENITOURINARY DYSFUNCTION

Delayed gastric emptying (gastroparesis), - anorexia, n/v,

early satiety, and abdominal bloating altered GI motility
(diarrhea & constipation) Tx: small frequent meals, low fat
& fiber

Cystopathy inability to sense full bladder and failure to

void completely urinary hesistancy, dec voiding freq,
incontinence, UTI; Tx: schedule voiding or selfcatheterization

Reduced female sexual dysfxn dyspareunia, reduced

lubrication Tx: vaginal lubricants, estrogen replacement

Erectile dysfunction & retrograde dysfxn Tx: drugs that

inhibit 5phosphodiesterase
CARDIOVASCULAR DISEASE

Tx
o ACE, ARBS, ASA
o Metformin stable CHF; not thiazeolinediones
o Antiplatement therapy

CV risk factors
o Dyslipidemia most common pattern in DM:
hypertrygly and reduced HDL, LDL particles in
DM more atherogenic; moderate statin
therapy; HMG-CoA reductase inhibitors agents of
choice for lowerimg LDL; nicotinic acid- raise
HDL; hypertrigly dont use bile acid resins
o HPN: Target BP:<140/80mmHg; Tx: ACE
inhibitors and ARBS

Lower Extremity Complications

o Pathogenic factors: neuropathy, abnormal foot
biomechanics, PAD, wound healing
o Foot ulcer: great toe or netatarsophalangeal area
o Ulceration amputation
o Tx: asymptomatic PAD: ABI testing; footwear,
daily inspection of feet, feet hygiene,
o Gas gangrene in the absence of clostridial
infection cultura raken from debrided ulcer not
surface of ulcer
o Osteomyelitis antbx
o Interventions: offloading, debridement, wound
dressing, appropriate antibx, revascularization,
and limited amputation
INFECTIONS

Hyperglycemia abnormal cell-mediated immunity,

phagocyte function as well as diminished vascularization;
aid colonization of growth of organisms

Pneumonia and UTI, skin and soft tissue infections

Staph A and MTB are frequent pathogens

UTI(lower/pyeloneph_ - E. coli, candida; complications:

emphysematous pyelo and cystitis
DERMATOLOGIC MANIFESTATIONS

Xerosis and pruritus relieved by skin moisturizers

Protracted healing and skin ulcerations

Diabetic dermopathy pigmented pretibial papules or skin

spots

Bullosa diabeticurom shallow ulcerations or erosions in

the pretibial region
o
o
o
o

Necrobiosis lipodica diabeticurom young women;

etythematous plaque that gradually develops irregular
marginswith atrophic centers and central ulceration
Vitiligo type 1 DM
Acanthosis nigricans hyperpigmented velvety plaques
seen on neck, axilla, or extensor surfaces
Granuloma annulare erythematous plaques on extr and
trunk
Slecroderma -0 skin thickening of back or neck at site of
prev superficial infections
Lipoatrophy.hypertrophy - insulin injection sites

420 Hypoglycemia

MC: drugs to treat DM, exposure to alcohol

Whipples Triad: (1) symptoms consistent with

hypoglycemia, (2) a low plasma glucose concentration
measured with a precise method (not a glucose moni-tor),
and (3) relief of symptoms after the plasma glucose level
is raised.

Decrease in insulin secretion is the first defense against

hypoglycemia.

Gucagon is the second defense against hypoglycemia.

Epinephrine is the third defense against hypoglycemia.

Cortisol and growth hormone play no role in defense

against acute hypoglycemia.

Shift to higher-than- normal glucose levels in people with

poorly controlled diabetes, who can experience symptoms
of hypoglycemia when their glucose levels decline toward
the normal range (pseudohypoglycemia). On the other
hand, thresholds shift to lower-than-normal glucose levels
in people with recurrent hypoglycemia

Signs & Sypmtoms

o Neuroglycopenic manifestation - behavioral
changes, confusion, fatigue, seizure, loss of
consciousness
o Neurogenic (or autonomic) manifestations

adrenergic symptom - palpitations,

tremor, and anxiety

cholinergic symptom - sweating, hunger,

and paresthesias.

Common signs of hypoglycemia include diaphoresis and

pallor.

Hypoglycemia is the limiting factor in the gly- cemic

management of diabetes mellitus.

Conventional risk factors for hypoglycemia in diabetes are

identified on the basis of the premise that relative or
absolute insulin excess is the sole determinant of risk.

insulin (or insulin secretagogue) doses are excessive, illtimed, or of the wrong type; (2) the influx of exogenous
glucose is reduced (e.g., during an overnight fast or after
missed meals or snacks); (3) insulin-independent glucose
utilization is increased (e.g., during exercise); (4)
sensitivity to insulin is increased (e.g., with improved
glycemic control, in the middle of the night, late after
exercise, or with increased fitness or weight loss); (5)
endogenous glucose production is reduced (e.g., after
alcohol ingestion); and (6) insulin clearance is reduced
(e.g., in renal failure)

422 METABOLIC SYNDROME

Metabolic syndrome (syndrome X, insulin resistance

syndrome) consists of a constellation of metabolic
abnormalities that confer increased risk of cardiovascular
disease (CVD) and diabetes mellitus.

most challenging feature of the metabolic syndrome to

define is waist circumference. Intraabdominal
circumference (visceral adipose tissue) is considered most
strongly related to

Insulin resistance and risk of diabetes and CVD,

o lipoatrophy or acanthosis nigricans

Associated Dses: CVD, Type 2 DM
Associated Condition: NAFLD, PCOS, OSA,
Hyperuricemia
OSA - associated with obesity, hypertension, increased
circulating cytokines, impaired glucose tolerance, and
insulin resistance; Continuous positive airway pressure
treatment

Risk Factors

Overweight/Obesity - central adiposity is a key feature of

the syndrome

Sedentary lifestyle - Physical inactivity is a predictor of

CVD events and the related risk of death.

Aging - lder than age 50, and at >60 years of age women
are more often affected than men. T

DM - eat majority (~75%) of patients with type 2 dia- betes

or impaired glucose tolerance have the metabolic
syndrome.

CVD - Individuals with the metabolic syndrome are twice

as likely to die of cardiovascular disease as those who do
not, and their risk of an acute myocardial infarction or
stroke is three- fold higher.

Lipodystrophy
Etiology

Insulin Resistance
o most accepted and unifying hypothesis to
describe the pathophysiology of the metabolic
syndrome is insulin resistance,
o An early major contributor to the development of insulin
resistance is an overabundance of circulating fatty acid
o inhibition of lipolysis in adipose tissue is the most sensitive
pathway of insulin action.
o Leptin resistance - reduces appetite, promotes energy
expenditure, and enhances insulin sensitivity.

Increased Waist Circumference

o WC most frequently applied diagnostic criteria

Dylipidemia
o Hypertriglyceredemia - excellent marker of the
insulin-resistant condition.
o reduction in HDL cholesterol.

Adiponectins

Proinflammatory cytokines

Clinical Features
o Not assoc with s/sx
o waist circumference may be expanded and blood
pressure elevated.
Drugs

MOA

Biguanide
s

Reduce hepatic gluc prod

and improves peripheral
glucose utilization

Insuin
Secretago
ues

Affect ATP-sensitive K
channel

Insuin
Secretago

Sample
suffix
Metformin

1 sulfonlyureas
(-mide)
2 sulfonylureas
(Gli-)
Nonsulfonylureas
(-glinide)

Advantage
Reduce FPG and insulin,
improves lipid profile, wt loss
Wt neutrak, no hypogly
Effective in Type 2 DM
recently diagnosed
Reduce both fasting and
prandial glucose

CI/SE
Major toxicity: lactic acidosis,
low B12; not used with renal
insufficiencyw/ GFR
<60mL/min; d/c if npo and
radiographic contrast
Hepatic/kidney dses
DI: warfarin, aspirin,
ketoconazole

ues
GLP-1 rc
agonists

Enhance GLP1 rc signaling

Aglucosidas
e inhibitors

Reduce postprandial
hyperglycemia by delaying
glucose absoption

Thiazoline
diones

Reduce insulin resistance by

binding to the PPAR-y
nuclear rc

NaGlucose
Transporte
r Inhibitor
(SLGT2)
Amylin
agonists

Lower bld glucose by

selectively inhibiting this cotransporter incluse in PCT
Slow gastric emptying,
decreases glucagon

Exanatide
(-tide)

(-glitazone)

No hypogly
Inc insulin secretion,
suppress glucagon, slow
gastric emptying

Promote redistribution of fat

from central to peripheral
locations
Inhibits glucose
reabsorption., lowers renal
threshold, and inc urinary
glucose excretion

Pramlintide

403 Bone and Mineral Metabolism

arrangement of compact and cancellous bone provides

strength and density suitable for both mobility and
protection

reservoir for calcium, magnesium, phosphorus, sodium,

and other ions necessary for homeostatic functions.

regulates hematopoiesis

skeleton is highly vascular and receives about 10% of the

cardiac output.

Remodeling of bone is accomplished by two distinct cell

types: osteoblasts produce bone matrix, and osteoclasts
resorb the matrix.

extracellular components of bone - type I collagen

mineral phase is made up of calcium and phosphate and

Reduce PP gylcemia, and wt

loss

Nausea
Renal dse
MTC
Diarrhea, flatulence, abdominal
distention
Avoid simultaneous admin with
bile acid resins and abtacids
Ci with IBD, gastroparesis, or
serum crea >2mg/d
Measure LFT prior therapy
Increase lipids
Associate with wt gain,
reduction in hct,
SE: peripheral edema and CHF
Increase urinary glucose:
urinary and vaginal infxns

Inhection, risk of hypogly with

insulin
Agents that slow GI motility

is best characterized as a poorly crystalline

hydroxyapatite.
Osteoblasts synthesize and secrete the organic matrix and
regulate its mineralization. As an osteoblast secretes
matrix, which then is mineralized, the cell becomes an
osteocyte; account for the vast majority of the cells in
bone.
osteocytes also secrete fibroblast growth factor 23
(FGF23), a major regulator of phosphate metabolism;
mutation in cleidocranial dysplasia, Runx2 +/) exhibit a
delay in formation of the clavicles and some cranial bones.
Both PTH and 1,25(OH) D increase osteoclast number
2
and activity by this indirect mechanism.
Calcitonin, in contrast, binds to its receptor on the basal
surface of osteoclasts and directly inhibits osteoclast

function.
Estradiol - decrease osteoclast number and decrease
bone resorption.

remodeling and replacing previously calcified cartilage

(endochondral bone formation) or, in a few bones, is
formed without a cartilage matrix (intramembranous bone
formation).

New bone, relatively high ratio of cells to matrix and is

characterized by coarse fiber bundles of collagen that are
interlaced and randomly dispersed (woven bone).

mature bone is organized with fiber bundles regularly

arranged in parallel or concentric sheets (lamellar bone).

bone plasticity reflects the inter- action of cells with each

other and with the environment.

Osteoblast activity can be assessed by measuring serum

bone-specific alkaline phosphatase.

Osteoclast activity can be assessed by measurement of

products of collagen degradation
CALCIUM

Alterations in serum protein concentrations directly affect

the total blood calcium concentration even if the ionized
calcium concentration remains normal. An algorithm to
correct for protein changes adjusts the total serum calcium
(in mg/dL) upward by 0.8 times the deficit in serum
albumin (g/dL) or by 0.5 times the deficit in serum
immunoglobulin (in g/dL).

ionized calcium indirectly affects PTH secretion by

lowering 1,25(OH) D production. This active vitamin D
2
metabolite inhibits PTH production

Optimal rates of calcium absorption require gastric acid.

large boluses of calcium carbonate are poorly absorbed

because of their neutralizing effect on gastric acid.

achlorhydric subjects and for those taking drugs that

inhibit gastric acid secretion, - calcium citrate

high levels of calcium intake, synthesis of 1,25(OH) D is

2
reduced

DCT is also the site of action of thiazide diuretics, which

lower urinary calcium excre- tion by inducing sodium
depletion and thereby augmenting proximal calcium
reabsorption.

Conversely, dietary sodium loads, or increased distal

sodium delivery caused by loop diuretics or saline
infusion, induce calciuresis.

Increased blood levels of PTH and 1,25(OH) D activate

2
osteoclastic bone resorption to obtain needed calcium
from bone, which leads to progressive bone loss and
negative calcium balance. Increased PTH and
1,25(OH) D also enhance renal calcium reabsorption, and
2
1,25(OH) D enhances calcium absorption in the gut. -2
>very high calcium intakes (>100 mmol/d [>4 g/d]),
passive intestinal absorption continues; this can cause
severe hypercalciuria, nephrocalcinosis, progressive renal
failure, and hypercalcemia (e.g., milk-alkali syndrome).
VITAMIN D

1,25-Dihydroxyvitamin D (1,25[OH] D) is the major steroid

2
hormone involved in mineral ion homeostasis regulation

Vitamin D synthesis and activation. Vitamin Dis

synthesized in the skin in response to ultraviolet radiation
and also is absorbed from the diet. It is then transported to
the liver, where it undergoes 25-hydroxylation. This
metabolite is the major circulating form of vitamin D. The
final step in hormone activation, 1-hydroxylation, occurs
in the kidney.

sources largely consist of fortified cereals and dairy

products, in addition to fish oils and egg yolks

vitamin D from plant sources is in the form of vitamin D ,
2
whereas that from animal sources is vitamin D .
3

Mild to moderate vitamin D deficiency is asymptomatic,

whereas long-standing vitamin D deficiency results in
hypocalcemia accompanied by secondary
hyperparathyroidism, impaired mineralization of the
skeleton (osteopenia on x-ray or decreased bone mineral
density), and proximal myopathy.
Rickets - In children, before epiphyseal fusion, vitamin D
deficiency results in growth retardation associated with an
expansion of the growth plate; characterized by expansion
of the hypertrophic chondrocyte layer.
hypophosphatemia, which in vitamin D deficiency is a
consequence of secondary hyper- parathyroidism, is a key
etiologic factor in the development of the rachitic growth
plate
hypocalcemia and hypophosphatemia that accompany
vitamin D deficiency result in impaired mineralization of
bone matrix proteins, a condition known as osteomalacia;
feature of long-standing hypophosphatemia, which may be
a consequence of renal phosphate wasting or chronic use
of etidronate or phosphate- binding antacids; prone to
bowing of weight-bearing extremities and skeletal
fractures.
Proximal myopathy is a striking feature of severe vitamin
D deficiency both in children and in adults.
most specific screening test for vitamin D deficiency in
otherwise healthy individuals is a serum 25(OH)D level.
Dx: levels of 25(OH)D <37 nmol/L (<15 ng/mL) are
associated with increasing PTH levels and lower bone
density.
vitamin D sufficiency as a vitamin D level >50 nmol/L (>20
ng/mL)
PTH is a major stimulus for the renal 25(OH)D 1hydroxylase, there is increased synthesis of the active
hormone, 1,25(OH) D.
2
Radiologic features of vitamin D deficiency in children
include a widened, expanded growth plate that is
characteristic of rickets; apparent in the long bones but
also are present at the costochondral junction, where the
expansion of the growth plate leads to swellings known as
the rachitic rosary.
If vitamin D deficiency occurs after epiphyseal fusion, the
main radiologic finding is a decrease in cortical thickness
and relative radiolucency of the skeleton.
specific radiologic feature of osteomalacia, whether
associated with phosphate wasting or vitamin D
deficiency, is pseudofractures, or Loosers zones. These
are radiolucent lines that occur where large arteries are in
contact with the underlying skeletal elements;

In patients in whom 1-hydroxylation is impaired,

metabolites that do not require this activation step are the
treatment of choice. They include 1,25(OH) D (calcitriol
2 3
[Rocaltrol], 0.250.5 g/d) and 1-hydroxyvitamin D
2
(Hectorol, 2.55 g/d). If the pathway required for
activation of vitamin D is intact, severe vitamin D
deficiency can be treated with pharmacologic repletion
initially (50,000 IU weekly for 312 weeks), followed by
maintenance therapy (800 IU daily). Pharmacologic doses
may be required for maintenance therapy in patients who
are taking medications, such as barbiturates or phenytoin,
that accelerate metabolism of or cause resistance to
1,25(OH) D
2

424 Disorders of Parathyroid Gland and Calcium

Homeostasis

parathyroid hormone (PTH), which is the primary regulator

of calcium physiology

PTH acts directly on bone, where it induces calcium

release; on the kidney, where it enhances calcium
reabsorption in the distal tubules; and in the proximal renal
tubules, where it synthesizes 1,25-dihydroxyvitamin D
(1,25[OH] D), a hor- mone that increases gastrointestinal
2
calcium absorption.

Calcium, reduce PTH release and synthesis.

Fibroblast growth factor 23 (FGF23), a phos- phaturic

hormone, can suppress PTH secretion.

Hyperparathyroidism, characterized by excess production

of PTH, is a common cause of hypercalcemia and is
usually the result of autonomously functioning adenomas
or hyperplasia. Surgery for this disorder is highly effective
and has been shown to reverse some of the deleterious
effects of long-standing PTH excess on bone density.

Humoral hypercalcemia of malignancy is also common

and is usually due to the overproduction of parathyroid
hormonerelated peptide (PTHrP) by cancer cells
Parathyroid Hormone

primary function of PTH is to maintain the extracellular

fluid (ECF) calcium concentration within a narrow normal
range;

acts directly on bone and kidney and indirectly on the

intestine through its effects on synthesis of 1,25(OH) D to
2
increase serum calcium concentrations; in turn, PTH
production is closely regulated by the concentration of
serum ionized calcium.
Parathyroid Hormone RT Protein

responsible for most instances of humoral hypercalcemia

of malignancy; a syndrome that resembles primary
hyperparathyroidism but without elevated PTH levels.

plays an essential role in endochondral bone formation

and in branch- ing morphogenesis of the breast, and
possibly in uterine contraction and other biologic functions.
Calcitonin

hypocalcemic peptide hormone

direct antagonist to the calcemic actions of PTH.

tumor marker in sporadic and hereditary cases of

medullary carcinoma and its medical use as an
adjunctive treatment in severe hypercalcemia and in
Pagets disease of bone.

hypocalcemic activity of calcitonin is accounted for

primarily by inhibition of osteoclast-mediated bone
resorption and secondarily by stimulation of renal
calcium clearance.

Calcitonin has been a useful pharmaco- logic agent to

suppress bone resorption in Pagets disease, and
osteoporosis, and in the treatment of hypercalcemia
of malignancy
Hypercalcemia

frequent cause of asymptomatic hypercalcemia,

earliest manifestation of malignancy, the second most

common cause of hypercalcemia in the adult.

false-positive diagnosis of hypercalcemia is usually the

result of inadvertent hemoconcentration during blood
collection or elevation in serum proteins such as albumin.

Hypercalcemia in an adult who is asymptomatic is usually

due to primary hyper- parathyroidism.

in malignancy-associated hypercalcemia, the disease is

usually not occult;

symptomatic individual has had hypercalcemia or some

manifestation of hypercalcemia such as kidney stones for
more than 1 or 2 years, it is unlikely that malignancy

Hypercalcemia not due to hyperparathyroidism or

malignancy can result from excessive vitamin D action,
impaired metabolism of 1,25(OH) D, high bone turnover
2
from any of several causes, or renal failure

Immunometric PTH assays serve as the prin- cipal

laboratory test in establishing the diagnosis.

hypercalcemia from any cause can result in fatigue,

depression, mental confusion, anorexia, nausea, vomiting,
constipation, revers- ible renal tubular defects, increased
urine output, a short QT interval in the electrocardiogram,
and, in some patients, cardiac arrhythmias.

Generally, symptoms are more common at calcium levels

>2.93.0 mmol/L (11.612.0 mg/dL), but some patients,
even at this level, are asymptomatic.

When the cal- cium level is >3.2 mmol/L (12.8 mg/dL),

calcification in kidneys, skin, vessels, lungs, heart, and
stomach occurs and renal insufficiency may develop,
particularly if blood phosphate levels are normal or
elevated due to impaired renal excretion.

Severe hypercalcemia, usually defined as 3.74.5

mmol/L (14.818.0 mg/dL), can be a medical emergency;
coma and cardiac arrest can occur.
Primary Hyperparathyroidism

generalized disorder of calcium, phosphate, and bone

metabolism due to an increased secretion of PTH.

usually leads to hypercalcemia and hypophosphatemia.

recurrent nephrolithiasis, peptic ulcers, mental changes,

and, less frequently, extensive bone resorption

This milder form of the disease is usually termed

asymptomatic hyper- parathyroidism

hyperparathyroidism develops or worsens abruptly and

causes severe complications such as marked dehydration
and coma, so-called hypercalcemic parathyroid crisis.

Parathyroid tumors are most often encountered as

isolated adenomas without other endocrinopathy.
Etiology

SOLITARY ADENOMAS A single abnormal gland is the

cause in ~80% of patients; the abnormality in the gland is
usually a benign neoplasm or adenoma and rarely a
parathyroid carcinoma.

HEREDITARY SYNDROMES AND MULTIPLE

PARATHYROID TUMORS MEN 1 (Wermers syndrome)
consists of hyperparathy- roidism and tumors of the
pituitary and pancreas, often associated with gastric
hypersecretion and peptic ulcer disease (Zollinger-Ellison
syndrome). MEN 2A is characterized by
pheochromocytoma and medullary carcinoma of the

thyroid, as well as hyperparathyroidism; MEN 2B has

additional associated features such as multiple neuromas
but usually lacks hyperparathyroidism.
hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs
in families with parathyroid tumors (sometimes
carcinomas) in association with benign jaw tumors.
Adenomas are most often located in the inferior parathyroid glands,
Calcium values of 3.53.7 mmol/L (1415 mg/dL) are
frequent with carcinoma and may alert the surgeon to
remove the abnormal gland with care to avoid capsular
rupture; parathyroid carcinoma is often not aggressive.
Many patients with hyperparathyroidism are
asymptomatic. Manifestations of hyperparathyroidism
involve primar- ily the kidneys and the skeletal system
Renal stones are usually composed of either calcium
oxalate or calcium phosphate. In occasional patients,
repeated episodes of neph- rolithiasis or the formation of
large calculi may lead to urinary tract obstruction,
infection, and loss of renal function. Nephrocalcinosis may
also cause decreased renal function and phosphate
retention.
distinctive bone manifestation of hyperparathyroidism is
osteitis fibrosa cystica, (Howships lacunae)
Dual-energy x-ray absorptiometry (DEXA) of the spine
provides reproducible quantitative estimates (within a few
percent) of spinal bone density. Similarly, bone density in
the extremities can be quanti- fied by densitometry of the
hip or of the distal radius at a site chosen to be primarily
cortical.
Asymptomatic primary hyperparathyroidism is defined as
biochemi- cally confirmed hyperparathyroidism (elevated
or inappropriately normal PTH levels despite
hypercalcemia) with the absence of signs and symptoms
typically associated with more severe hyperparathyroidism such as features of renal or bone disease.

Surgical excision of the abnormal parathyroid tissue is the

defini- tive therapy for this disease.
The hypercalcemia is dependent on continued lithium
treatment, remitting and recurring when lithium is stopped
and restarted.
Familial Hypocalcemic Hypercalcemia- the primary defect
is abnormal sensing of the blood calcium by the
parathyroid gland and renal tubule, causing inappropriate
secretion of PTH and excessive reabsorption of calcium in
the distal renal tubules.
Treatment of the hypercalcemia of malignancy is first
directed to control of tumor;
PTHrP is the responsible humoral agent in most solid
tumors that cause hypercalcemia.
many patients with squamous cell carcinoma of the lung
develop hypercalcemia.
Clinical suspicion that malignancy is the cause of the
hypercalcemia is heightened when there are other signs or
symptoms of a para- neoplastic process such as weight
loss, fatigue, muscle weakness, or unexplained skin rash,
or when symptoms specific for a particular tumor are

present. Squamous cell tumors are most frequently associated with hypercalcemia, particularly tumors of the lung,
kidney, head and neck, and urogenital tract.
In patients with sarcoid- osis and other granulomatous
diseases, such as tuberculosis and fungal infections,
excess 1,25(OH) D is synthesized in macrophages or
2
other cells in the granulomas. Indeed, increased
1,25(OH) D levels have been reported in anephric
2
patients with sarcoidosis and hypercalcemia.
Mild hypercalcemia, <3 mmol/L (12 mg/ dL), can be
managed by hydration. More severe hypercalcemia (levels
of 3.23.7 mmol/L [1315 mg/dL]) must be managed
aggres- sively; above that level, hypercalcemia