ENDOCRINOLOGY

NUTRITIONAL REQUIREMENTS o Essential fatty acids

o Low in cholesterol, saturated fat, trans fat
INFANTS AND CHILDREN MONITORING
 Energy and protein needed per kg of body weight  Best indicator of nourishment is growth pattern
decreases with age, but total amount of each o Spurts and plateaus but overall predictable
increases as body size increases o If growth pattern changes, dietary intake
ENERGY evaluated to determine reason
 Infants: high-fat diet (40%-55% of energy) to o Underweight when <3rd percentile of BMI-
support rapid growth and development, for-age distribution
carbohydrate (45%-65%) same as adults o Overweight when 85-95th percentile
 2: 1,000kcal and 13g protein/day o Obese when >95th percentile
 4: recommended proportion of kcal from fat  First year: infant’s length increases by 50%
reduced to 25%-35%  Second year: 12.5cm
 6: 1,600kcal and 19g protein/day  Third year: 10cm
 Adults: 0.8g/kg protein  Thereafter: 5-7.5cm per year
WATER AND ELECTROLYTES  Puberty: grow about 28cm and gain about 40% of
 1-3: 1.3L of water daily eventual skeletal mass
 4-8: 1.7L of water daily o From age 10-17, girls gain about 24kg and
 UL of Na: 2.3g/day boys 32kg
MICRONUTRIENTS  Adolescent growth spurt: 18-24 month period
 Nutrient-dense diet that follows Canada’s Food o 10-13 in girls
Guide recommendations o 12-15 in boys
 Meat, grains for B vitamins and zinc  Infants: weight-for-age, length-for-age, and head
 Fruits, vegetables for vitamins C and A circumference-for-age growth charts
 Milk for calcium, vitamins A and D  2-19: weight-for-age, length-for-age, and BMI-for-
 Fortified grains, raisins, eggs, lean meats for iron age growth charts
CALCIUM, VITAMIN D, BONE HEALTH
 1-3: 700mg/day NUTRITION CONCERNS
 4-8: 1000mg/day
 Vitamin D >1 year: 15ug/day  Dental caries:
 *Essential for maximum peak bone mass and o Added sugars decrease nutrient density
preventing osteoporosis later in life o Diet high in sugary foods promotes tooth
IRON AND ANEMIA decay and formation of cavities
 7-12 months: 11mg/day  Hyperactivity:
 Toddlers: 7mg/day o Extreme physical activity, excitability,
 4-8: 10mg/day impulsiveness, distractibility, short
ADOLESCENTS attention span, and low tolerance for
ENERGY frustration
 Proportion from carbohydrates, fat, protein similar
to adults but total amount exceeds adult needs EXERCISE RECOMMENDATIONS
 Girls: 2100-2400kcal/d
 Boys: 2200-3150kcal/d  Children and adolescents:
MICRONUTRIENTS o 60 minutes/day in moderate- to vigorous-
 More needed than in childhood intensity physical activity
 B vitamins much higher in adolescence because o Vigorous activity (e.g. running, soccer) at
involved in energy metabolism least 3d/wk and muscle- and bone-
CALCIUM strengthening activities (e.g. skipping,
 1300mg/day for both sexes jumping) at least 3d/w
 1000mg/day for adults aged 19-50  Adults:
 *Essential for maximum peak bone mass and o Accumulate at least 150 minutes of
preventing osteoporosis later in life moderate- to vigorous-intensity aerobic
IRON physical activity per week
 14-18: 11mg/day for boys and 15mg/day for girls o Muscle and bone-strengthening activities
 Adult is 8mg RDA for men using major muscle groups at least 2 d/wk
ZINC
 14-18: 11mg/day for boys and 9mg/day for girls EATING DISORDERS
CAVEATS
 Fibre:  Psychiatric conditions involving abnormal eating
o Whole grains, fruits, vegetables patterns that disrupt health or psychosocial function
 Fats:  More common in women
  Usually present in adolescence or young adulthood
ANOREXIA NERVOSA
 Diet and exercise leads to dangerously low weight
o WHO: BMI < 18.5kg/m2
 Intense fear of gaining weight
 Distorted perception of body weight
 Physical exam:
o Mild: 17-18.5; moderate: 16-16.99; severe:
15-15.99; extreme: <15
o Bradycardia and hypotension because body
can’t work normally
o Decreased bowel sounds
o Xerosis (dry, scaly skin)
o Hair loss (not enough calories)
o Lanugo hair growth
 Soft, fine
 Effects of malnutrition and low calorie intake:
o Decreased GnRH secretion  decreased
LH/FSH  amenorrhea (axis is sensitive)
 “Functional hypothalamic
amenorrhea”
o Do not take enough calories to fuel cells of
nephron  inability to concentrate urine
 Free water loss
 Volume depletion  lower GFR
 Normally GFR falls, Cr
increases, but low or
normal here due to low
muscle mass
 Hyponatremia rare
o If purging: hypokalemia
o Bone density falls
 Low estrogen because suppression
of hypothalamic pituitary axis
 Increased stress  high cortisol
 Loss of cortical and trabecular bone
 Osteopenia, osteoporosis, fractures
o Bone marrow suppression if not enough
calories
 Anemia, leukopenia,
thrombocytopenia
 Therapy:
o 1) Nutritional rehabilitation
 Structured meals with observation
 Calorie goals
o 2) Psychotherapy
o Medications aren’t very effective
 Olanzapine (antipsychotic) has
most evidence of benefit
 Causes weight gain
 Complications:
o Often co-exists with other conditions:
 Depression, anxiety, OCD, PTSD,
substance abuse
o Often secondary to eating disorder 
improves with weight restoration (esp.
depr.)
o Can lead to mortality from malnutrition
REFEEDING SYNDROME
 Hallmark is hypophosphatemia
o Low PO4 from poor nutrition  give
glucose  increased insulin  increased
metabolism  further decreased PO4 from
cellular uptake  not enough to make ATP
 cardiac and respiratory failure
 Most fatalities are cardiac
o Poor contractility and low SV
o Heart failure, arrhythmias
 Prevention:
o Slow refeeding
o Gently increase calorie intake
BULIMIA NERVOSA
 1) Binge eating
 2) Inappropriate compensation to avoid weight gain
o Vomiting (purging, classic)
o Laxatives, diuretics, enemas (urine or
feces)
o Fast or severely restrict diets
o Excessive exercise
 Occurs at least once a week for three months
 Clinical presentation:
o Weight usually normal
o Commonly coexists with other disorders:
 Anxiety, depression, PTSD,
substance abuse
o Russell’s sign: scars on knuckles from
induced vomiting
 Therapy:
o Nutritional rehabilitation, psychotherapy,
SSRIs
 Purging complications:
o Contraction alkalosis
o Hypokalemia
o Urine chloride is low (<20)
o Parotid swelling/sialadenosis
o Erosion of dental enamel because gastric
acid in mouth
BINGE EATING DISORDER
 Binge eating:
o Compulsive and often quick overeating
o Excessively large amount
o Patient feels lack control or shame or
embarrassment
 No appropriate compensation  weight gain
 Occurs once a week for at least 3 months
 Treatment:
o Psychotherapy (CBT) is first-line
 Large clinical effect in trials greater
than medication effect
o SSRIs less effective
o Lisdexamfetamine (ADHD stimulant)
o Topiramate (seizure medication)
 Both 1) lead to decreased weight
and 2) clinical trials showed
increased abstinence from binge
episodes
 Complications:
o Often occurs with other disorders, e.g.
anxiety and depression
o High risk of T2DM
ALTERNATIVE CAUSES OF MALNUTRITION
 Excessive exercise, hyperthyroidism, alternative
diets
 Alcohol and smoking
OBESITY IN CHILDREN AND ADOLESCENTS
 Refers to excess of fat, but methods to directly
measure body fat not in daily practice
 Weight-for-height in children <2 years
 BMI in children >=2 years old
o Underweight - <5th percentile for age/sex
o Normal weight – 5-85th percentile
o Overweight – 85-95th percentile
o Obese - >95 percentile
th
o Overweight and obese ~ 25 and 30kg/m
o Severe obesity – BMI>=120% of 95 th
percentile OR BMI>=35kg/m 2 gestational age  increased risk
 Morbid obesity: obesity-related comorbidities
RISK FACTORS
 Environmental:
o Sedentary lifestyle
 Television: displacement of
activity, depressed metabolic rate,
sleep
 Digital-oriented entertainment
o Excess caloric intake
 Sugar-sweetened beverages
 Increasing trends in glycemic index
of foods, portion sizes, fast food
o Shortened or irregular sleep
 Insulin resistance, cardiometabolic
risk factors, alterations in serum
leptin and ghrelin levels, increased
neural reward processing
o Medications
 Psychoactive drugs, antiepileptic
drugs, glucocorticoids
o Ambiguous: gut microbiome,
environmental toxins, viruses
 Genetic:
o Polygenic
 Genetic factors play permissive
role and interact with
environmental
 No molecular mechanisms
o Syndromic obesity
 Syndromes in which obesity is
primary manifestation
 Prader-Willi, Bardet-Biedl
o Monogenic
 Single-gene defects, many of which
in melanocortin pathway in CNS
 Deficiencies in leptin or receptor
 Endocrine:
o Associated with overweight or mild obesity
o Most have short stature w/wo
hypogonadism
o Cortisol excess (use of corticosteroid)
o Growth hormone deficiency
o Hypothyroidism,
pseudohypoparathyroidism type 1a
 Hypothalamic obesity:
o Lesions, trauma, tumor, inflammatory
disease may cause rapidly progressive
severe obesity
o Rare cause is ROHHAD: rapid-onset
obesity, hypothalamic dysfunction,
hypoventilation, and autonomic
dysregulation
 Metabolic programming:
o Environmental and nutritional influences
during critical periods in development can
predispose to obesity and metabolic disease
o Gestation
 Maternal body weight, nutritional
factors, intrauterine environment
 Lack of maternal nutrition,
2 increasing prepregnancy weight
and weight gain, small/large for
 Maternal DM, preeclampsia 
higher BMI in offspring
o Infancy and early childhood
 Rates of weight gain in these
periods associated with obesity or
metabolic in childhood,
adolescence, adulthood
 Breastfeeding may have protective
effect against childhood obesity
COMPLICATIONS
 Cardiovascular:
o Hypertension (presence during childhood
predicts HTN and metabolic syndrome in
adulthood)
o Dyslipidemia, esp. those with central fat
distribution and increased adiposity
o Heart: increased LV mass, LV and LA
diameter, epicardial fat, systolic and
diastolic dysfunction
o Premature atherosclerotic CVD
o Adult CVD
 Dermatologic:
o Acanthosis nigricans, associated with
insulin resistance
o Striae distensae (stretch marks), intertrigo,
furunculosis, hidradenitis suppurativa
(inflammatory nodules in in axillae and
groin)
 Endocrine:
o Subclinical insulin resistance (prediabetes)
in adolescence  T2DM in adulthood
o Metabolic syndrome: abdominal obesity,
hyperglycemia, dyslipidemia, HTN
o Hyperandrogenism and early-onset
polycystic ovary syndrome
o Accelerated linear growth and bone age
 Psychosocial:
o QOL, social exclusion, distorted peer
relationships, poor self-esteem, distorted
body image, anxiety, depression
 Pulmonary:
o Asthma
o Obstructive sleep apnea (complete
obstruction of upper airway during sleep)
o Obesity hypoventilation syndrome
 Gastrointestinal:
o Nonalcoholic fatty liver disease
o Cholelithiasis
o Impaired renal function
 Neurologic:
 o Idiopathic intracranial HTN
 Nutritional:
o Vitamin D deficiency and iron deficiency
seemingly associated w/ obesity
 Orthopedic:
o Slipped capital femoral epiphysis, tibia vara
(Blount disease)
o Increased prevalence of fractures, genu
valgum, musculoskeletal pain, impaired
mobility, lower extremity malalignment
MANAGEMENT FRAMEWORK
 Only environmental factors can be changed, so
focussed on modifying behaviors that lead to:
o Excessive energy intake
o Insufficient energy expenditure
 Behavioral strategies:
o Self-monitoring (logs of food, activity,
contributors) + clinician feedback
o Stimulus control (reduce access to
unhealthy behaviors)
o Goal-setting (for health rather than weight)
o Contracting (explicit agreement to give
reward for achievement of goal)
o Positive reinforcement (praise or reward)
 Family involvement:
o Parent is important agent of behavior
change, along with caregivers, close friends
 Patient-centered communication:
o Behavior change should be collaborative
rather than prescriptive
o E.g. include child in making meal plan
MANAGEMENT
 Staged approach:
o 1: prevention plus
o 2: structured weight management
o 3: comprehensive multidisciplinary
evaluation
o 4: tertiary care intervention
 Nutritional assessment:
o Child’s eating habits, parent feeding styles,
family factors (e.g. shopping habits, who is
present at meals, whether media used),
economic challenges, cultural factors
 Activity assessment:
o Home, school, lifestyle activity, sleep
 Actionables:
o Diet: quality and quantity of fats and
carbohydrates
 Avoid limited sugar beverages,
limit restaurants and portion size
o Activity: reduce sedentary activity and
increase physical activity (structured vs.
less structured)
o Sleep: adequate amount of sleep
 Pharmacotherapy:
o Liraglutide (>12 years), orlistat
(adolescents), phentermine (>16 years)
SURGERY FOR SEVERE OBESITY
 Sleeve gastrectomy – majority of greater curvature
of stomach removed, creating tubular stomach
 Roux-en-Y gastric bypass – proximal gastric
pouch that anastomoses to Roux-limb of small
bowel
 Adjustable gastric banding – compartmentalizes
upper stomach with tight, adjustable prosthetic band
around entrance to stomach
PUBLIC LEVEL
 Health policies, recommendations e.g. sugar tax
 School-based programs e.g. breakfast program
 Increasing environments that promote physical
activity e.g. parks
PREVENTION
 Actionable from above plus:
 Maternal:
o Maternal weight prior to contraception and
during pregnancy, breastfeeding
 Psychosocial:
o Healthy feeding patterns, encouraging
family that eats together
ENDOCRINE PANCREAS
HISTOLOGY
 Millions of islets of Langerhans
 Alpha cells: glucagon
 Beta cells: insulin
o Most abundant cell type
o Centrally located
 Delta cells: somatostatin
o Alpha/delta in outer islet (ring)
INSULIN
 Protein hormone (contrast steroid rings)
SYNTHESIS
 1. Ribosomes of RER synthesize preproinsulin
 2. Preproinsulin cleaved to proinsulin
o Connecting peptide (C-peptide) connects α
chain and β chain
 3. Transported to Golgi apparatus
 4. Packaged into secretory granules, wherein
 5. Proinsulin cleaved to insulin and C-peptide
o α and β chains linked by disulfide bridges
o C-peptide longer half life
 Indicator of insulin production
RELEASE
 1. Beta cells have GLUT2 which will bring in
glucose
 2. Glucose metabolized to ATP
 3. Increased ATP:ADP ratio closes KATP channel
 4. K trapped in cell  raise RMP  depolarization
 5. Depolarization causes voltage-gated Ca 2+
channels to open
 6. Ca2+ influx triggers exocytosis of vesicles
RELEASE REGULATION
 Insulin produced in response to glucose, amino
acids (e.g. meal is powerful stimulant)
 Inhibited by EN
o Beta-2 receptors: increases insulin
o Alpha-2 receptors: decrease insulin
o Alpha effect is dominant, so fight or flight
response  increased plasma glucose
INSULIN RECEPTOR/TYROSINE KINASE RECEPTOR
  Tetramer two α (extracellular) and β
(transmembrane) units joined by disulfide bonds
o Many tyrosine molecules on inside
 1. Insulin binds
 2. Tyrosine kinase domains within receptor
complex activated
 3. Tyrosine autophosphorylation
 4. Binds insulin receptor substrates (IRS-1, IRS-2)
 5. Downstream signaling:
 A) PIK3 pathway
o Phosphatidylinositol 3-kinase
o Intracellular lipid kinases 
phosphorylation of 3’-hydroxyl group of
phospholipids  conversion of PIP2 to PIP3
 Sugar moiety # of hydroxyl groups
of phosphatidylinositol
phosphorylated determines
subscript
o Catalyzes many intracellular processes
 Glycogen formation, fatty acid
synthesis, increase expression of
GLUT-4 glucose transporter
 B) RAS/MAP kinase pathway
o 1. Insulin receptor activates RAS, G protein
o 2. RAS can activate many growth pathways
 Raf, mitogen-activated
extracellular kinase (MEK),
mitogen-activated protein (MAP)
o 3. Modifies cell growth and gene
expression
IMPORTANT COMPONENTS
GLUCOKINASE
 First step in glycolysis
 In liver and pancreas
 Insulin activates AND promotes transcription
 High KM (more active when higher glucose)
 High VM (can convert lots of glucose)
GLUT-2 TRANSPORTER
 Bidirectional glucose transporter
 In liver, kidney, pancreas
o Liver, kidney: both glycolysis and GNG
o Beta: glucose in/out based on plasma levels
 Also found in intestines and other tissues
GLUT-4 TRANSPORTER
 Stored in vesicles in cells, especially muscle/fat
 Insulin  PIK3 pathway  GLUT-4 activation
 Major mechanism for increased glucose uptake
HORMONE-SENSITIVE LIPASE
 Breaks triacylglycerol (TAG is a TG) in adipocytes
to FA (fuel) and glycerol (liver)
 Inhibited by insulin, activated by glucagon and
EN
INCRETINS
 Hormones that increase insulin secretion e.g. GIP
 GLP-1:
o Produced by L-cells of small intestine
o Secreted after meals and stimulates insulin
release similar to GIP
o Blunts glucagon release, slows gastric
emptying
 All of incretins responsible for how oral glucose
metabolized faster than IV glucose
INSULIN-DEPENDENCY
 Dependent: muscle and fat because use GLUT-4
for glucose uptake (no insulin no GLUT-4)
 Independent:
o Brain and RBCs:
 Use GLUT-1, does not depend on
insulin and takes up available
glucose
 RBCs: no mitochondria, so
glycolysis
 Brain: no FA metabolism, so
glucose and ketone bodies
o Liver, kidney, intestines
 Use GLUT-2, also insulin
independent
o Nerves, lens of eye
INSULIN EFFECTS
 Glucose uptake in skeletal muscle and adipose
tissue
 Stimulates glycogen synthesis
o Activates glycogen synthase
o Inhibits glycogen phosphorylase
 Inhibits GNG
o Raises fructose-2,6-biphosphate levels in
liver cells  inhibits fructose-1,6-
biphosphastase 1
 Stimulates fatty acid synthesis
o Activates acetyl-CoA carboxylase
o Inhibits hormone sensitive lipase
 Stimulates protein synthesis
o Stimulates entry of aa into cells  protein
synthesis
o Important for muscle growth
 FA and proteins cannot for weight gain side effect
when prescribe insulin therapy
 Increase Na+ retention
o Increases Na resorption in the nephron
 Lowers potassium
o Enhances Na-K-ATPase pump in muscle so
bring in more K from serum to cell
o Insulin plus glucose (to prevent
hypoglycemia) used in tx of hyperkalemia
 Inhibits glucagon release
GLUCAGON
 Protein hormone
 Single polypeptide chain (contrast 2)
 Opposes actions of insulin
 Main stimulus: low plasma glucose
 Effects:
o Increases liver (not muscle) glycogen
breakdown  raises blood glucose level
 Muscle stimulant is Ca and
exercise
o Increases GNG
o Increases amino acid uptake in liver 
more C skeletons for GNG (fall in plasma
aa)
o Activates lipolysis via hormone sensitive
lipase
GLUCAGON RECEPTOR
 G-protein receptor  AC  cAMP  PKA
 Mostly in liver
 o Many activated processes occur in liver,
e.g. glycogen breakdown and GNG
 Most other lower density, none in skeletal muscle
CLINICAL UTILITY
 Hypoglycemia
o Unconscious patient with hypoglycemia
o 1) IV dextrose (optimal)
o 2) IM glucagon when IV access N/A
 Beta blocker overdose
o Presents with bradycardia and hypotension
o Glucagon drug of choice: activates AC
(same pathway as beta-receptors but
glucagon receptor)  raises cAMP 
increased myocyte Ca2+  resolve
symptoms
RARE ISLET HORMONE-SECRETING TUMORS
INSULINOMA
 Occurs in adults (median 50 years)
 Clinical presentation:
o Fasting hypoglycemia hallmark
 Elevated insulin when fasting
o Neuroglycopenic symptoms
 Confusion, odd behavior
o Sympathetic activation from low glucose
 Palpitation, diaphoresis, tremor
 Diagnosis:
o Elevated fasting insulin level, C-peptide,
and proinsulin
 Differential diagnosis:
o Exclude exogenous insulin (C-peptide low)
and oral hypoglycemics (e.g. sulfonylureas
 increased insulin, C-peptide high,
screen+)
GLUCAGONOMA
 Clinical presentation:
o Glucose intolerance similar to DM
o Elevating fasting glucose
o Weight loss (liver GNG consumes proteins
and amino acids)
o Necrolytic migratory erythema
 Red, blistering rash, itchy, painful
 Fluctuates in severity
 Genitals, buttocks, groin
o Rare to develop DKA (insulin funct.
intact)
 Diagnosis:
o Increased glucagon levels
 Treatment:
o Somatostatin analogs (e.g. octreotide)
 Produced by pancreas, intestines
 Inhibits many hormones
MEN SYNDROMES
 Multiple endocrine neoplasias
 Rare inherited disorders
 MEN Type 1: insulinomas/glucagonomas
o 3 Ps: pituitary, parathyroid, pancreas
o Mutations of MEN1 tumor suppressor gene
DIABETES MELLITUS
 Chronic disorder of elevated blood glucose level
 Due to insufficient insulin, response to insulin, both
TERMINOLOGY
 Mellitus = sweet (urine was sweet)
 Insipidus = lacking flavor (urine lacks flavor)
o Rare disorder of low ADH activity
 Different mechanisms but both polyuria, polydipsia
CLINICAL PRESENTATION
 Often asymptomatic, esp. in early stages
o “Silent killer”  basis for screening
o Often no symptoms until complications
 Classic hyperglycemia symptoms
o Polyuria (osmotic diuresis from glucose)
o Polydipsia
 Acanthosis nigricans
o Hyperpigmented plaques on skin
o Intertriginous sites (folds) classically back
of neck and axillae
o Associated with insulin resistance
 Often seen in obesity, diabetes
o Rarely associated with malignancy: gastric
adenocarcinoma most common
DIAGNOSIS
 1) Asymptomatic
o Fasting blood glucose level (no food for 8
hours because will elevate after meal)
 <100mg/dL = normal
 100-125 is prediabetes
 >=126 is diabetes
 3) Symptoms plus glucose >200mg/dL = diabetes
 3) Glucose tolerance test
o Oral glucose load administered
o Plasma glucose measured 1-3 hours later
o High glucose indicates DM
o Often used to screen for gestational DM
 Some insulin resistance normal in
pregnancy, so study response
 4) Hemoglobin A1c
o Small fraction of Hb is glycated
 Glucose combines with a/b chains
o Subfraction HbA1c used in DM
 Non-enzymatic glycation of b-
chains at amino-terminal valines
 Higher glucose = higher glycation
o Reflects average glucose over past 3
months (RBCs survive around 3 months)
 Normal <5.7%
 Prediabetes 5.7-6.4%
 Diabetes >=6.5%
o Sometimes diagnosis but important for
monitoring therapy
 Higher value = worse control and
need to adjust medication
TYPE 1 DIABETES MELLITUS
 Autoimmune, type IV hypersensitivity disorder
 Etiology:
o Associated with HLA-DR3 and HLA-DR4
o Mostly a childhood disorder
 Bimodal distribution
 Peaks at 4-6 and 10-14 years
 Pathophysiology:
o T-cell mediated destruction of beta cells
 Inflammation of islets
 Lymphocytes on biopsy
(“insulitis”)
  Clinical presentation:
o Often with symptomatic hyperglycemia
(polyuria, polydipsia, glucosuria)
o Commonly presents as DKA
o Autoantibodies may be present
 Islet-cell and insulin antibodies
 Lifelong insulin treatment
TYPE 2 DIABETES
 Insulin resistance in muscle, adipose, liver
 Pancreas responds with increased insulin but
eventually pancreas can fail
o Insulin can be high or low depends on stage
 Epidemiology:
o Much more common than T1DM
o Common in adults and becoming more
common in children
 Risk factors:
o Obesity is major risk factor
 Central or abdominal obesity
carries greater risk
o Intra-abdominal (visceral fat) greater risk
than subcutaneous fat
 Visceral fat breakdown less
inhibited by insulin  more
lipolysis if lots of visceral fat 
more free FAs to be used as fuel 
decreased glucose transport into
cells  worse DM
o “Apple” shape (more visceral fat) worse
than “pear” shape (more subcutaneous fat)
o Weight loss improves glucose levels
o Family history
 Strong genetic component, stronger
than T1DM
 Any first degree relative w/T2DM:
2-3x increased risk
 Histology:
o Amylin peptide normally made by beta
cells  packaged and secreted with insulin
 accumulates in islets in T2DM
o Amyloid in pancreatic islets
 Pathophysiology:
o Reason is unknown
o Data suggest insulin receptor
abnormalities
o FAs my activate serine-threonine kinases
 phosphorylate aa on beta chain of
insulin receptors  inhibit tyrosine
phosphorylation
o Increased TNF-a may be synthesized by
adipocytes  activate S-T kinases
COMMON COMPLICATIONS
 Chronic hyperglycemia  cardiac disease, renal
failure, neuropathy, blindness
 Two key mechanisms:
o A) Non-enzymatic glycation: glucose
added to aa groups on proteins (high
glucose drives)
 Crosslinked proteins  ‘advanced
glycosylation end products’
(AGEs)
o B) Sorbital accumulation: polyol pathway
is glucose  aldose reductase  sorbitol
 sorbitol dehydrogenase  fructose
 Little activity at physiologic
glucose
 Chronic hyperglycemia 
increased sorbitol  osmotic
damage
A) ATHEROSCLEROSIS
 Example of diabetic macroangiopathy
 AGEs trap LDL in large vessels  atherosclerosis
o Strokes/TIA
o CAD: angina, MI
o Peripheral vascular disease: claudication,
arterial ulcers, poor wound healing,
gangrene
A) DIABETIC KIDNEY DISEASE
 Example of diabetic microangiopathy
 AGEs damage to glomerulus and arterioles 
ESKD
o Afferent arteriole: decreased renal blood
flow and ischemia
o Efferent arteriole: hyperfiltration and
albuminuria
o BM: glomerulosclerosis
 Decreased RBF, hyperfiltration
contribute to glomerulosclerosis
o All  renal failure
 Renal arterioles:
o Possible AGEs  crosslink collagen 
hyaline arteriosclerosis (also seen in HTN)
 Thickening of arterioles
o Efferent rarely seen except DM
 Proteinuria in diabetics:
o Annual screening for albuminuria because
early indicator of kidney disease
o Proteinuria is indication of ACE-I
 Possible dilation of efferent
arteriole  reduction in
hyperfiltration  reduce
progression to ESRD
 Glomerular BMs:
o Visible on EM
o AGEs  diffuse BM thickening  can
mesangial (cells in matrix that surround
capillaries) proliferation 
fibrosis/scarring
 Diffuse glomerulosclerosis:
o Deposits of proteins (collagen IV) diffuse
on BMs of glomerular capillary loops
o Also occurs with aging and hypertension
o Severe  nephrotic syndrome
 Nodular glomerulosclerosis:
o Nodules form in periphery of glomerulus in
mesangium
o Rarely occurs outside of DM
o Kimmelstiel-Wilson nodules hallmark
B) CATARACTS
 Sorbitol accumulates in lens  increased
osmolarity  fluid into lens  opacification
B) DIABETIC NEUROPATHY
 p accumulates in Schwann cells (myelinating cells
of peripheral nerves)  osmotic damage
  Clinical presentation:
o Classically ‘stocking-glove’ sensory loss
 Longest axons affected most
 Often feet/legs
 Worse distally; better proximally
o 1) loss of vibration sense, proprioception
o 2) impairment of pain, light touch, temp.
o Motor symptoms usually less significant
o Autonomic neuropathy:
 Postural hypotension
 Delayed gastric emptying
AB) DIABETIC FOOT DISEASE
 Peripheral vascular disease (ischemia) + neuropathy
can  ulcers, infection, amputation
o Cannot feel small cuts and poor blood flow
does not allow wounds to heal
 Prevention: regular foot exams
 Ulcer treatment:
o Wound management
o Sometimes antibiotics
o Hyperbaric oxygen chamber several
times/wk (drive oxygen into wound)
AB) DIABETIC RETINOPATHY
 Can cause blindness
 Pathophysiology:
o Capillary BM thickening (AGEs)
o Hyaline arteriosclerosis
o Pericyte degeneration from osmotic
damage due to sorbitol accumulation
 Cells that wrap capillaries
 Microaneurysms  rupture 
hemorrhage
 Clinical presentation:
o Microaneurysms, hemorrhages
o Exudates
 Leakage proteins, lipids)
o Cotton-wool spots
 Nerve infarctions
 Occlusion of precapillary arterioles
o Vessel proliferation (proliferative
retinopathy)
 Retinal ischemia  new vessel
growth  damage retina
 “Neovascularization”
 Prevention: annual eye exams
DIFFERENTIAL COMPLICATIONS
DIABETIC KETOACIDOSIS
 Life-threatening more common in T1DM
 Often precipitated by infection/trauma
 Pathophysiology:
o Requires low insulin (more common in T1)
o Low insulin leads to high glucagon
o In trauma and infection, high EN
o Low insulin + high glucagon + high EN
 increased glucose and lipolysis 
increased ketone bodies  urine ketones
and glucose
 Increased glucose:
o Polyuria  dehydration (low BP) and/or
hypophosphatemia
 Ketone bodies:
o Acetyl-CoA from FAs can normally
combine with oxaloacetate to become
citrate
 1) In low insulin/high EN,
oxaloacetate driven toward glucose
 2) FAs  NADH  favors
conversion of oxaloacetate to
malate
 TCA stalls  increased acetyl-
CoA  ketone production
o One is acetone  fruity breath
o Some ketone bodies acids  acidosis 
hyperkalemia and hypophosphatemia
 Acidosis shifts phosphate to
extracellular fluid  phosphaturia
caused by osmotic diuresis
 High EN and acidosis  slowed GI motility 
abdominal pain, nausea, vomiting
 Clinical presentation:
o Abdominal pain, nausea, vomiting
o Dehydration, fruity smell
o Hyperglycemia, hyperkalemia
o Elevated plasma/urine ketones, glucosuria
o AG metabolic acidosis  Kussmaul
breathing
 Hyperventilating to blow off CO2
 Complications:
o If phosphate becomes too low  loss of
ATP  muscle weakness (resp. failure)
and heart failure (decreased contractility)
o Hyperkalemia  arrhythmias
o Cerebral edema (mechanism poorly
understood but common cause of death)
o Mucormycosis
 Caused by Rhizopus sp., Mucor sp.
 Starts in sinuses and spreads to
adjacent structures
 Thrives in high glucose,
ketoacidosis
 Patient with DKA in recovery
phase develops fever, headache,
eye pain
 Treatment:
o Insulin lowers glucose and shifts K into
cells
o IV fluids treats dehydration
o Careful monitor glucose
 Continue insulin until acidosis
resolves, so may need to add
glucose
o Careful monitor K
 Total body K is low despite
hyperkalemia because lost in urine
 Insulin can lead to hypokalemia
 Usually need to administer K in IV
HYPERGLYCEMIC HYPEROSMOLAR SYNDROME
 Life-threatening more common in T2DM
 Pathophysiology:
o Markedly elevated high glucose (can be
>1000)  diuresis  severe dehydration
o Differences from DKA:
 Few/no ketone bodies (insulin here)
so no acidosis either
  Very high serum osmolarity 
CNS dysfunction
 Clinical presentation:
o Dehydration
o Mental status changes: confusion, coma
 Treatment:
o Similar to DKA (insulin, IVF)
T1DM TREATMENT
 Treated mainly with insulin
TYPES
 All administered SQ at home
 Vary by time to peak, peak effect, duration of
action
 Fast peak, short duration  slow peak, long
duration:
o Rapid acting insulin  regular insulin 
NPH insulin  Detemir  Glargine
INSULIN HEXAMERS
 Insulin forms hexamers in body
o Six linked together = stable structure
 Activity relates to speed of absorption
o Hexamers  slower onset of action
o Monomers  faster onset of action
INSULIN ANALOGS
 Analogs do not contain human insulin molecules
o Modified insulin structure
o Rapid-acting, detemir, glargine
 Regular insulin, NPH contain human insulin
RAPID ACTING (PRANDIAL) INSULIN
 AA-modified human insulin
 Aa mods reduce hexamer/polymer formation
o Onset: 15 minutes
o Peak: 1 hour
o Duration: 2-4 hours
 Often used pre-meal
REGULAR INSULIN
 Synthetic analog of human insulin made by
recombinant DNA techniques
o Onset: 30 minutes
o Peak: 2-3 hours
o Duration: 3-6 hours
 Only type given IV
o Regular and rapid-acting have same onset
when given IV; rapid only faster when SQ
 Commonly used in hospitalized patients
o Blood sugar elevated commonly with
infection/surgery
o “Regular insulin sliding scale”: sliding
scale dose given based on finger stick blood
sugar
 IV insulin also used in DKA/HHS and
hyperkalemia (given with glucose)
NPH INSULIN
 Regular insulin combined with neutral protamine
 Slows absorption
o Peak: 4-8 hours
o Duration: 12-16 hours
 Historical mainstay, been replaced by other types
GLARGINE
 Insulin with modified aa structure
o Soluble in acidic solution for dosing
o Precipitates at body pH after SQ
o Insulin molecules slowly dissolve from
crystals
 Low, continuous level of insulin
o Onset: 1-1.5 hours
o Duration: 11-24 hours
 Injected OD (“basal/background insulin”)
DETEMIR
 Insulin with FA side chain
o Aggregation in subcutaneous tissue
o Also binds reversibly to albumin
 Slowed absorption but less continuous
o Onset: 1-2 hours
o Duration: >12 hours
 Injected OD or BID
o May cause less weight gain
INTEGRATED REGIMEN
 Used to be NPH with insulin
 Now OD glargine or detemir with rapid-acting at
mealtimes
SIDE EFFECT
 Major of all insulin regimens is hypoglycemia:
o Tremor, palpitations, sweating, anxiety 
pts will eat cookie/cracker/juice
o Seizure, coma if severe
 Adjust dosages, frequency to 1) avoid low glucose
but 2) maintain lowest possible HbA1c value
 *Always check blood sugar in unconscious
patients because easily reversible cause
 Another major side effect is weight gain:
 Occurs in most patients because promotes FA and
protein synthesis
T2DM TREATMENT
 Initial: oral or SQ drugs that 1) boost amount of
insulin production or 2) increase sensitivity
 Advanced: insulin required
LIFESTYLE MODIFICATIONS
 First line in non-severe newly diagnosed T2DM
 Weight loss, exercise improves glucose levels
o Usually 3-6 month trial if initial A1c not
markedly increased
ORAL/SQ ANTIDIABETIC AGENTS
BIGUANIDES (METFORMIN)
 Many nitrogen molecules
 Oral therapy with unknown exact mechanism
 Primarily decreases hepatic glucose production
(inhibits GNG)
 Lowers serum free FAs  decreases substrates for
GNG, decreases TG, small decrease in LDL, small
increase in HDL
 Other effects
o Reduced glucose absorption from GI tract
o Direct stimulation of glycolysis in tissues
 increased glucose uptake
o Reduced glucagon levels
o  leads to increased insulin
effect/sensitive.
 Insulin falls slightly in therapy
 Usually 1st line therapy in T2DM
 o Associated with weight loss
o Rarely causes hypoglycemia unlike insulin
or sulfonylureas
o Can be given to patients with advanced
T2DM because not dependent on beta cells
 Adverse effects:
o Most common GI upset:
 Nausea, vomiting, sometimes
metallic taste in mouth
o Rarely lactic acidosis: can be life-
threatening
 Controversial mechanism
 Possibly because increase
conversion of glucose to lactate 
beneficial for lowering glucose 
but excess is LA
 Metformin not used in conditions that are always
associated with LA:
o Renal insufficiency, liver disease or alcohol
abuse, acute HF, hypoxia, serious acute
illnesses
o Not used in low GFR, held when patients
acutely ill, held during IV contrasts which
can cause renal insufficiency
SULFONYLUREAS
 Urea attached to sulfonyl moiety
 Oral therapy
 Bind to sulfonylurea receptor in beta cells  closes
ATP-dependent K+ channels  raises RMP 
depolarization  Ca2+ influx  release insulin
o More sensitive to glucose/amino acids
o Increases insulin release “secretagogues”
 Each generation more potent
o Decreased usage  decreased side effects
o 1st gen: tolbutamide, chlorpropamide,
tolazamide (not used anymore)
o 2nd gen: glyburide, glipizide
o 3rd gen: glimepiride
 Adverse effects:
o Hypoglycemia, so metformin preferred
 Glucagon falls
 May occur w/ exercise/skip meals
o Weight gain
 Due to insulin release
 Adverse effects of chlorpropamide:
o Flushing with alcohol consumption due to
inhibition of acetaldehyde dehydrogenase
o Hyponatremia due to increased ADH
activity
MEGLITINIDES (REPAGLINIDE, NATEGLINIDE)
 No sulfur moiety so used in sulfa allergy
 Oral therapy
 Different chemical structure to sulfonylureas but
similar mechanism
 Short acting, given prior to meals
 Adverse effect: hypoglycemia
THIAZOLIDINEDIONES/GLITAZONES
 Oral therapy all ending in glitazone
 Decreases insulin resistance
 Bind to peroxisomal proliferator activated receptor
(PPAR-y) in nucleus of adipose (highest), muscle,
liver, other tissues  TZD/PPAR bind retinoid X
receptor (RXR)  entire complex modifies gene
transcription
o Fibrates activate PPAR-a which lower TGs
 Potential mechanisms:
o 1) Upregulate GLUT-4
o 2) Upregulate adiponectin (adipocyte
secretory protein)  increased insulin
sensitivity via several mechanisms
o 3) Decrease TNF-a which is associated with
resistance
 Adverse effects:
o Weight gain
 May cause proliferation of
adipocytes + edema
o Edema
 Due to PPAR-y effects in nephron
 increased Na retention
 Risk of pulmonary edema, so not
used in advanced HF
o Risk of hepatotoxicity
 Troglitzone removed
GLUCOSIDASE INHIBITORS
 Three classes: acarbose, miglitol, voglibose
 Taken orally before meals  less spike in glucose
 lowers A1c AND less insulin used (insulin
sparing)
 Competitive inhibitors of intestinal a-glucosidases
which hydrolyze 1,4 bonds in glucose molecules 
slows absorption of glucose  less in upper small
intestine, more in distal small intestine
o Brush border enzymes that hydrolyze
starches, oligosaccharides, disaccharides
e.g. sucrase, maltase, glucoamylase,
dextranase
 Adverse effects:
o GI upset: flatulence, diarrhea
AMYLIN ANALOGS (PRAMLINTIDE)
 Physiological role of amylin not understood
 Given SQ with meals AND always together with
insulin (type 1 or type 2)
 Amylin analogs has several effects:
o Suppresses glucagon release
o Delays gastric emptying, reduces appetite
o  allows insulin to work more effectively
 Side effect:
o Hypoglycemia  need to decrease insulin
o Nausea
GLP-1 ANALOGS
 Exenatide: usually given SQ prior to meals but
once weekly version available
 Liraglutide: SQ OD
 Similar function to GLP-1
 Adverse effects: nausea, vomiting, diarrhea
DPP-4 INHIBITORS
 Oral drugs OD
 DDP-4: dipeptidyl peptidase 4
o Enzyme expressed on many cells
o Inhibits release of GIP and GLP-1 
increased levels of these
 Adverse effects: infections (e.g. urinary,
respiratory) hypothesized due to immune
disturbances
SGLT2 INHIBITORS
  Oral drugs OD
 SGLT2:
o Expressed in PCT reabsorbs ~90% glucose
 Inhibition of SGLT2  loss of glucose in urine 
mild osmotic diuresis
 Good effects:
o Lead to mild weight loss due to glucosuria BLOOD SUPPLY
o May improve outcomes in HF due to
diuresis
 Adverse effects:
o Vulvovaginal candidiasis and UTIs due to
glucose as food for fungi and bugs
o Not recommended with advanced renal
disease
TIPS
 Renal failure: avoid metformin (LA)
 Advanced HF: avoid metformin (LA ) and TZDs
(fluid retention)
 Insulin generally safe with any comorbidity
MONITORING WITH HBA1C
 Too high = increased risk of complications  more
tx
 Too low = risk of hypoglycemia  less tx
 Goal <=7.0% used in most patients
THYROID GLAND
EMBRYOLOGY
 Pharyngeal grooves between pharyngeal arches and
in the middle are pharyngeal pouches
 At center of pouches, copula and tuberculum impar
with thyroid diverticulum in between
o Outgrowth from floor of pharynx/tongue
that dives down into neck and form thyroid
 Initially in fetus maintain connection to tongue
o Thyroglossal duct
o Disappears later in development
 Two remnants of duct in child/adult
o Foramen cecum at end of median sulcus in
tongue
o Pyramidal lobe of thyroid
THYROGLOSSAL DUCT CYST
 Persistent remnant of thyroglossal duct
 Presentation:
o Midline neck mass usually painless and
discovered in childhood
o Moves up with swallowing or tongue
protrusion (some connection still)
o May contain thyroid cells
ECTOPIC THYROID
 Functioning thyroid tissue outside of gland
 Presentation:
o Some thyroid tissue gets left behind, does
not descend, so mass in tongue
o Commonly detected when increased
demand for hormones (e.g. puberty and
pregnancy)
 Pathophysiology:
o May be only functioning thyroid tissue
o May under-produce thyroid hormone 
hypothyroidism  increased TSH 
increased growth of ectopic tissue
 Once remove, hyperthyroidism
after surgery and need HRT
THYROID ANATOMY
 Left and right lobe
 Thin band of tissue between called isthmus
 Sometimes pyramidal lobe above isthmus
 Superior and inferior thyroid arteries
 Superior is 1st branch of external carotid
 Inferior is branch of thyrocervical trunk which
comes off subclavian
THYROID HISTOLOGY
 “Follicles” are circular structures lined by single
layer of epithelial, follicular cells
o Filled with colloid (protein material)
CALCITONIN
 Synthesized by C-cells (parafollicular cells)
 Minor role in Ca homeostasis, major role from PTH
 Lower serum Ca by:
o A. suppresses resorption of bone by
inhibiting osteoclasts
o B. inhibits renal reabsorption of Ca, P
 Increased calcium in urine
 Used as pharmacologic tx for hypercalcemia
THYROID HORMONES
 T3, triiodothyronine vs. T4, thyroxine
 T4 is major hormone (>90%) but T3 is more potent
 Most T3 in body by peripheral conversion by 5’
deiodinase from T4 (prohormone)
A) THYROGLOBULIN
 Large protein produced by thyroid follicular cells
containing numerous tyrosine molecules
B) IODINE
 Iodide = iodine bound to another atom
o “iodide salt” with negative charge I-
o Plasma iodine exists as iodide salt
 Iodine needed in diet
o Iodized salt: table salt mixed with minute
amount to prevent iodine deficiency
SYNTHESIS
 1. Na-iodine symporter in follicular cells brings
iodide from plasma into cell with sodium
o Can also import other negatively charged
ions, perchlorate (ClO4-), pertechnetate
(TcO4-)  these are inhibitors
 2. Oxidation of iodide to iodine (I2)
o Catalyzed by thyroid peroxidase (TPO)
 3. Organification, adding iodine to tyrosine
molecules sitting on thyroglobulin in follicular
lumen
o Monoiodotyrosine, diiodotyrosine (DIT)
coupled to T3
o Two DIT coupled to T4
o Both steps are catalyzed by TPO
 4. Thyroglobulin brought into cell  T3 and T4
proteolysed from it  into plasma
WOLFF-CHAIKOFF EFFECT
 Thyroid protects from excess iodide  hyperthyr.
 Organification inhibited by increased iodide
THYROXINE-BINDING GLOBULIN (FROM LIVER)
 T4 and T3 both poorly soluble in water
 Most T4 bound to TBG because high affinity
 o Small # bound to transthyretin and albumin
o Small # unbound T4
 Less TBG  less available T4/T3 that can become
free and delivered to tissues
 Scenarios:
o O raises TBG levels by slightly modifying
and slowing clearance from plasma 
more bound T4 and less free T4 
increased TSH  increased total T4 
free T4 back to normal  TSH back to
normal
 Pregnancy, OCP users
o Liver failure lowers TBG levels  lower
T4
THYROID HORMONE RECEPTOR
 Family of nuclear receptors  hormone-activated
transcription factors  modulate gene expression
 Major regulator of metabolic activity and growth
GLUCOSE/LIPID METABOLISM
 Increase carbohydrate metabolism
o Increased glycogenolysis, GNG
 Increase fat metabolism
o Increase lipolysis, lowers concentration of
cholesterol, TG, LDL (decrease LDL
receptors in liver), increased cholesterol
secretion into bile
 Increase basal metabolic rate
o Basal rate of energy use per time if just
slept
o One mechanism: increased Na/K ATPase
pumps  more ATP consumed (raised
body temperature)  increased oxygen
demand to replenish ATP  increased
respiratory rate
CARDIAC FUNCTION
 Increase CO/HR/SV/contractility
 One mechanism: increase B1 receptors in heart so
catecholamines have greater effect
BONE GROWTH AND CNS DEVELOPMENT
 T3/T4 required for normal bone and CNS
THYROID HORMONE REGULATION
 Hypothalamus thyroid releasing hormone (TRH) 
TSH (thyrotropin) released by anterior pituitary 
binds to receptors on follicular cells  activated
cAMP/PKA  increased T3/T4 via:
o A. increased proteolysis of thyroglobulin
(rapid)
o B. stimulated thyroid cell growth, TG
synthesis (sustained increase)
 T3/T4 rise negative feedback on both TRH and
TSH
 T3/T4 low stimulates hypothalamus to release TRH
PREGNANCY
 Rise in TBG levels (estrogen)  rise in total T4/T3
 hCG stimulates thyroid (same alpha unit as TSH)
o Raises free T4  lower TSH
THYROID DISORDERS
 Hyperthyroid, hypothyroid, thyroiditis
o Inflammation initially increases TH
because spill into plasma  eventually
inflammation decreases TH produced
(hyper then hypo)
HYPOTHYROIDISM
CAUSES
IODINE DEFICIENCY
 “Endemic goiter” in regions with iodine deficiency
 Common in mountainous areas because run-off
depletes iodine from soil and water
IODINE EXCESS
 Chronic, high iodine intake 
goiter/hypothyroidism via Wolff-Chaikoff effect
o Differs from iodide load which ‘feeds’ pre-
existing and causes hyperthyroidism
GOITROGENS
 Substances that inhibit TH production
 Common: iodine, lithium (used in psychiatry,
inhibits release of TH), certain foods (cassava,
millet)
CONGENITAL HYPOTHYROIDISM
 Iodine deficiency, thyroid dysgenesis, inborn errors
of hormone synthesis (dyshormonogenesis, TPO
most common)  childhood hypothyroidism 
cretinism
o Stunted growth, intellectual disability,
coarse facial features, umbilical hernia, big
tongue
 Deficiency most treatable cause of intel. disability
o Most babies appear normal because
maternal T3/T4 cross placenta
o Newborn screening programs to measure
T4 or TSH from heel-stick blood specimens
 Treat early to prevent cretinism
AMIODARONE
 Class III antiarrhythmic drug common in AF
o Contains two iodine molecules
 Pathophysiology:
o A. Excess iodine and Wolff-Chaikoff
o B. Mimics T4  inhibits 5’-deiodinase 
decreased T3
o Both lead to increased TSH  mild
increase in TSH (noted after tx then
normalizes)
 Course:
o Normal patients ‘escape’ in a few weeks
o Pre-existing subclinical thyroid disease 
“failure to escape”  permanently
hypothyroid
 ** Always check TSH before amiodarone
THYROIDITIS
HASHIMOTO’S/CHRONIC THYROIDITIS
 Most common cause of non-dietary hypothyroidism
 Etiology:
o Associated with HLA-DR3, DR5, others
 Pathophysiology:
o Autoimmune disorder  lymphocytes
infiltrate thyroid gland  T-cells attack, B-
cells activated (but Abs not involved)
 Presentation:
o Predominantly females
o Enlarged non-tender thyroid
o Gradual loss of thyroid function 
hypothyroidism symptoms
 Evaluation:
 o Labs of hypothyroidism
o Anti-TPO, anti-thyroglobulin antibodies
o Histology:
 Massive lymphocytic infiltrate (if a
lot then form germinal centers)
 Hurthle cells (enlarged eosinophilic
follicular cells)
 Treatment:
o Thyroid hormone replacement
 Complications:
o Increase risk non-Hodgkin B cell
lymphoma
LYMPHOCYTIC (HASHIMOTO VARIANT)
 Pathophysiology:
o Lymphocytic infiltration of thyroid gland
 Course:
o Transient hyperthyroidism can look like
Grave’s without eye/skin findings BUT
serum thyroid stimuling Igs not elevated
o Followed by hypothyroidism can look like
Hashimoto’s but not chronic, usually self-
limited to weeks
SUBACUTE/DE QUERVAIN’S/GRANULOMATOUS
 Pathophysiology:
o Granulomatous inflammation of thyroid
o Granulomas and giant cells on biopsy
 Presentation:
o Young females
o Tender (unique), enlarged thyroid gland
 Treatment:
o Often no tx because thyroid Sx usually mild
o Anti-inflammatories (aspirin, NSAIds,
steroids) but often no tx
 Usually self-limited, few weeks
RIEDEL’S THYROIDITS
 Pathophysiology:
o Fibroblast activation/proliferation 
fibrous tissue (collagen) deposition in
thyroid  “rock hard thyroid”
o Parathyroid glands  hypoparathyroidism
o Recurrent laryngeal nerves  hoarseness
o Trachea compression  difficult breathing
 Evaluation:
o IgG4 plasma cells identified in biopsy
o May be IgG-4 related disease such as
autoimmune pancreatitis
IATROGENIC HYPOTHYROIDISM
 Thyroid surgery OR radioiodine therapy
o For Grave’s or malignancy
 Neck radiation
o Hodgkin’s lymphoma, head and neck
cancer
CLINICAL PRESENTATION
 Lethargy, fatigue, weakness, dyspnea on exertion
 Dry and cool skin, coarse and brittle hair
 Weight gain with loss of appetite
 Bradycardia, hyporeflexia, constipation
 Cold intolerance
 Hyperlipidemia:
o Increased total chol. and LDL cholesterol
o T3 upregulates LDL receptor gene
activation less T3 decreased LDLR
density
 Myxedema:
o Non-pitting edema
 Usually in facial/periorbital
swelling
 Pretibial myxedema: over shin
o Hyaluronic acid deposits in dermis 
draws water out because osmotic agent 
swelling
 Myxedema coma:
o Coma from hypothyroidism
 Hypothyroid myopathy:
o Weakness, cramps, myalgias
o Increased CK common (up to 90%)
 Hyponatremia:
o High levels of ADH (SIADH)
o May contribute to confusion
TREATMENT
 Liothyronine (Cytomel): synthetic T3 rarely used
 Levothyroxine (Synthroid): synthetic T4 preferred
o T3 absorbed from intestines rapidly  may
cause mild hyperthyroidism Sx (e.g.
tachycardia and tremor)
o T4 converted to T3 so also replenished
 Titrate dose until TSH is normal
HYPERTHYROIDISM
CAUSES
GOITER (MOST COMMON)
 High TSH but inability to produce T3/T4
o Causes enlarged thyroid
 Commonly seen in iodine deficiency and thyroid
stimulating antibodies (e.g. Grave’s)
GRAVE’S DISEASE
 Autoimmune disease
 Thyroid-stimulating antibodies/immunoglobulins
behave like TSH and stimulate thyroid gland
 Presentation:
o Sx of hyperthyroidism, goitre, AND:
o Exophthalmos (bulging eyes)
 Proptosis (protrusion of eye) and
periorbital edema
 Usually no ocular symptoms
o Pretibial myxedema (shins)
 Pathophysiology:
o T-cell lymphocyte activation of fibroblasts
 have TSH receptors and stimulated by
ab  secretion of glycosaminoglycans:
 Hydrophilic substances, mostly
hyaluronic acid
 Draws in water  swelling
 Diagnosis:
o Hyperthyroid labs plus exophthalmos
o Can measure TSH stimulating Igs
 Treatment:
o Symptoms: beta blockers, thionamides
 Often started in preparation for
definitive therapy:
o Radioactive iodine ablation or surgery
THIONAMIDES
 Methimazole: inhibits TPO  blunt organification
and coupling of MIT/DIT
  Propylthiouracil: inhibits TPO and 5’-deiodinase
 Adverse effects:
o Skin rash common
o Agranulocytosis rare (drop in WBC)
 May present as fever, infection
after starting drug
 WBC improves with stopping drug
 Aplastic anemia cases reported
o Hepatotoxicity
o Methimazole: teratogen
 Associated with congenital
malformations, esp. 1st trimester
 PTU often during early pregnancy
GRAVE’S OPHTHALMOLOGY
 Chronic eye symptoms, w/ or w/o worsening,
despite treating Grave’s hyperthyroidism
 Presentation:
o Irritation, excessive tearing, pain
o Can worsen from cold air, wind, bright
lights
 Treatment:
o For severe cases
o Steroids, radiation, surgery rare
TOXIC ADENOMAS
 One (toxic adenoma) or multiple (toxic
multinodular goiter) nodules in thyroid that
function independently
 Pathophysiology:
o Usually contain mutated TSH receptor so
does not respond to TSH
 Findings:
o Palpable nodule + hyperthyroidism
symptoms/labs
 Treatment:
o Radioactive iodine or surgery
JOD-BASEDOW PHENOMENON
 Iodine-induced hyperthyroidism
 Regions of iodine deficiency  introduce iodine
will develop hyperthyroidism
 Regions of normal iodine  pts w/ toxic adenomas
o Drugs with high iodine content,
expectorants for cough (KI), CT contrast
dye, amiodarone
AMIODARONE
 Type I amiodarone hyperthyroidism
o Occurs in patients with pre-existing thyroid
disease (e.g. Grave’s)
o Provides iodine  excess TH production
 Type II amiodarone hyperthyroidism
o Absence of pre-existing thyroid illness
o Toxic effect of drug  destructive
thyroiditis  excess release T4/T3 without
increased hormone synthesis
EARLY THYROIDITIS
CLINICAL PRESENTATION
 Hyperactivity
 Warm moist skin, fine hair
 Weight loss with increased appetite
 Tachycardia (occasionally AF), hyperreflexia,
diarrhea
 Heat intolerance
THYROID STORM/THYROTOXICOSIS
 Life-threatening hyperthyroidism
 Usually precipitated by acute event:
o Pre-existing hyperthyroid disease
o Surgery, trauma, infection triggers rise in
TH
 Massive TH + catecholamine surge:
o Fever, delirium
o Tachycardia, often death from
arrhythmias
o Hyperglycemia (catecholamines/TH)
o Hypercalcemia (bone turnover)
 Treatment:
o Propranolol beta-blocker of choice
o Thionamides
o SSKI (saturated solution of potassium
iodide)
 Iodide load shuts down T4
production via Wolff-Chaikoff
o Steroids
 Reduce T4-T3 conversion
 Suppress autoimmune damage (e.g.
from Grave’s)
 Treat possible concomitant adrenal
insufficiency (from depleted
cortisol)
TREATMENT
 Thionamide:
o Decrease thyroid gland production
 Propranolol:
o Weak inhibitor of 5’-deiodinase
o Excellent drug in thyrotoxicosis: block
catecholamines and T4-T3 conversion
EVALUATION
 Best initial test is TSH
o Testing what tissue level is seeing in TSH
o Can become abnormal before T3/T4
o T3/T4 not preferred because fluctuating
 Thyroid panel:
o TSH: 0.4-5mU/L
o Total T4: 60-145nmol/L
o Total T3: 1.1-3nmol/L
o Free T4: 0.01-0.03nmol/L
 Most primary thyroid disease
o Disorder of thyroid gland itself
o This means TSH is OPPOSITE of T3/T4
 Rarely central thyroid disease
o Thyroid gland is normal
o Pituitary or hypothal. is over/undersecreting
 Usually hypothalamic-pituitary
tumours  block TRH/TSH (hypo)
or rarely TSHoma (hyper)
 Pituitary resistance to TH (hyper)
o This means TSH is SAME as T3/T4
REVERSE T3
 rT3 is isomer of T3 also derived from T4
o Levels usually parallel T4
o Exception: euthyroid sick syndrome
 Critically ill patients  low TSH
related to illness  low T3/T4
 rT3 rises due to impaired clearance
o Critically ill patients with low TSH/T4/T3:
 rT3 low = central hypothyroidism
  rT3 high = sick euthyroid  Release inhibited by: glucose, somatostatin
syndrome (released in response to IGF-1;GH), IGF-1 (direct
RADIOACTIVE IODINE FOR NODULES and indirect)
 I131 as 53 protons like elemental I2 but extra GROWTH HORMONE RECEPTOR
neutrons  Membrane-bound receptor because protein
o Emits radiation (B-decay)  Activates Janus kinase 2 (JAK2), cytoplasmic
 Exposure  radioactive I131 in thyroid  competes tyrosine kinase)  phosphorylates tyrosine residues
with I2 for uptake  concentrate in thyroid gland within JAK2 and GH receptor forms many
 Small dose: imaging, I123 can also be used binding sites for many signaling molecules  alter
o Administer I131 (lower than ablation) gene expression
 Not in pregnancy/breast feeding IGF-1/SOMATOMEDIN
o “Hot” nodule:  GH  many receptors in liver  release IGF-1
 Takes up I131, non-cancerous   Also produced in peripheral tissues but paracrine on
toxic adenoma nearby sites
o “Cold” nodule:  Hormone mediates many GH effects
 Chance of cancer (~5%)  Measured in serum as indicator of GH function
 Biopsied by fine-needle aspiration GROWTH HORMONE DEFICIENCY
 Large dose: destroy thyroid tissue  Etiology:
o I131 administered orally as solution or o Most commonly from pituitary tumor
capsule  beta-emission damage tissue  o Mass effect or due to surgery/radiation
ablation of thyroid function over weeks  Presentation:
o Children: failure to grow
PITUITARY GLAND o Adults: increased fat, decreased lean body
mass, low energy
 Brain base in small cavity of sphenoid bone: sella  Treatment:
turcica o Synthetic GH
 Optic chiasm above pituitary gland o Monitor with serum IGF-1 level
 Connected to median eminence of hypothalamus BULIMIA
via pituitary stalk  Binge
o One of circumventricular organs BULIMIA
o Does not contain BBB  Binge
ANTERIOR PITUITARY BULIMIA
GLAND/ADENOHYPOPHYSIS  Binge
 Derive from Rathke’s pouch, outgrowth of oral BULIMIA
cavity  Binge
 Hypothalamic portal system main blood supply and BULIMIA
delivers releasing/inhibiting hormones  Binge
 Contains five cell types: BULIMIA
o Corticotrophs: ACTH from CRH  Binge
o Gonadotrophs: LH/FSH from GnRH BULIMIA
o Thyrotrophs: TSH from TRH  Binge
o Somatotrophs: GH from GHRH BULIMIA
o Lactotrophs: prolactin  Binge
o Dopamine inhibits prolactin release BULIMIA
o Somatostatin inhibits GH, TSH  Binge
POSTERIOR PITUITARY
GLAND/NEUROHYPOPHYSIS ADRENAL GLANDS
 Derive from neural ectoderm in floor of forebrain
 Contains axons and nerve terminals which originate ANATOMY
from hypothalamus BLOOD SUPPLY
o Paraventricular nuclei makes oxytocin  Arteries:
o Supraoptic nuclei makes ADH o Left and right suprarenal arteries
GROWTH HORMONE o Superior, middle, inferior on both sides
 Protein hormone important for linear (height)  Veins:
growth in childhood o Left adrenal  renal vein  IVC
 Released in pulsatile manner o Right adrenal  IVC
o Between pulses level may be undetectable LAYERS
 Direct effects:  Fibrous capsule, cortex, medulla
o df  Cortex: derived from mesoderm
 Release stimulated by: GHRH, exercise, sleep o Synthesizes 3 groups of hormones
(very high just after onset of sleep) o Zone glomerulosa (outermost):
mineralocorticoids
 o Zona fasciculata: glucocorticoids
o Zona reticularis (medulla): androgens
 Medulla: derived from neural crest
o Synthesize EN and NE
o Sympathetic NS control, nicotinic R, Ach
MINERALOCORTICOIDS
 Weak: corticosterone, 11-deoxycorticosterone
 Most important is aldosterone
o Release controlled by RAAS system
o In principal cells, increase ENaC and Na/K
ATPase insertions
o In intercalated cells, increase H+ pumps
EFFECTS
 Increased Na/water, decreased K and H+
ADRENAL ANDROGENS
 Dehydroepiandrosterone (DHEA), androstenedione,
testosterone (converted primarily in testes)
o Production and release stimulated by
ACTH like cortisol
o Small contribution to androgen production
in males due to testes
o ~50% androgens for females
EFFECTS
 Minor role in males because de novo synthesis of
testosterone in testes much greater than from
adrenal androgenic precursors
 Major role in females because adrenal androgens
are major androgens
o Development of pubic and axillary hair
o Libido
 Adrenogenital syndrome is increased DHEA and
androstenedione
o Masculinization in females
o Early development of axillary/pubic hair
o Suppression of gonadal function
GLUCOCORTICOID (CORTISOL)
 Secretion controlled by pituitary-adrenal axis
o Hypothalamus: CRH from paraventricular
nucleus (PVN)
o Anterior pituitary: ACTH
o Adrenal: cortisol via cAMP/PKA from
ACTH
 Cortisol negative feedback on
pituitary and hypothalamus
 Cortisol made of many C and H, poorly soluble in
plasma, >90% bound to cortisol-binding globulin
o CGB increases when estrogen increases
EFFECTS
 Stress hormone, divert energy to help survive
 Binds to cytosolic receptors (glucocorticoid
receptor GR)  translocates to nucleus  activates
or suppresses gene transcription
 Maintains blood pressure
o Increases vascular sensitivity to NE/EN on
vascular smooth vessel via α1
o Blunts NO-mediated vasodilation
 Suppresses immune system
o Sequester lymphocytes in spleen/nodes
 Reduce T and B cells in plasma
o Block neutrophil migration out of
vasculature into tissues
 Increase peripheral neutrophil
count
o Blocks histamine release from mast cells
o Lower eosinophil counts
o Inactivate NF-KB, inflamm. transcription
factor mediates response to TNF-a and
controls synthesis of inflammatory
mediators COX-2, PLA2, lipoxygenase
 Because cortisol is potent immunosuppressant,
drugs with similar structure often used
o Corticosteroid drugs (e.g. drugs)
o Prednisone (oral), methylprednisolone (IV),
dexamethasone, cortisone, triamcinolone,
betamethasone, hydrocortisone
 Increase serum glucose
o Enhance effects of glucagon, EN
 Chronic: insulin resistance 
diabetes in long term steroid use
o Increase liver production of glucose
 Increased synthesis of G6P,
PEPCK  increased GNG
o Decrease peripheral glucose uptake in
muscle, fat
o Increase glycogen storage in liver
 Increase synthesis of glycogen
synthase (offset by glucagon)
 Increase fat deposition
o Activate lipolysis in adipocytes
 Increases free FA
 Chronic: increase total cholesterol,
TG
o Stimulate adipocyte growth
 Negative effects on muscle, skin, bones
o Muscle atrophy
o Inhibits osteoblasts  osteopenia and
osteoporosis
 Easy fracturing
o Skin:
 Blunted epidermal cell division in
skin, decreased collagen, inhibition
of fibroblasts
 Thin skin, easy bruising, striae
 Fragile thin stretches over trunk,
breasts, abdomen and thinness
cannot hide venous blood in dermis
CIRCADIAN RHYTHM
 Since cortisol is stress hormone, variable serum
levels
 Highest early morning ~6AM
o 10-20 mcg/dL
 Lowest one hour after sleep onset
o <5 mcg/dL
 Thus rarely done with single blood test
HORMONE SYNTHESIS
 All adrenal cortical hormones begin with
cholesterol
o Enzymes named by carbon # on cortisol
 Each zone uses molecules from zone above
ZONA GLOMERULOSA
 Cholesterol  desmolase (stimulated by ACTH)
 pregnenolone  3B-hydroxysteroid
dehydrogenase  progesterone  21a-
hydroxylase  11-deoxycorticosterone  11B-
 hydroxylase  corticosterone  aldosterone
synthase (stimulated by AGII)  aldosterone
ZONA FASCICULATA
 Pregnenolone or progesterone  17a-hydroxylase
 17-hydroxypregnenolone or 17-
hydroxyprogesterone
 17-hydroxypregnenolone  3B-hydroxysteroid
dehydrogenase  17-hydroxyprogesterone 
21a-hydroxylase  11-deoxycortisol  11B-
hydroxylase  cortisol
ZONA RETICULARIS
 17-hydroxypregnenolone or 17-
hydroxyprogesterone  17,20 lyase  DHEA or
androstenedione
 DHEA  3B-hydroxysteroid dehydrogenase 
androstenedione  testosterone
CLINICAL PRESENTATION
17A HYDROXYLASE
 Part of larger cytochrome P450c17 enzyme
(CYP17A1)
o Found in adrenal glands and gonads
o Catalyzes 17a-hydroxylase and 17,20 lyase
 Deficiency decreases androgen production in both
adrenal glands and gonads
CATECHOLAMINE METABOLISM
 Monoamine oxidase (MAO)
 Catechol-O-methyltransferase (COMT)
 Dopamine  MAO/COMT  intermediate 
COMT/MAO opposite  homovanillic acid
 NE  COMT  normetanephrine
 EN  COMT  metanephrine
o  MAO  vanillylmandelic acid
 EN, NE  MAO  dihydroxymandelic acid
o  COMT  vanillylmandelic acid
CONGENITAL ADRENAL HYPERPLASIA
 Rare enzyme deficiency syndrome
 Loss of one of four enzymes for cortisol synthesis:
o 17a-hydroxylase, 3B-hydroxysteroid
dehydrogenase, 21a-hydroxylase (most
common), 11B-hydroxylase
PATHOPHYSIOLOGY
 General mechanism:
o Cortisol cannot be synthesized  ACTH
increased  adrenal hyperplasia 
cholesterol is driven into mineralocorticoids
or androgens
o Effects depend on enzyme affected
 Low cortisol in baby
o Hypoglycemia
o Nausea/vomiting (classic GI symptoms in
adult adrenal insufficiency)
 High ACTH:
o Proopiomelanocortin  melanocyte
stimulating hormone (MSH) and ACTH
o High levels of MSH  increase melanin
synthesis  skin hyperpigmentation
(dark)
o Sometimes in congenital, but classic in
Addison’s, adult adrenal insufficiency
 Aldosterone deficiency
o Na loss  water loss  hypovolemia 
shock
o Hyperkalemia
o Increased renin
 Aldosterone excess
o Na retention  hypertension
o Hypokalemia
o Decreased renin
 Androgen excess
o XX: ambiguous genitalia
o XY: precocious (early) puberty
 Androgen deficiency
o XX: normal genitalia
o XY: ambiguous or female (severe) genitalia
 21a-hydroxylase deficiency (90% of CAH) :
o Cannot make cortisol or aldosterone 
deficient mineralo. and excess androgen
 Classic/salt-losing form: 0-2% normal enzyme
activity
o Nausea/vomiting, volume depletion,
hyperkalemia, 7-14 days
 Non-classic/milder: 20-50% normal enzyme
activity
o Ambiguous genitalia in females, precocious
puberty in males
 11B-hydroxylase deficiency:
o Cannot make cortisol or aldosterone BUT
11-deoxycorticosterone which has weak
effects  excess mineralo. and excess
androgen
o Nausea/vomiting, hypertension,
hypokalemia, ambiguous genitalia in
females, precocious puberty in males
 17a-hydroxylase deficiency:
o Cannot make cortisol or androgens 
excess mineralo. and deficient androgen
o Nausea/vomiting, hypertension,
hypokalemia
o Males:
 Female or ambiguous external
genitalia
  Absent uterus/fallopian tubes
(Sertoli cells secrete mullerian
inhibitory hormone)
 Undescended tests (testes depend
on normal androgen levels)
o Females:
 Normal at birth
 Primary amenorrhea at puberty
because theca cells lack androgens STEP 1: ESTABLISH CUSHING’S SYNDROME
 lack estradiol
o Often diagnosed at puberty:
 Cortisol deficiency symptoms mild
 XX females fail to develop
secondary sex characteristics
 XY male but phenotypic female
fails to develop because absent
uterus
 Hypertension, low K
 3B-hydroxysteroid dehydrogenase deficiency:
o Cannot make any adrenocortical hormones
CAH SCREENING
 Measure level of 17-hydroxyprogesterone
 Elevated in 21a-hydroxylase deficiency (common)
TREATMENT
 Many forms treated with glucocorticoids
o Replenish cortisol, lowers ACTH, stops
overproduction of other hormones
 Can also use mineralocorticoids (fludrocortisone)
DISORDERS OF SEX DEVELOPMENT
 Ambiguous genitalia:
o 46, XX: excess androgens often CAH
o 46, XY: lack of androgens from synthesis
or effect rarely due to CAH
CUSHING’S SYNDROME
 Set of clinical features due to excess cortisol
ETIOLOGY
 ACTH-independent (ACTH low)
o Most common cause is corticosteroid
medication, often for inflamm. disease
o Adrenal adenoma
 ACTH-dependent (ACTH high  adrenal
hyperplasia  increased cortisol)
o Pituitary ACTH-secreting tumor
(Cushing’s disease)
o Ectopic ACTH/small cell lung cancer
PATHOPHYSIOLOGY
 Hypertension, hyperglycemia, DM
 Immune suppression
o Risk of infections, esp. opportunistic
 Stimulation of fat deposition
o Progressive central obesity
o Face, neck, trunk, abdomen
 “Moon face”, “buffalo hump” fat
mound at base of neck and back
 Skin changes
o Thinning, easy bruising commonly under
forearm, striae or purple stretch marks
commonly on sides and lower abdomen
o Skin hyperpigmentation in ACTH-
dependent causes, but classic Addison’s
 Cortisol alters GnRH release  decreased FSH, LH
o Women:
 Menstrual irregularities (80%
abnormal cycles, 30%
oligomehorrhea, 30% amehorrhea)
 Hirsutism
o Males:
 Erectile dysfunction
DIAGNOSIS
 Measuring plasma cortisol is difficult:
 1) Circadian rhythm and high levels in AM where
most patients want test, 2) most bound to CBG,
CBG levels can affect serum measurement
 24-hour urine free cortisol:
o Integrates cortisol level over time
 Salivary cortisol:
o No CBG in saliva
o Free level measured at night
 Low dose dexamethasone suppression test:
o Low dose 1mg dexamethasone at bedtime
 suppresses normal pituitary ACTH
release because mimics cortisol  morning
blood test  cortisol levels should be low
o Cortisol remains high in Cushing’s
syndrome
o Adenomas, tumors are not suppressed
STEP 2: ESTABLISH CAUSE
 Measure serum ACTH level
 High dose dexamethasone suppression test: 8mg
to differentiate causes of high ACTH vs. diagnosis
o Will suppress cortisol in Cushing’s disease
(still respond but higher set point)
o Will not suppress cortisol in ectopic ACTH
STEP 3: IMAGING
 CT abdomen/pituitary MRI
TREATMENT
 Surgery:
o Remove adenoma in adrenal, pituitary
o Remove lung tumor
KETACONAZOLE
 Antifungal blocks ergosterol synthesis in fungi
 Similar enzyme structure to steroid hormones so
blocks enzymes in hormone synthesis
 Potent inhibitor of 17,20 lyase
o Decreased androstenedione/testosterone
o Key side effect: gynecomastia
 At higher doses, inhibits desmolase, 17a-
hydroxylase
o Blocks 1st step of cortisol synthesis
o Can treat Cushing’s syndrome
ADRENAL INSUFFICIENCY
 Insufficient cortisol production
ETIOLOGY
COMMON CAUSES OF ADDISON’S
 Autoimmune adrenalitis
o Antibody and cell-mediated disorder
o Atrophy of adrenal gland and loss of cortex
but medulla generally spared
o Abs to 21a-hydroxylase common
 Infections
 o Tuberculosis, fungal if systemic
(histoplasmosis, cryptococcus), CMV
 Metastasis from lung cancer
o Usually found on imaging without
symptoms
COMMON CAUSES OF SECONDARY
 Glucocorticoid therapy
o Most common cause
o Chronic suppression of ACTH release 
adrenal atrophy over time  sudden
discontinuation  hypoadrenalism
o 1) basis for ‘weaning off steroids’ i.e. slow
discontinuation for rising ACTH production
o 2) basis for ‘stress dose steroids’ i.e. high
dose of glucocorticoids for prevention
PATHOPHYSIOLOGY
 Primary (Addison’s disease):
o Failure of adrenal gland
o Cortisol and aldosterone low, ACTH high
 Secondary:
o Failure of pituitary ACTH release
o Low ACTH and cortisol, aldosterone
normal
CLINICAL PRESENTATION
 Loss of cortisol:
o Weakness, fatigue, weight loss
o Hypoglycemia
o Postural hypotension
o Nausea, abdominal pain, diarrhea
ONLY IN ADDISON’S
 Loss of aldosterone:
o Hypovolemia, hyperkalemia, acidosis
 Skin hyperpigmentation in Addison’s
o Most obvious in sun-exposed areas: face,
neck, backs of hands
o Areas of friction/pressure: elbows, knees,
knuckles
o May occur in palmar creases
 Addison’s: GI (nausea, pain) + darkening skin
DIAGNOSIS
 8AM serum cortisol
o Low level indicates disease
 Serum ACTH
o High ACTH low cortisol = primary
o Low ACTH low cortisol = secondary
 ACTH (cosyntropin) stimulation test
o Exogenous synthetic ACTH  cortisol
should rise 30-60 minutes later
o Failure to rise = primary; normal =
secondary
ADRENAL CRISIS
 Acute adrenal insufficiency  abrupt loss of
cortisol and aldosterone
o Often when acute increase in adrenal
function cannot be met
o Infection, surgery, trauma in patient:
 With adrenal insufficiency
 Chronic steroids need stress dose
 Main manifestation is shock
o May have hypoglycemia
o Nausea, vomiting, fatigue, confusion
WATERHOUSE-FRIDERICHSEN SYNDROME
 Rare cause of acute adrenal insufficiency
 Strongly associated with meningococcemia
 Acute hemorrhage into adrenal glands
 Classic presentation:
o Patient with bacterial meningitis and acute
onset of shock
o Need steroids to survive
PRIMARY ALDOSTERONISM
ETIOLOGY
 Bilateral idiopathic hyperaldosteronism (60%)
o Producing too much for unknown reasons
 Aldosterone-producing adenoma (30%)
o Conn’s syndrome
CLINICAL PRESENTATION
 Hypertension, esp. at young age
 Metabolic alkalosis
 Hypokalemia
o Weakness, muscle cramps
o Unreliable finding  many cases normal K
because enough from diet
DIAGNOSIS
 Plasma aldosterone concentration (PAC)
 Plasma renin activity (PRA)
o Plasma incubated  renin in sample
cleaves AG  AGI produced  measured
by assay
 Low PRA and high PAC = primary
 High PRA and high PAC = secondary
o E.g. renal artery stenosis, CHF, low volume
 Abdominal imaging
o Adrenal nodules and tumors
 Adrenal vein sampling
o Differentiate unilateral vs. bilateral disease
by PAC and PRA in each vein
TREATMENT
 Surgical adrenalectomy
o Adenomas and unilateral hyperplasia
 Spironolactone is mainstay
o K-sparing diuretic blocks aldosterone
LICORICE
 Renal 11B-hydroxysteroid dehydrogenase, which
converts cortisol to cortisone  protects kidneys
because cortisol can stimulate aldosterone receptors
 Contains glycyrrhetinic acid, a steroid
o Inhibits the enzyme  weak
mineralocorticoid effect
 Large amounts  hypertension, hypokalemia, low
aldosterone
CATECHOLAMINE-SECRETING TUMORS
 Catecholamine-secreting tumor: EN, NE, dopamine
PHEOCHROMOCYTOMA
 Derived from chromaffin cells of adrenal medulla
and by extension the neural crest
 Etiology:
o 1/3 are heritable, so genetic testing
important
o Mostly sporadic
 Clinical presentation:
 o Release of catecholamines is released in
spurts  classically episodic symptoms
 HTN, headaches, palpitations,
sweating, pallor (pale skin)
 Diagnosis:
o Serum catecholamine not routinely used
 Levels fluctuate some metabolism
intratumoral so not seen in plasma
o Breakdown products of catecholamines
measured, usually 24h urine collection
 Metanephrine and normetanephrine
on 24h urine or plasma
 Older: 24h urine collection of
VMA
o Then CT abdomen for adrenal nodule
o MIBG to look for mets in other parts of
body
 Treatment:
o Surgical removal
o Pre-operative management important:
 Risk of high exposure to
catecholamines
 Pre-treat with phenoxybenzamine,
reversible α blocker
 Afterward, non-selective beta
blocker e.g. propranolol so no
unopposed a-vasoconstriction
PARAGANGLIOMA
 Derived from sympathetic ganglia (extraadrenal)
 Clinical presentation:
o Similar to pheocytochroma
NEUROBLASTOMA
 Derived from primitive sympathetic ganglion cells
and by extension neural crest cells
 Can arise anywhere in sympathetic NS:
o Adrenal gland most common 40%
o Abdominal 25%, thoracic 15%
 Almost always occur in children
o 3rd most common childhood cancer after
leukemia, brain tumors
o Most common extracranial tumor
 Pathophysiology:
o Can synthesize catecholamines but rarely
cause symptoms of pheo
o 24h urine HVA/VMA levels for diagnosis
 Clinical presentation:
o Related to tumor mass effect
o Commonly present as abdominal pain
 Prognosis:
o Diverse range of disease progression
o Age at diagnosis:
 Infants with disseminated disease
often cured
 Children over 18 months often die
despite therapy
 Younger = better prognosis
o N-myc, a proto-oncogene
 Amplified/overexpressed in some
tumors, associated poor prognosis
 Complications:
o Opsoclonus-myoclonus-ataxia (OMA)
o Rare paraneoplastic syndrome, in half of
patients with neuroblastoma
o
Rapid eye movement, rhythmic jerking,
ataxia
METAIODOBENZYLGUANIDINE
 Chemical analog of NE  concentrate in
sympathetic tissue and tumors  labelled with I131
 detect because emit radiation
o Diagnosis of pheo AND neuroblastoma
 Thyroid gland must be protected
o If thyroid takes up I131 can destroy tissue
o Thus concurrent KI, non-radioactive iodine
will be preferentially taken up by thyroid
ADRENAL ADENOMA
 Small areas of hyperplasia in adrenal gland
 Often discovered on abdominal imaging
 Concern for malignancy and/or functioning
adenoma
 May secrete cortisol/aldosterone, so rule out:
o 24h urine metanephrines (pheo)
o 24h urine free cortisol (Cushing’s)
o Low dose dexamethasone suppression
(Cushing’s)
o Serum PRA/aldosterone (aldosteronism)
 1) If non-functional and small, monitored for
growth
 2) If large >5cm, often removed out of concern may
represent malignancy
DEVELOPMENT OF THE REPRODUCTIVE SYSTEM
SEXUAL DIFFERENTIATION
 Begins at conception, ends with sexual
characteristics acquisition
 First 5 gestational weeks: gonadal ridge develops,
later becomes differentiated gonads
 Week 6: primordial germ cells start migrating from
yolk sac towards gonadal ridge
 Week 7: primordial germ cells promote gene
expression contained in sex chromosomes
 Week 8: Wolffian, Müllerian ducts, will develop
into rest of reproductive tract, start differentiating
 Week 12: phenotypic differentiation complete,
earliest to perform US-based sex determination
MALE GONADAL DEVELOPMENT
 Gene expression in sex-determining region in Y
chromosome (SRY) promoted
o SRY-region genes promote testis-
determining factor production  transform
undifferentiated gonads into testes
o Gonadal ridge becomes seminiferous
tubules, rete testis, straight tubules
 Testes contain 3 functional cell types
o Germ cells: produce spermatogonia 
produce male gametes in puberty
o Sertoli cells: synthesize anti-Müllerian
hormone
o Leydig cells: synthesize testosterone
MALE INTERNAL DEVELOPMENT
 Wolffian ducts/mesonephric ducts/mesonephros:
o Connects primitive kidney to cloaca
o Develops into male internal genitalia
 o Growth, differentiation stimulated by
testosterone
 Sertoli: synthesize Müllerian inhibiting substance
 promotes Müllerian/paramesonephric duct
atrophy
 Leydig: synthesize, secrete testosterone  become
internal male genitalia
 Urogenital sinus: urethral folds  urethra
MALE EXTERNAL DEVELOPMENT
 Urogenital sinus differentiates from week 9 to
male external genitalia
o Urethral folds  urethra
o Labioscrotal swellings  scrotum
o Primordial phallus  penis
 Differentiation depends on testosterone presence
o 5a-reductase in target tissues converts
testosterone  more potent dihydro “” 
masculinizes external genitalia
FEMALE GONADAL DEVELOPMENT
 Without functional SRY gene,
o Week 9: ovaries begin developing
o Week 10: ovarian cortex, inner medulla
distinguishable
 Ovaries contain 3 functional cell types:
o Germ cells: produce oogonia located in
ovarian cortex
o Granulosa cells: synthesize estradiol
o Theca cells: synthesize progesterone
 Ovarian follicle: oogonium surrounded by
granulosa cells, connective tissue
FEMALE INTERNAL DEVELOPMENT
 Müllerian duct/paramesonephric
duct/paramesonephros  female genitalia
o Growth, differentiation depends on no
testes
 Lack of testosterone  Wolffian duct
degeneration
 Lack of anti-Müllerian  Müllerian ducts
develop into fallopian tubes, uterus, upper 1/3 of
vaginal canal
 Urogenital sinus  rest of reproductive organs
FEMALE EXTERNAL DEVELOPMENT
 Urogenital sinus differentiates from week 9 to
female external genitalia
o Urethral folds  urethra, labia minora
o Labioscrotal swellings  labia majora,
mons pubis
o Primordial phallus  clitoris
 Differentiation depends on absence of androgens
ANDROGEN INSENSITIVITY SYNDROME
 Etiology:
o Loss-of-function mutations in coding
sequence of androgen receptors 
androgen resistance from partial to
complete
o X-linked recessive
 Pathophysiology:
 Testosterone no effect, mesonephric do not develop
into internal male genitalia
o Seminal vesicles, epididymis, vas deferens
 DHT no effect, urogenital sinus does not develop
into external male genitalia
o Penis, scrotum, prostate
 Testes form in utero (SRY gene present)  Sertoli
cells secrete MIH  internal female structures
degenerate
 Clinical presentation of complete AIS:
o XY male with female appearance + external
female genitalia
o Abdominal (undescended) testes
o No internal male or female genitalia
 At puberty:
o Amenorrhea because no uterus/ovaries
o Breasts develop (testes make more
testosterone  converted to estrogen)
o No armpit/pubic hair because depends on
androgens
 Investigations:
o Karyotype and genetic workup
o Serum electrolytes and renin (evidence of
salt-wasting in CAH); 17-OH-progesterone,
androgens, FSH, LH
o Abdominal U/S to look for uterus, testicles,
ovaries
 Management:
o Avoid announcement of sex or personal
pronouns until all tests complete
o Continuous psychosocial support
o Elective surgical reconstruction of genitalia
LIPID METABOLISM
Lipids mostly C-H so insoluble in water
Types: phospholipids, steroids, glycolipids
o FAs: long chain C chain attached to COOH
o Glycerol: three hydroxyl groups
o Triglyceride: glycerol molecule with three
acyl bonds connecting to three FAs
 Lipoproteins: insoluble lipids are packaged with
apolipoproteins so can be transported in plasma
o Chylomicrons, VLDL, IDL, LDL, HDL
o Density: low  high
o Size: large  small
o TG:cholesterol ratio: high  low
 Apolipoproteins: surface receptors, co-factors for
enzymes
CHYLOMICRONS
 FA: FAs converted into TGs
 Cholesterol: acyl-CoA cholesterol acyltransferase
(ACAT) adds FA  cholesteryl ester
o Cholesteryl esters can be more tightly
packed together, more efficient transport
 Chylomicrons: synthesized in enterocytes
o Transport TGs, cholesteryl esters, vitamins
ADEK  lymph  blood stream
o Usually only present in plasma after meals
(gives milky appearance), clear 1-5h later
APOLIPOPROTEINS
 Apolipoprotein B48: found only on chylomicrons
o Contains 48% of apo-B protein
o Required for secretion of chylomicrons
from enterocytes
  In plasma, picks up C-II and Apo E from HDL
o C-II: chylomicrons, VLDL/IDL
 Co-factor required for activation of
lipoprotein lipase
o Apo E: chylomicrons, VLDL/IDL
 Binds to liver receptors
 Required for uptake of chylomicron
remnants
DELIVERY OF TRIGLYCERIDES
 Extracellular enzymes anchored to capillary walls
 Mostly found in adipose tissue, muscle, heart
o Not in liver, liver has hepatic lipase
 Converts TGs  FAs and glycerol  FAs removed
and used for storage (adipose) or fuel 
chylomicron becomes chylomicron remnant  Apo
E liver uptake via receptor-mediated endocytosis
LIVER
 1. Only liver can synthesize cholesterol
 Acetyl-CoA + acetoacetyl-CoA  HMG-CoA
synthase  HMG-CoA  HMG-CoA reductase 
mevalonate  cholesterol
 2. Liver secretes two main lipoproteins: VLDL,
HDL
HDL
 Secreted as small ‘nascent’ HDL  develop into
mature particles with A-I, C-II and ApoE (donated)
 Lecithin-cholesterol acyl transferase (LCAT):
o Esterifies cholesterol that HDL picks up
from tissues  packed densely in core
o Activated by A-I
 Cholesteryl ester transfer protein (CETP):
o Exchanges esters in HDL for TGs in VLDL
 Transports cholesterol and TGs back to liver
o “Scavenger,” “reverse transport”
VLDL and IDL
 Secreted as nascent VLDL dependent on surface B-
100  pick up C-II and ApoE from HDL
 Initially contains many TGs  LPL and CETP
removes TGs  IDL with less TGs
 Transports cholesterol and TGs to tissues
o “Transport” protein
LDL
 IDL undergoes two changes:
o Hepatic lipase removes TGs in liver
capillaries, releases FA like LPL
o HDL takes back C-II and ApoE
 LDL has only B-100, high concentration
cholesterol/esters, small amount TGs
 Transfers cholesterol to cells with LDL receptors
via receptor-mediated endocytosis
o LDL receptors recognize B-100
o Can be delivered to any tissue, but greatest
amount to adrenal cortex and gonads
FOAM CELLS
 Macrophages filled with cholesterol because
contain LDL receptors
 Found in atherosclerotic plaques
LIPOPROTEIN(A)
 Lp(a) is modified form of LDL
 Contains large glycoprotein, apolipoprotein(a)
 Elevated levels risk factor for CVD
o Not routinely measured
o No proven therapy for high levels
ABETALIPOPROTEINEMIA
 Autosomal recessive disorder
 Defect in microsomal TG transfer protein (MTP)
 MTP forms/secretes lipoproteins with apo-B
o Chylomicrons cannot be secreted from
intestine (B48)  lipids and ADEK cannot
be absorbed
o VLDL cannot be secreted from liver (B100)
 low levels of VLDL, IDL, LDL in
plasma
 Clinical features:
o Presents in infancy
o Steatorrhea, abdominal distention, failure to
thrive
o Fat-soluble vitamin deficiencies:
 E  ataxia, weakness, hemolysis
 A  poor vision
 Diagnosis:
o Low or zero VLDL/ILD/LDL, TG, total
cholesterol, vitamin E
o Peripheral blood smear: acanthocytosis
 Abnormal RBC membrane lipids
o Biopsy: lipid accumulation in enterocytes
HYPERLIPIDEMIA
LIPID MEASUREMENTS
 Total cholesterol, LDL-C, HDL-C, TG
o *Cholesterol associated with LDL or HDL
 Friedewald formula for LDL-C = total cholesterol
– HDL-C – TG/5
o If TG is normal, formula is accurate
o One of reasons ask patient to fast so TG
doesn’t increase
HYPERLIPIDEMIA
 Elevated total cholesterol, LDL TGs, or all three
 Risk factor for coronary disease and stroke
 Modifiable: smoking, obesity, hyperlipidemia from
sedentary lifestyle, dietary HIGH saturated and
trans-fatty acid foods and LOW fiber
ETIOLOGY
 Primary: genetics or obesity
 Secondary:
o Nephrotic syndrome (LDL)
o Alcohol use, pregnancy, beta blockers but
not usually significant (TG)
o Hydrochlorothiazide (TC, LDL, TG)
CLINICAL SYMPTOMS
 Most patient no sign/symptoms
 Physical findings occur in patients with severe
elevated lipids, usually familial syndromes:
 Xanthoma:
o Plaques of lipid-laden histiocytes
(macrophages)
o Appear as skin bumps or on eyelids
 Tendinous xanthoma
o Lipid deposits in tendons
o Common in Achilles
 Corneal arcus
o Lipid deposit in cornea seen on fundoscopy
COMPLICATIONS
PANCREATITIS
  Elevated TG (>1000mg/dL, normal <150)
 Mechanism unclear, may involve chylomicrons:
o Always present when TGs > 1000 
obstruct capillaries  ischemia
o Vessel damage exposes TGs to pancreatic
lipases  free FAs  acids lead to tissue
injury  pancreatitis
FAMILIAL DYSLIPIDEMIA
TYPE I
 Familial hyperchylomicronemia
 Pathophysiology:
o Autosomal recessive
o Severe LPL dysfunction, either LPL
deficiency or C-II deficiency  elevated
chylomicrons and TGs
 Clinical presentation:
o Recurrent pancreatitis
o Enlarged liver, Sx of >1000 TG
 Treatment:
o Very low fat diet
o Reports of normal lifespan with no apparent
increased risk of atherosclerosis
TYPE II – NEED MORE
 Familial hypercholesterolemia
 Pathophysiology:
o Autosomal dominant
o Mutation in LDL-R or rarely apo B100
o Few or zero LDL receptors  elevated
LDL (>300 heterozygous, >700
homozygous)
 Clinical presentation:
o Severe atherosclerosis (can have MI in 20s)
o Sx of >1000 TG
 Screening:
o Over 40 or certain conditions regardless of
age (e.g. DM, xanthomata)
 Risk assessment:
o Framingham Risk Score (FRS) limitation is
doesn’t take into account family history
 Treatment:
 Statins: competitive inhibitor of HMG-CoA
reductase
o Reduce hepatic cholesterol synthesis 
upregulate LDL receptors  increased
hepatic uptake of LDL-C from circulation
 Ezetimibe: inhibits absorption of cholesterol at
brush border of small intestine mediated by sterol
transporter, Niemann-Pick C1-Like-1
o Reduction in cholesterol delivery to liver,
increase in cholesterol clearance from
blood, and reduction in hepatic cholesterol
stores
 PCSK9: from hepatocytes, binds to LDL-R and
results in lysosomal degradation of receptor
TYPE III
 Familial dysbetalipoproteinemia
 Pathophysiology:
o Have Apo-E2 subtype of ApoE
o Poor clearance of chylomicron remnants 
accumulation of B-lipoproteins
(chylomicrons and VLDL)  elevated total
cholesterol and TGs
 Usually TG mild > 300mg/dL
 Clinical presentation:
o Premature coronary disease
TYPE IV
 Familial hypertriglyceridemia
 Pathophysiology:
o Autosomal dominant
o Associated with diabetes type II
o VLDL overproduction or impaired
catabolism  elevated VLDL and TG
(200-500)
 Diagnosis:
o Routine bloodwork in DM2
 Clinical presentation:
o Premature coronary disease
BONES
TYPES OF BONES
 Long bones: support weight and allow movement,
in legs and arms
 Flat bones: protect organs such as skull
 Short bones: wrists, ankle
 Irregular bones: vertebrae
 Sesamoid bones: embedded in tendons e.g. patella
MACROSCOPIC STRUCTURE
 Periosteum:
o Membrane covers outer surface
o Contains blood vessels and sensory nerves
 Cortical bone:
o Hard, compact bone on exterior
 Trabecular bone:
o Soft, flexible, spongy, cancellous bone on
ends of long bones
o Trabeculated (many curved spaces)  SA
 Medullary cavity:
o Contains marrow in shaft of long bones
LONG BONES
 Epiphysis (end), metaphysis (widening just before
epiphysis), diaphysis (shaft)
 Epiphysis is covered by cartilage
MICROSCOPIC STRUCTURE
CELLULAR COMPONENT
 Osteoblasts: synthesize bone matrix
o Control bone turnover
 Osteoclasts: specialized macrophages derived from
circulating monocytes
o Secrete acid, proteases dissolve bone matrix
 Osteocyte: osteoblasts buried in bone matrix
become osteocytes
o Control local calcium and phosphate levels
EXTRACELLULAR COMPONENT
 Bone matrix synthesized by osteoblasts
o 1. Osteoid: non-mineralized bone matrix,
mostly proteins
o 2. Mineralized: calcium/phosphate added
o A. Woven/primary/immature bone:
disorganized collagen fibers and weaker
 Seen in adults after injury
o B. Lamellar bone: remodeled woven bone
now layered, organized, stronger
  Major components: type I collagen,
hydroxyapatite (Ca10(PO4)6)OH2)
o 99% of body calcium and 85% of body
phosphorus found in hydroxyapatite of
bone
 A. first type of
BONE TURNOVER
 Balance between formation/breakdown modulated
by signals from osteoblasts
o Either stimulate or limit osteoclasts
 RANK
o Receptor-activating nuclear factor kB
o Receptor expressed on osteoclast surface,
only thing that osteoclasts make
o RANK-L binding  synthesis of NF-kB 
osteoclast stimulation
 RANK-L
o RANK ligand expressed by osteoblasts
 Osteoprotegerin (OPG)
o Decoy receptor for RANK-L made by
blasts
o Binds RANK-L and prevents from binding
to RANK
 Macrophage-CSF
o Made from blasts stimulates osteoclasts
BONE FORMATION IN UTERO
ENDOCHONDRAL OSSIFICATION
 Occurs during embryogenesis
 Long bones develop from hyaline cartilage secreted
by chondroblasts and chondrocytes
 1. Anlagen: cartilage mold of bone forms
 2. As mold grows, chondrocytes die, osteoblasts
from blood lay down matrix to turn into bone
 3. Lay down matrix from two places:
o Center (diaphysis): “primary centre of
ossification”
o Ends (epiphysis): “secondary centre of
ossification”
 4. Anlagen (cartilage) trapped in line, forming
epiphysial growth plate
MEMBRANOUS OSSIFICATION
 Flat bones (e.g. calvaria aka skull, facial bones)
formed from this method
 Bone matrix formed directly rather from cartilage
o Woven bone then remodelled to lamellar
GROWTH PLATE
 In long bone ends between metaphysis and
epiphysis
o Contains hyaline cartilage
 As chondrocytes grow toward epiphysis, osteoblasts
lay down matrix toward centre of bone, so growth
plate proceeds toward ends of bones
 Growth plate “closes” at puberty  epiphyseal
lines
OSTEBOLAST ACTIVITY MARKERS
 Alkaline phosphatase
o Enzyme in bone and liver
 Also placental form (PALP) seen in
some germ cell tumors
o Major protein present in bone tissue both
bound to osteoblasts and free
o Creates alkaline environment around
osteoblast for Ca deposition
 Osteocalcin
o Major non-collagen protein in bone matrix
 Type 1 procollagen
o Secreted from osteoblasts, modified
extracellularly to tropocollagen and
collagen
ACHONDROPLASIA
 Most common cause of dwarfism
 Etiology:
o Fibroblast growth factor receptor-3
(FGFR3) gain-of-function mutation
o 80% cases due to spontaneous mutation
o 20% autosomal dominant
o Homozygous stillborn, heterozygous
survive
 Pathophysiology:
o Defective endochondral ossification
o Growth factor receptor activated inhibits
chondrocyte proliferation  long bones do
not grow  short arms, legs
MUCOPOLYSACCHARIDES
 Hunter’s and Hurler’s syndromes
o Enzyme deficiency and cannot metabolize
mucopolysaccharides e.g. heparan and
dermatan sulfate
 Accumulate in chondrocytes  chondrocytes
normally degrade mucopolysaccharides 
chondrocyte death
 Short stature, malformed bones common
ACIDOSIS
 Stimulates osteoclasts
 May cause hypercalcemia from bone breakdown
 May reduce bone mineral density and osteoporosis
 Complication of some RTAs
REGULATION OF CALCIUM AND PHOSPHATE
FORMS OF CA2+ IN BLOOD
 Normally 10mg/dL
 40% bound to plasma proteins, mainly albumin
 60% ultrafilterable
o Small portion bound to anions, e.g.
phosphate, sulfate, citrate
o Free, ionized Ca ~5mg/dL and only form
that is biologically active
HYPOCALCEMIA
 Hyperreflexia, spontaneous twitching, muscle
cramps, tingling, numbness
o Decreased extracellular Ca lowers (more
negative) the threshold potential  less
inward current required to depolarize
o Increased excitability of excitable cells
including sensory, motor nerves, muscle
 Chvostek sign: twitching of facial muscles elicited
by tapping on facial nerve
 Trousseau sign: carpopedal spasm upon inflation of
BP cuff
HYPERCALCEMIA
 Constipation, polyuria, polydipsia, neurologic signs
(hyporeflexia, lethargy, coma, death)
o Decreased excitability
CHANGES TO CALCIUM CONCENTRATION
  Plasma protein: alter total Ca2+ concentration in
same direction as protein concentration
o Develop slowly  regulatory mechanisms
make correction  no change in ionized
Ca2+
 Anion concentration: alter ionized Ca2+ by
changing fraction complexed with anions (more
anions = less Ca2+)
 Acid-base abnormalities: alter ionized Ca2+ by
changing fraction bound to albumin
o Albumin can either bind H+ or Ca2+
o In acidemia, free ionized Ca increases
o In alkalemia, free ionized Ca decreases
HOMEOSTASIS
 Three organ systems: bone, kidney, intestine
 Three hormones: PTH, calcitonin, vitamin D
PARATHYROID HORMONE
 Synthesized by chief cells of PTH glands
 Structure: 84-aa single-chain polypeptide
o Biologic activity in N-terminal of 34 amino
acids
 Acute regulation: chief cells have Ca-sensing
receptors linked via G protein to phospholipase C
 IP3/Ca2+ which inhibits PTH secretion
o When 10mg/dL or higher, low basal level
o When <10mg/dL, PTH release stimulated,
reaching maximal at 7.5mg/dL
o Mg has same effects but less important;
severe Mg depletion inhibits PTH
synthesis, storage, secretion
 Chronic regulation: changes in plasma Ca2+ alter
transcription of gene for pre-proPTH, synthesis and
storage of PTH, and growth of PTH glands
o Chronic hypocalcemia causes secondary
hyperparathyroidism
 Effects:
o Bone: initial and transient bone formation;
long-term bone resorption
 Bone resorption by cytokines from
osteoblasts that increase # and
activity of osteoclasts
 Deliver both Ca and phosphate
o Kidney: 1) inhibits phosphate reabsorption
by inhibiting Na-phosphate cotransport in
PCT 2) stimulates Ca reabsorption in DCT
o Intestine: activates renal 1a-hydroxylase 
25-hydroxycholecaliferol converted to
active 1,25-dihydroxycholecalciferol 
stimulates intestinal Ca absorption
 Pathophysiology:
o Hypercalcemia, hypophosphatemia
o Increased urinary Ca can precipitate in
urine as Ca-phosphate or Ca-oxalate stones
VITAMIN D/CHOLECALCIFEROL
 Synthesized in skin from 7-dehydrocholesterol and
UV as well as directly from diet
 Structure: hydroxylated in liver to 25-
hydroxylcholecalciferol, bound to a-globulin in
plasma
o In kidney, can be hydroxylated at C1 
1,25-dihydroxycholecalciferol (active)
o OR hydroxylated at C24  24,25-
dihydroxycholecalciferol (inactive)
 Regulation: 1a-hydroxylase increased by decreased
plasma Ca or phosphate concentration, increased
circulating PTH  favor formation of active form
 Effects:
o Intestine: major actions to increase both Ca
and phosphate absorption
 Induces synthesis of calbindin D-
28K, which carries diffused
calcium to basolateral membrane
o Kidney: stimulates reabsorption of both
calcium and phosphate
o Bone: synergistically with PTH to stimulate
osteoclast activity
CALCIUM HOMEOSTASIS
PARATHYROID HORMONE
 On bone:
o Stimulates bone resorption and formation
o Dominant effect varies with dosage/timing
as well as type of bone
 Continuous administration of PTH
o Bone resorption  increased serum Ca
o Predominant effect physiologically
 Low dose OD bolus administration
o Bone formation  increased bone mass
o Teriparatide to treat osteoporosis
 Cortical bone
o Decreases in response to continuous PTH
 Trabecular bone
o Increases in response to intermittent, low
dose PTH
o Teriparatide strengthens spine because lots
of trabecular bone and head of femur
 On osteoblasts:
o Contains PTH receptors  increased bone
mass in response to PTH
 On osteoclasts:
o No PTH receptors
o Activated indirectly by osteoblasts through
M-CSF and RANK-L
ESTROGENS
 Effects on bone:
o 1) Close growth plate at puberty in both
sexes
o 2) Increase bone density
 2) inhibit and induce apoptosis of osteoclasts via:
o Stimulates OPG synthesis by osteoblasts
o Decreases M-CSF and RANK production
 Loss of estrogen at menopause  osteoporosis
HYPERCALCEMIA
 Ca is most abundant cation in body
 Role in neural transmission, enzyme activity,
myocardial function, coagulation
 Location:
o Most found in bones as Ca phosphate while
small percentage found in cells and ECF
o In plasma, 45% bound proteins, 45% free
or ionized calcium (active), 10% bound to
anions
  Regulation:
o Plasma membrane calcium receptor, PTH,
calcitonin, and actions of vitamin D. on
kidneys, bones, intestines
 Definition: serum calcium two SDs above mean
values (normal ranges from 8.8mg/dL-10.8mg/dL)
ETIOLOGY
 Primary hyperparathyroidism and malignancy
accounts for 90% of hypercalcemia
 Causes of PTH: adenoma/hyperplasia, familial
hypocalciuric hypercalcemia (autosomal dominant),
multiple endocrine neoplasia syndromes (type1,
2A)
 Malignancy: renal carcinomas, leukemias,
lymphomas
PATHOPHYSIOLOGY
 PTH:
o Mobilizes calcium directly by enhancing
bone resorption
o Indirectly by stimulation 1a-hydroxylase 
increases vitamin D3 production 
increased absorption of Ca from gut and
increased bone resorption
CLINICAL PRESENTATION
 Usually when Ca>12mg/dL
 Groans: GI symptoms e.g. pain, nausea, vomiting
 Bones: bone pain, osteoporosis, osteomalacia,
arthritis, pathological fractures
 Stones: renal stones
 Moans: fatigue and malaise
 Thrones: polyuria, polydipsia, constipation
 Psychic overtones: lethargy, confusion, depression,
memory loss
 If severe, inhibits neuromuscular and myocardial
depolarization  muscle weakness and arrhythmias
o ECG: prolonged PR, short QT, widened
QRS, bradycardia
EVALUATION
 Mild: 10.5-11.9mg/dL
 Moderate: 12-13.9mg/dL
 Crisis: 14-16mg/dL
 Workup: serum PTH, calcitonin, vitamin D, ionized
Ca, phosphorus, magnesium, alkaline phosphatase
levels, renal functions, urinary Ca-creatinine ratio
TREATMENT
 Symptomatic or Ca>15mg/dL
 Promote calcium excretion in urine with infusion of
0.9% saline at twice maintenance rate until fluid
deficit replaced and diuresis occurs
 Hemodialysis in patients with HF or renal
insufficiency
 Surgical removal of adenoma/malignancy
 Biphosphonates (e.g. etidronate) for hypercalcemia
of malignancy as they inhibit osteoclastic activity
 Hypercalcemia associated with excess vitamin D
can be treated with steroids as they inhibit 1a-
hydroxylase
HYPOCALCEMIA
 Without
ETIOLOGY
 Without
PATHOPHYSIOLOGY
 Without
CLINICAL PRESENTATION
 Without
EVALUATION
 Without
TREATMENT
 Without
PROLACTIN
 Synthesized by lactotrophs
o Number of lactotrophs increases during
pregnancy and lactation
 Structure: 198 aa in single-chain polypeptide with
3 internal disulfide bridges
 Regulation: by altering transcription of prolactin
gene
o From hypothalamus, dopamine inhibits and
TRH stimulates
 Inhibitory effect of dopamine
overrides stimulatory effect of TRH
 Normally prolactin inhibited
o Prolactin stimulates hypothalamus to make
more dopamine
o Stimuli: pregnancy and breast-feeding
DOPAMINE
 1) major source is dopaminergic neurons in
hypothalamus  median eminence 
hypothalamic-hypophysial portal vessels
 2) dopaminergic neurons of posterior lobe of
pituitary  short connecting portal veins
 3) nonlactotroph cells of anterior pituitary 
diffuse
EFFECTS
 Breast development:
o At puberty, stimulates proliferation and
branching of mammary ducts
o At pregnancy, stimulates growth and
development of mammary alveoli
 Lactogenesis:
o Stimulates milk production and secretion in
response to suckling
o Induces synthesis of components of milk
including lactose, casein, lipids via
transcription of enzymes in that pathway
o Does not occur until parturition because
estrogen and progesterone in pregnancy
downregulate prolactin receptors
 Inhibit ovulation:
o Inhibit synthesis and release of GnRH
o F: decreased fertility during breast-feeding
PATHOPHYSIOLOGY
 Excess prolactin:
o Galactorrhea, gynecomastia
o Amenorrhea, infertility in males due to
decreased GnRH  decreased
spermatogenesis
GASTRIN
 Synthesized by G cells in antrum of stomach
  Structure: 17-aa straight chain peptide (little
gastrin) after meal vs. 34-aa (big gastrin) in
interdigestive
o Minimum fragment needed for activity is
C-terminal tetrapeptide, 1/6 as active as
gastrin
 Regulation:
o Stimuli: products of protein digestion (esp.
phenylalanine and tryptophan), distention
of stomach by food, vagal stimulation
(GRP)
o Inhibit: low pH of gastric contents and
somatostatin
EFFECTS
 Stimulates H+ secretion from parietal cells
 Stimulates growth of gastric mucosa
PATHOPHYSIOLOGY
 Zollinger-Ellison syndrome:
 Gastrinoma in pancreas/duodenum
 Increased H+ secretion, hypertrophy of gastric
mucosa, duodenal ulcers
 Acidification of intestinal lumen  inactivates
pancreatic lipase  dietary fats not adequately
digested or absorbed
MEN SYNDROMES
 Multiple endocrine neoplasia
 Rare genetic disorders
 Autosomal dominant germline mutations
 MEN1, 2A, 2B
MEN 1
ETIOLOGY
 Germline mutation of MEN1 gene (11q13) codes
for menin, tumor suppressor
 Patients born with 1 abnormal MEN1 gene, second
hit occurs in endocrine glands
o 3 P’s: pituitary adenoma, parathyroid
adenoma, pancreatic tumours
CLINICAL PRESENTATION
 Parathyroid adenoma: first in 90%, occurs in 94%
o Will present as hyperparathyroidism (often)
detected when asymptomatic
o May cause recurrent kidney stones
 Pituitary adenoma: occurs in up to 70%
o Mostly commonly prolactinoma
o Second common GH-secreting adenoma
o Not seen in other MEN syndromes
 Pancreatic-duodenal neuroendocrine tumors:
o Neuroendocrine = release hormones
o Most commonly gastrinomas
 Zollinger-Ellison syndrome:
multiple peptic ulcers
o Rarely insulinomas, glucagonomas,
VIPomas
DIAGNOSIS
 Clinically:
o Two or more primary MEN1 tumor types
(PTH, anterior pituitary, enteropancreatic)
o If family member, occurrence of one tumor
 DNA testing:
o Germline MEN1 mutation if clinical
diagnosis unclear or asymptomatic family
member
o Controversy: dearth of robust data showing
that preclinical detection of MEN1-related
improves morbidity or mortality
SCREENING
 Family members of person diagnosed
 1. Test MEN1 gene usually from peripheral blood
or buccal cells of index case
 2. Test pathologic mutation in at-risk relatives
 3. Regular surveillance of family with mutation
o Signs and symptoms: nephrolithiasis,
amenorrhea, galactorrhea, growth
abnormalities, etc.
o Bloodwork: serum calcium, PTH, prolactin
o Imaging: conservative, often initially
enteropancreatic neoplasia + endoscopic
US
 Serum calcium is DNA alternative because high
penetrance of hyperparathyroidism in MEN1
TREATMENT
PARATHYROID TUMOURS
 Indications for surgery: symptomatic or marked
hypercalcemia, nephrolithiasis, evidence of bone
disease such as bone density or fracture, severe
PUD or other Sx caused by gastrinoma
 Asymptomatic: surgery for any of the indications
 Three and one-half gland parathyroidectomy
PITUITARY ADENOMA
 Indications: neurologic symptoms due to large size,
hypogonadism or other Sx due to
hyperprolactinemia, women with mild
hyperprolactinemia and normal cycles who are
trying to conceive
 Dopamine agonists are first-line
o Decrease serum prolactin concentrations
and decrease size of most lactotroph
adenomas
o Cabergoline first, bromocriptine second
ENTEROPANCREATIC TUMOURS
 Based one efficacy of treatment for previous, these
are the primary life-threatening parts of MEN1
ZOLLINGER-ELLISON
 Medical: PPI such as omeprazole or lansoprazole to
inhibit acid secretion
 Surgery: controversial but generally favor when
>2cm
 Gastric resection last resort
INSULINOMA
 Local excision of any tumors found in head of
pancreas plus distal subtotal pancreatectomy
MEN 2A AND 2B
 Etiology:
 Germline mutations in RET (10), codes for receptor
tyrosine kinase, proto-oncogene
 Gain-of-function for cell growth/differentiation
 Clinical presentation:
 “Medullary” tumors
o Medullary thyroid carcinoma (MTC)
~100% over lifetime, earlier than sporadic
cases
 Sporadic: 60s; MEN: 30s
 o
Pheochromocytoma (adrenal medulla)
usually occurs after MTC
 Medullary thyroid carcinoma:
o Cancer of parafollicular C cells
o Calcitonin normally has minimal effect on
Ca, but with malignancy  hypocalcemia
 MEN 2A:
o Medullary tumors + PTH adenoma
o No physical findings
 MEN 2B:
o Medullary + M’s (two phenotypic findings)
o Usually no PTH involvement
 #1: mucosal neuromas
o Benign growth of nerve tissue
o Often lips tongue
o Sometimes intestinal neuromas
 #2: marfanoid body habitus
o Tall, long wing span
o High arched palate
o Skeletal deformations of spine:
 Kyphoscoliosis (L/R) or lordosis
(forward)
o No lens or aortic involvement so ‘like’
THYROIDECTOMY
 Often done prophylactically in MEN2 syndromes at
young age (<5 years)

PARATHYROID HORMONE

FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without
FEMALE
 Without

Go look for the adenoma please: any pituitary hormone will

result in deficient hormones in this following order: GRH,
LH, FSH, TSH, ACTH, prolactin. From mass effect. If lose
everything then panhypopituitarism. Patients die of adrenal
insufficiency so want to find it before that.

Three main effects of pituitary adenomas: hormonal

hyperfunction (more likely microadenoma), hormonal
hypofunction (more likely macroadenoma), space-
occupying effects (e.g. headache, optic chiasm, etc.)