Endocrine Pathology Kristine Krafts, M'D' November 18

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Endocrine PathologyKristine Krafts,
M.D.November 18 19, 2008
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Endocrine pathology in a nutshell
problem up here
problem down here
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Endocrine pathology in a nutshell
Problem too much too little
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Endocrine Pathology

• Organs
• Pituitary
• Thyroid
• Parathyroids
• Adrenals
• Pancreas

Diseases Non-neoplastic ? too much hormone ?
too little hormone Neoplastic ? benign ?
malignant
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Pituitary

• Introduction
• Hyperpituitarism
• Hypopituitarism

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Pituitary Introduction

• Anterior pituitary (adenohypophysis)
• GH, ACTH, TSH, LH, FSH, and prolactin.
• Controlled by hypothalamus.
• Most problems happen here.

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What happens to pituitary hormone output if you
cut off hypothalamic input?
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? prolactin ? all other hormones
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Pituitary Introduction

• Posterior pituitary (neurohypophysis)
• oxytocin, ADH (vasopressin)
• hypothalamus makes them
• posterior pituitary stores them

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Pituitary Introduction

• Oxytocin
• labor
• milk let-down
• cuddling (after orgasm)
• monogamy (vole studies)
• trust (investment experiment)
• female bonding (UCLA study)

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www.verolabs.com
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Hyperpituitarism

• Definition too much anterior pituitary
  hormone(s)
• Most common cause pituitary adenoma
• Pituitary adenoma symptoms
• None, for a while
• Endocrine abnormalities
• Mass effects
• Many types

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Hyperpituitarism
Growth Hormone Adenoma

• Produces gigantism or acromegaly
• Other findings
• diabetes mellitus
• hypertension
• arthritis
• gastrointestinal carcinoma
• Lab findings
• ? GH (spurts)
• ? IGF-I (better)
• GH unresponsive to glucose

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Hyperpituitarism
Other Pituitary Adenomas

• Prolactinoma
• ACTH-producing
• FSH-LH-producing
• TSH-producing
• Non-functioning

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Hypopituitarism

• Definition too little anterior pituitary
  hormone(s)
• Causes
• Pituitary destruction
• Ischemic necrosis
• Pituitary apoplexy
• Symptoms usually insidious
• Dwarfism
• Loss of libido, menstrual abnormalities
• Hypothyroidism
• Adrenal insufficiency

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Sponge Bob, why is panhypopituitarism so rare?
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Why, Clucky, its because the pituitary has such
a big reserve!
Sponge Bob, why is panhypopituitarism so rare?
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Thyroid Pathology
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Thyroid

• Introduction
• Hyperthyroidism
• Hypothyroidism
• Non-neoplastic diseases
• Neoplasms

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TRH
2
TSH
hormone synthesis
thyroid growth
1
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• Most thyroid hormone is bound.
• Only the free form is active!
• Thyroid hormone
• binds to nuclear receptors
• changes gene expression
• increases carb and fat breakdown
• stimulates protein synthesis
• Result increased basal metabolic rate.

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TSH
T4
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Endocrine pathology in a nutshell
problem up here
problem down here
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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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TSH
low
normal
high
primary hypothyroidism
2 or 3 hypothyroidism
low

subclinical hyperthyroidism
subclinical hypothyroidism
T4
normal
euthyroidism
2 or 3 hyperthyroidism
primary hyperthyroidism
high

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A hypermetabolic state caused by ? thyroid
hormones.

• cardiac rapid pulse, arrythmias
• neuromuscular tremor, emotional lability
• eye lid lag
• skin warm, moist
• gastrointestinal diarrhea
• skeletal osteoporosis
• thyroid storm ??? thyroid hormone

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A hypometabolic state caused by ? thyroid
hormones.

• slowing of mind and body
• myxedema deepened voice
• cardiac slow pulse
• gastrointestinal constipation
• skin dry, cool, pale
• cold intolerance
• delayed reflexes
• myxedema coma

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• iodine deficiency or genetic problems.
• symptoms are mild to severe
• treatment thyroid hormone replacement
• prevention better

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Definition Inflammation of the thyroid

• Hashimoto thyroiditis
• DeQuervain thyroiditis
• Lymphocytic thyroiditis
• Fibrosing thyroiditis

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Definition Inflammation of the thyroid

• Hashimoto thyroiditis
• Commonest cause of hypothyroidism in US!
• FgtgtM
• Autoimmune destruction of gland

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• Mrs. Potatohead
• female
• hash
• myxedema?

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Definition Inflammation of the thyroid

• Hashimoto thyroiditis
• DeQuervain thyroiditis
• Recent URI
• Self-limiting

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• Rex
• looks scary
• really harmless
• goes away by itself

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Definition Inflammation of the thyroid

• Hashimoto thyroiditis
• DeQuervain thyroiditis
• Silent thyroiditis
• Post-partum or middle age
• Mild symptoms

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• Bullseye
• silent
• doesnt cause problems

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Definition Inflammation of the thyroid

• Hashimoto thyroiditis
• DeQuervain thyroiditis
• Lymphocytic thyroiditis
• Fibrosing thyroiditis
• Rock-hard neck mass
• Can compress trachea

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• Woody
• woody.

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• Common autoimmune disease!
• Triad
• Hyperthyroidism
• Ophthalmopathy
• Dermopathy
• Anti-TSH receptor antibodies
• Stimulate thyroid growth
• Cause T4 release
• React with retro-orbital tissues, skin of legs

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• Goiter general term for a big thyroid gland
• Latin guttar (throat)
• Cause defective T4 synthesis.
• iodine deficiency (endemic)
• other defects (sporadic)

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• no iodine

? T4
? TSH
enzyme defects
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• Most neoplasms present as nodules.
• Nodules are common!
• Most are benign.
• Thyroid carcinoma is uncommon.

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biopsy or FNA
cancer
follicles
thyroiditis
take it out!
treat it!
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• Common!
• Most patients are euthyroid (some are
  hyperthyroid)
• Radioactive iodine uptake most adenomas are
  cold

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Thyroid adenoma
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Thyroid adenoma
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Thyroid adenoma
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• Take it out!
• Why, if its benign?
• Need to see the whole tumor (including capsule )
  to make sure its not carcinoma

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• Papillary thyroid carcinoma
• Follicular thyroid carcinoma
• Medullary thyroid carcinoma
• Anaplastic thyroid carcinoma

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• Papillary thyroid carcinoma
• Most common
• Best prognosis
• Orphan Annie tumor

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Papillary thyroid carcinoma
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Papillary thyroid carcinoma
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Papillary thyroid carcinoma
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Papillary thyroid carcinoma
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Papillary Carcinoma The Little Orphan Annie Tumor

• often affects younger women
• tends to stay around for years without getting
  any bigger
• is usually well-behaved seldom kills
  people
• has nuclei that resemble Orphan Annies eyes
• has psammoma bodies (from the greek psammos, or
  sand) - Annies dog is named Sandy

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• Papillary thyroid carcinoma
• Follicular thyroid carcinoma
• 2nd most common
• Good prognosis

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Which one is follicular carcinoma?
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• Papillary thyroid carcinoma
• Follicular thyroid carcinoma
• Medullary thyroid carcinoma
• Rare
• Endocrine tumor
• Bad prognosis

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Medullary thyroid carcinoma
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• Papillary thyroid carcinoma
• Follicular thyroid carcinoma
• Medullary thyroid carcinoma
• Anaplastic thyroid carcinoma
• Rare
• Bulky, fast-growing, metastatic at diagnosis
• Very bad prognosis

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Medullary thyroid carcinoma
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Parathyroid Pathology
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• Introduction
• Hyperparathyroidism
• Hypoparathyroidism

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• Four glands in two pairs
• Upper pair from fourth branchial cleft,
• descends with the thyroid
• Lower pair from third branchial cleft,
• descends with the thymus
• 3-4 mm, 35 mg each
• Secrete parathormone (PTH)

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Parathyroid
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• PTH raises serum calcium
• PTH release controlled by serum calcium
• Several actions
• stimulates osteoclasts
• ? renal reabsorption of calcium
• ? absorption of dietary calcium.

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Causes of hypercalcemia

• Hyperparathyroidism
• Malignancy
• mets
• PTH-related protein
• Vitamin D overdose
• Thiazide diuretics
• Milk-alkali syndrome

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Causes of hypercalcemia

• Hyperparathyroidism
• Malignancy
• mets
• PTH-related protein
• Vitamin D overdose
• Thiazide diuretics
• Milk-alkali syndrome

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• Causes of hypercalcemia MD PIMPS ME
• Malignancy
• Diuretics
• Parathyroid (hyperparathyroidism)
• Idiopathic
• Megadose of vitamin D
• Pagets disease
• Sarcoidosis
• Milk-alkali syndrome
• Endocrine (thyrotoxicosis)

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• Common! (2.5 cases per 1000)
• Most common cause parathyroid adenoma
• Symptoms
• asymptomatic!
• stone kidney stones, other stones
• bone pain, brown tumors
• groan gastrointestinal problems
• moan mental changes

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Parathyroid adenoma
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Bone changes in hyperparathyroidism
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Bone changes in hyperparathyroidism
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Brown tumor
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Dental changes in hyperparathyroidism

• Loss of lamina dura
• Alveolar bone demineralization
• Brown tumors

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Demineralized maxillary bone, loss of lamina dura
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Osteitis fibrosa cystica
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• Uncommon!
• Causes
• Iatrogenic
• Congenital absence
• Idiopathic atrophy
• Familial
• Symptoms
• tetany (perioral numbness)
• other changes

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Enamel hypoplasia
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Adrenal Pathology
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• Introduction
• Too much stuff
• Too little stuff
• Tumors

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• two glands
• upper pole of kidneys
• 4 g each
• cortex (three zones)
• medulla

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• Cortex
• Zona glomerulosa (mineralocorticoids)
• Zona fasciculata (glucocorticoids)
• Zona reticularis (sex steroids)
• Salt, sugar, sex.
• The deeper you go, the sweeter it gets.
• Medulla
• (epinephrine/norepinephrine)

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Adrenal gland
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• Too much glucocorticoids
• Causes
• Ingested steroids
• Adrenal adenoma
• Pituitary adenoma
• Paraneoplastic syndrome
• Symptoms
• Hypertension, weight gain
• Characteristic habitus
• Glucose intolerance

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Cushing syndrome
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• Too little cortisol and mineralocorticoids
• Primary chronic adrenal insufficiency
• Cause usually autoimmune
• Symptoms
• Slow onset (need to destroy 90 of cortex!)
• Weakness, fatigue, GI complaints
• Hypotension
• Skin hyperpigmentation

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M.J. 33 y/o female

• Previously healthy 33 y/o female, who began
  having symptoms fatigue, skin bronzing, weight
  loss, salty food cravings
• Wednesday
• Headache
• Thursday
• Very fatigued, vomiting
• Saturday
• Husband brought to ER
• Vision loss right eye
• IV fluids unhelpful

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• Sunday
• Right side paralyzed
• Oxygen levels dropping
• CT brain swelling
• Coma
• BP 70/33
• Given IV fluids, respirator
• 40 pound weight gain
• Tuesday
• No brain activity, kidneys
• shutting down
• Nothing else can be done

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• Thursday
• Different doctor
• IV Na, hydrocortisone, dextrose
• Saturday
• Opened eyes
• Sunday
• Started removing IVs
• Next weeks
• Removed feeding tube
• Speech, physical, occupational
• therapy

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• Two months later
• Back to work
• Feeling normal
• Cortisol and prednisone
• daily, for life
• Carry crisis kit
• (hydrocortisone)

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M.J. 33 y/o female

• Previously healthy 33 y/o female, who began
  having symptoms fatigue, skin bronzing, weight
  loss, salty food cravings
• Wednesday
• Headache
• Thursday
• Very fatigued, vomiting
• Saturday
• Husband brought to ER
• Vision loss right eye
• IV fluids unhelpful

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• Sunday
• Right side paralyzed
• Oxygen levels dropping
• CT brain swelling
• Coma
• BP 70/33
• Given IV fluids, respirator
• 40 pound weight gain
• Tuesday
• No brain activity, kidneys
• shutting down
• Nothing else can be done

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• Thursday
• Different doctor
• IV Na, hydrocortisone, dextrose
• Saturday
• Opened eyes
• Sunday
• Started removing IVs
• Next weeks
• Removed feeding tube
• Speech, physical, occupational
• therapy

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• Bacterial infection (N. meningitidis)
• Hypotension, shock
• DIC
• Massive, bilateral adrenal hemorrhage
• Rapidly progressive

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• Neoplasm of catecholamine-producing cells
• Rare cause of hypertension!
• Urine catecholamines, VMA and metanephrines
• The 10 tumor!
• 10 extra-adrenal (paraganglioma)
• 10 bilateral
• 10 familial (MEN)
• 10 bad (malignant)

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Pheochromocytoma
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Pheochromocytoma
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Pheochromocytoma
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• Derived from neural crest cells
• Relatively common childhood tumor
• Genetic features
• 1p deletion
• N-myc amplification

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Neuroblastoma
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Neuroblastoma
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Diabetes
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• Common, common, common!
• 100 million worldwide have it (3 of the world)!
• 13 million in US have it (only half diagnosed)!
• 54,000 die in US each year (7 cause of death)!
• Lifetime risk of getting diabetes up to 5!

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• A disease in which the body does not produce or
  properly use insulin
• Primary vs. secondary
• Primary type 1 vs. type 2
• Pathogenesis different, but end result same

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• All have in common

not enough insulin.
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• Problem not enough ß cells
• Lots of susceptibility genes, one in MHC II
  region
• MHC II antigen abnormal
• T cells attack islets
• Slow, persistent attack

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• Problem cant make enough insulin, and tissues
  cant use insulin properly
• Probably lots of contributory genes
• Deranged insulin secretion
• Insulin resistance

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• Non-enzymatic glycosylation
• glucose attaches itself to proteins, forming AGEs
  
• AGEs crosslink, trap stuff
• AGEs bind to receptors, do nasty stuff
• Intracellular hyperglycemia
• some cells take up the glucose without insulin
• cells swell, ion pumps get damaged
• nerves, lens, kidney, vessels injured in this way

advanced glycosylation end-products
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• Increased infections
• Microangiopathy
• Retinopathy
• Nephropathy
• Neuropathy

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• Increased infections
• Oral (and other) candidiasis
• Malignant otitis externa

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Oral candidiasis
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Malignant otitis externa
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• Increased infections
• Microangiopathy
• accelerated, severe atherosclerosis
• increased permeability

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Atherosclerosis aorta
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Atherosclerosis coronary vessels
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Peripheral vascular disease
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• Increased infections
• Microangiopathy
• Retinopathy
• retinopathy
• cataracts
• glaucoma

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• Increased infections
• Microangiopathy
• Retinopathy
• Neuropathy
• peripheral neuropathy
• motor, sensory

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• Increased infections
• Microangiopathy
• Retinopathy
• Neuropathy
• Nephropathy
• glomerular lesions
• vascular lesions
• pyelonephritis

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Glomerular lesions
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Fungal bladder infection
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MEN Syndromes
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Brad Pitt vs. John Cleese
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No contest!
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• genetic disorders
• predispose to endocrine tumors
• MEN-1 and MEN-2

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MEN tumors are worse!

• younger
• multiple organs
• multifocal
• hyperplasia
• aggressive

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• Parathyroid hyperplasia
• Pancreatic carcinoma
• Pituitary adenoma
• Other stuff

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• mutation in MEN1 gene
• MEN1 encodes menin
• classic tumor suppressor gene

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MEN-1

• Pit
• MEN gene
• Run-of-the-mill
• Inactive

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• Medullary thyroid carcinoma
• Pheochromocytoma
• Parathyroid hyperplasia
• Other stuff

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• RET mutation
• Proto-oncogene ? oncogene
• Tyrosine kinase receptor
• Constitutively activated
• Unusual!
• Genetic testing required

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MEN-2

• Cleese-cell hyperplasia
• bRETon gene
• one-of-a-kind
• always turned on