Endocrine Pathology
Crines… Molecular signaling
Autocrine Paracrine
Endocrine
Endocrine Pathology Endocrine Pathology
Cell signaling system Too much hormone activity Surface receptors Too little hormone activity cAMP and tyrosine kinase system Autoimmune destruction Cytoplasmic receptors Inflammatory destruction Penetrate cell membrane Tumor or vascular destruction Gene activation -> transcription -> translation Space occupying lesions (tumors) Intranuclear receptors Malignant Gene activation -> transcription -> translation Benign
1 Endocrine Pathology Endocrine Pathology
All parts of the endocrine system interconnect. All parts of the endocrine system interconnect
Pituitary Pathology
Too much Too little
Especially space occupying lesions
The Basics Pituitary Vascular
Signaling proteins Anterior are release in hypothalmus. Comes from GI Travel by blood to Controlled by hypothalmus anterior pituitary Cause release of Posterior many activating Hormones orginate hormones further up. System of amplification
2 Pituitary Control
Space Occupying Lesions
Tumors
Embryonic rests
Squeeze gland out of existence.
Generalized failure
Visual field changes
Visual Fields
Loss of temporal fields.
Nasal retina
Damage to decusating optic nerve fibers
3 Acromegaly Pituitary Adenomas
Rare Growth hormone excess after closing Make nothing or of epiphyses. Prolactin Periosteal bone ACTH, GH,TSH are very rare growth.
More often end up with pituitary Diabetes failure. Prognathism
Squeeze the daylights out of the gland.
Hypopituitarism Craniopharyngioma
Destruction of gland.
Ischemia
‘Benign’ adenoma destroying gland
Craniopharyngioma
Rathke’s pouch remenant
Benign cyst, but really in the wrong place.
Ischemic Destruction Sheehan’s Syndrome
Sheehan’s syndrome
Post delivery problem
No lactation
In time general failure of ‘downstream’ systems
Ovulation
Loss of ADH
Diabetes insipidis
Dose not make concentrated urine
Large volumes of dilute urine
Head injuries
Tumors of periventricular area
Control of Thyroid Hormone
Thyroid Disease Hypothalmus Pituitary
Thyroid
Tissue level
Establishes metabolic rate for the whole organism
Laboratory Measurement
Be sure the values fit the clinical story. Repeat if necessary. TSH T4 Total Free FTI Approximates Free T4 T3RU Binding sites T3 RIA Anti-thyroid antibodies
5 Total T4 is of little value Available binding sites
Most T4 is protein bound Be sure the values fit the clinical story. Circulating storage Repeat if necessary. 99% bound TSH T4 1% free and available for Total metabolism Free FTI Free T4, this is it Approximates Free T4 Computed, no label Change in protein changes T3RU (resin uptake) total, but not free Measures binding sites T3 RIA Pregnancy, total is up Free T3 Liver disease, total is down Anti-thyroid antibodies They are euthyroid
T3RU tried to take binding sites into account Attempted Fix was the T 7
Here serum protein T 7 or FTI (free thyroxin index) content changed Total T4 X T3RU = T 7 Changed number of T4 FTI closely followed free T4 binding sites Today we measure Free T4 Total T4 changed to Not always where we start make up for extra sites
Free T4 did not
All are euthyroid
See the problem?
Hyperthyroidism
Clinical findings Heat intolerance Tremor Tachycardia Hyperactive Increased body metabolism and temperature Ocular changes Main causes Graves Disease Toxic goiter Toxic adenoma
6 Hyperophthalmia
Grave’s disease Antibody stimulates TSH receptors in extraocular muscles. Increased tissue in orbit causes eye to protrude. Won’t go down Dry conjunctiva and increased risk of eye infections.
Hyperthyroidism People Share
Clinically hyperthyroid
Low TSH
High or above normal T4
No thyroid enlargement
No tenderness
No masses
Struma Ovari Hypothyroidism
Genetics Gland destruction Inflammatory Surgical removal Radiation treatment for hyperthyroidism Iodine deficiency Can’t make T4 Hypothalmic and/or pituitary failure
7 Hypothyroidism Cretinism
Genetics: Cretinism
Cannot make T4
Growth retarded
Severe mental retardation
Must recognize early
Hypothyroidism Hypothyroidism
Clinical
Cold intolerance
Bradycardia Heart failure
High lipids Lethargic
Photophobia
Myxedema Skin and hair changes
Tumor(ous) Enlargement
Excess growth True neoplasm
Benign
Malignant
Cell type Activity and TSH response?
8 Tumors and Changes in Size Goiter
Nodular
Uniform increase
Scarring
Cysts
Generally euthyroid
May cause airway compression
Goiter Mutlinodular Goiter
Thyroid Nodules
Radioactive iodine injection then scan the gland.
‘Cold Nodule’ ‘Hot Nodule’
9 Thyroid Adenomas Thyroid Adenoma
Benign Benign
Solitary Three features
Common Encapsulatd Compression of Encapsulated surrounding tissue Generally not Different from the rest hyperactive of the gland
Malignancies of Thyroid Origin
Arising from follicular cells
Papillary Carcinoma
Follicular Carcinoma
Mixed pattern
Interstitial cells (Calcitonin producing cells)
Anaplastic, who knows
Very aggressive tumor
Papillary Carcinoma
Papillary groups May have multiple sites Not actively producing T4 Readily treated Spread Nodes Lung Bone Brain
10 Psamommoma Bodies Papillary Carcinoma
Orphan Annie Nuclei
Needle aspirates
Open eyed Little Orphan Annie debuted in the special pink edition nuclei of the New York Daily News on August 5, 1924. Harold Gray injected his own conservative beliefs into indicative of his strip. Little Orphan Annie was highly motivated, fiercely independent, minded her own business, and papillary ca believed in action. In the years that followed, Gray created a family for Annie by introducing "Daddy" Warbucks in 1924 "Daddy" Warbucks and Harold Gray were diagnosed with cancer in 1967, and while "Daddy" beat it, Gray died of cancer on May 9, 1968 after a 44-year career of drawing and writing one of the world's greatest newspaper comic strips, Little Orphan Annie.
Follicular Carcinoma
Sometime hard to distinguish from adenoma.
Capsular invasion
Vascular invasion
11 C Cell Carcinoma C Cell Carcinoma
Interstitial cells Makes calcitonin Makes amyloid Beta pleated sheet protein Often part of a multiple endocrine neoplasia syndrome
Inflammatory Conditions
Autoimmune Viral
Bacterial
Hashimoto’s Thyroiditis Hashimoto’s Thryoiditis
Many antibodies T & B cells Active germinal centers Women 5:1 Scarring In time hypothyroid Other autoimmune Arthritis PA Lupus Addison’s
12 Hashimoto’s Thryoiditis Hurthle Cells
Reidel’s Struma (Thyroiditis) De Quervain’s Thyroiditis
Super scaring Subacute Neck structures Giant cells Airway trapped Granulomas Viral? Destroyed Painful neck parathyroids
Parathyroid
Come from the pharyngeal pouches Most of us have 4
Make PTH
Mobilizes calcium
Released by low serum calcium
High serum phosphate
13 Forms of Serum Calcium
Hyperparathyroidism
Primary
Parathyroid adenoma 80%
Hyperplasia 10-15% Parathyroid ca <5%
Hypercalcemia
Stones, bones, abdominal groans and psychic moans
Bone wasting Generalized Osteoitis fibrosa cystica
Parathyroid Adenoma
14 Secondary Hyperparathyroidism
Renal failure almost always
Phosphates build up in the blood.
Cause calcium to drop.
PTH is made
Phosphate itself can cause release of PTH
Glands begin to function autonomously
Non PTH Driven Hypercalcemia
Osteolytic bone mets
Osteoclast activation
Multiple myeloma
Vitamin D Intoxication
Hypoparathyroidism
Increased neuromuscular excitability May lead to tetany Irritability and possibly even psychosis Parkinson-like symptoms Cataracts Causes Autoimmune destruction Accidental removal with thyroid Congenital absence
15 Pseudohypoparathyroidism
End-organ insensitivity All tissues Skeletal abnormalities Labs Low calcium, High phosphate High PTH Look for low urinary cAMP Pseudopseudohypo…. Physically look like this, but no hormonal abnormality
Calcium and PTH together
Endocrine Pancreas
16 Diabetes Mellitus Beta Cell Insulin Release
Chronic disease
Carbohydrates
Fats Amino acids
Small vessel disease
AGE proteins
DM 1
DM 2
Monogenic (rare)
Insulin Action Diabetes, Many Possibilities
Insulin response
Absent beta cells
End-organ response
Diabetes Mellitus
Chronic disease
Carbohydrates
Fats Amino acids
Small vessel disease
AGE proteins
DM 1
DM 2
Monogenic causes
17 Type 2 Diabetes AGE Proteins
Structural proteins Obesity Leaky membranes Insulin resistance Crosslinking Liver a special problem LDL entrapment because of gluconeogenesis Signally proteins FFA Smooth muscle cell growth Inflammation Neovascularization Insulin potentiates Increased production Adipokines of extracellular PPAR material.
18 Intracellular High Glucose
Sorbitol production
Use up the NADPH
Cannot regenerate glutathione
Oxidative damage
Sorbitol is also an osmotic force.
Nerve swelling and entrapment
Diabetic Neuropathy Diabetic Neuropathy
Vascular
Sorbitol
Sensory
DM Nephropathy
19 Osmotic Force and Blood Brain Barrier Dr. Joseph Bell and Sir Arthur Conan Doyle
Diagnosis and Follow-up
Ketoacidosis
Random BS >200 mg%
Fasting BS > 126 mg%
GTT
Monitoring
Regular BSs Hbg A1c
Urine for microalbuminuria
Good ocular exam
Pancreatic Islet Cell Tumors Extrapancreatic Gastrinomas
Benign or malignant Hormone depends on cell of origin Beta cell, insulin secreting Hypoglycemic episodes Delta cell, Zollinger- Ellison syndrome Gastrin secreting Intractable ulcers Alpha cell adenoma Glucagon secreting Become diabetic
20 Adrenal Gland Adrenal Pathology
Really two glands in Same as for all one. Too much Cortex -> Too little Salt Sugar Tumors Sex
Medulla Epinephrine Norepinephrine
Cushing Syndrome Cushing Syndrome
Effects of too much cortisol Moon face Central obesity Buffalo hump Osteoporosis Fractures Hypertension Weakness Endogenous or exogenous streroids.
21 Cushing Disease Serum Cortisol Levels
Altered feedback regulation at level of hypothalmus and pituitary It only takes a small increase in ACTH Loss of cortisol diurnal cycle Pituitary adenoma Ectopic ACTH Small cell carcinoma of lung Adrenal tumors autonomously functioning
Cushing Syndrome Diagnosis
Syndrome vs. Disease Urinary Free Cortisol (UFC) AM and PM blood levels Loss of Diurnal variation Serum ACTH level Dexamethasone Suppression Test High Dose: 2 mg q6h X 2-3 days (adenoma) Various modifications An option: CRH stimulation test Problems of interpretation: Alcoholism & liver ds, depression, exogenous, neoplastic source of ACTH
High Dose Suppression Results
22 Cushing Disease Hyperaldosteronism
Conn syndrome Adenoma (65% of the time) causing high blood pressure. Over production of aldosterone Zona glomerulosa Minnmal ACTH control Angiotensinogen II Serum K + Retention of Na+ Urinary loss of K+ Serum alkalosis
Conn Syndrome
Congenital Defect Congenital Enzyme Deficiency
A number of possibilities, but 21-beta-hyroxylase is most common. Salt losing Androgenizing
23 Ambiguous Genitalia
Hypoadrenalism Waterhouse-Fridericshen
Acute loss vs. Chronic Pituitary vs. adrenal
Acute Waterhouse-Fridericshen syndrome -> Overwhelming infection with encapsualted bacteria. Leads to vascular infection. Hemorrhagic destruction of adrenal glands Medical crisis
Addison’s Disease
Slowly develops Loss of adrenal glands
Lots of ACTH, but nothing it can do. Metastatic tumor
TB
Clinical Weight loss Hypotension Hyperpigmentation
24 Addison’s Disease Adrenal Medulla
Pheochromocytoma Catacholamines Elevated blood pressure Syncopal episodes Headaches Nose bleeds Anxiety Maybe an isolated tumor or part of a multiple endocrine tumor syndrome.
Pheochromocytoma
Gustav Klimt (1862- 1918): Bildnis Amalie Zuckerkandl (unvollendet), 1917/18 Wien, Österreichische Galerie
16 Month Old Girl
25 Horner Syndrome Neuroblastoma Interruption of the sympathetic nerve supply to the eye Classic triad of Miosis (ie, constricted pupil), Partial ptosis, and Loss of hemifacial sweating (ie, anhidrosis) Sympathetic innervation to the eye consists of a 3-neuron arc. First-order fibers descend from the ipsilateral hypothalamus through the brain stem and cervical cord to T1/T2. Fibers synapse on ipsilateral preganglionic sympathetic fibers, exit the cord, travel to the sympathetic chain as second-order neurons to the superior cervical ganglion, and then synapse on postganglionic sympathetic fibers. The third-order neurons travel via the internal carotid artery to the orbit and innervate the (dilator) radial smooth muscle of the iris.
Neuroblastoma Neuroblastoma
Urinary HVA
Online translation
A bird in the hand is worth two in the bush.
English -> German -> French -> English
A bird in the hand is worth of both in the shrub.
26 Multiple Endocrine Neoplasia, MEN
Neural crest derivative cells Give rise to hormonally active tissue
Migrate from the neural crest to many organs Anterior pituitary Parathyroids Adrenal Medulla Thyroid, interstitial cells Bronchial and bowel mucosa
Sometimes Called APUD Cells MEN Syndromes
Germ line mutations
Younger age group
Multiple
Multifocal
Hyperplasia first
More aggressive
MEN I MEN IIA
MEN I, Wermer’s Syndrome Sipple syndrome Tumor suppressor gene, Proto-oncogene, chromosome 11 chromosome 10 Parathyroid adenomas Thyroid, medullary Pancreas Islet cell adenomas carcinoma
Pituitary adenomas (prolactin) Adrenal medulla, pheochromocytoma
Parathyroid adenoma
27 MEN IIB Marfanoid Habitus
Thyroid, medullary carcinoma Adrenal, pheochromocytoma Ganglioneuromas and neurofibromas Lips Face Oral cavity Eyes GI tract
The Colossal Colon College Mall
28 Hypopituitarism Short Stature
Destruction of gland.
Ischemia
‘Benign’ adenoma destroying gland
Craniopharyngioma
Rathke’s pouch remenant
Benign cyst, but really in the wrong place.
Craniopharyngioma Woman with intermittent nose bleeds
Headache
BP
K+ and Na+
Hyperaldosteronism Cushing Disease
Conn syndrome Adenoma (65% of the time) causing high blood pressure. Over production of aldosterone Zona glomerulosa No ACTH control Retention of Na+ Urinary loss of K+ Serum alkalosis
29 Go to it High Strung Young Woman
Nervous, palpitations
Cervical nodes
Anything else?
Labs
T4 T3
Temp and vomiting?
Hyperophthalmia
Grave’s disease Antibody stimulates TSH receptors in extraocular muscles. Increased tissue in orbit causes eye to protrude. Won’t go down Dry conjunctiva and increased risk of eye infections.
Hyperthyroidism 61 YO Woman with a Goiter
Clinical findings Heat intolerance Tremor Generalized enlargement
Tachycardia T-3 and T-4 OK Hyperactive TSH must be a mistake Increased body metabolism and Exogenous T-4 ? temperature Ocular changes Main causes Graves Disease Toxic goiter Toxic adenoma
30 Substernal Goiter Is someone knocking at the door?
38-Year-Old Woman
Mrs. JG is 38-year-old woman who presents with a history of 60 lb weight gain over the past six months. Physical examination reveals truncal obesity, hypertension, a round face, and abdominal cutaneous striae.
MRI Results Cushing Syndrome
Syndrome vs. Disease Urinary Free Cortisol (UFC) AM and PM blood levels Loss of Diurnal variation Dexamethasone Suppression Test Overnight: 1 mg at 11:00 Low Dose: 0.5 mg q6h X 2 days High Dose: 2 mg q6h X 2-3 days (adenoma) Various modifications Problems of interpretation: Alcoholism & liver ds, depression, exogenous, neoplastic source of ACTH
31 Endoscopic surgery
Gamma Knife
Recurrence
Optic nerve
Any gland remaining?
Next
43-year-old man with progressive weakness Work Up
Mr. JK is a 43-year-old man is Serum chemistry admitted to the hospital for progressive weakness and loss Normal serum calcium, of 50 pounds during the phosphorus and previous 6 months. The creatinine, patient reports that he has "no Low serum glucose and desire to eat anything". Physical examination reveals sodium hypotension as well as Elevated potassium hyperpigmentation of the skin and oral mucosa. The plasma A.M. cortisol is low on several occasions Does not rise after ACTH administration.
32 Addison’s Disease
Slowly develops Loss of adrenal glands
Lots of ACTH, but nothing it can do. Metastatic tumor
TB
Clinical Weight loss Hypotension Hyperpigmentation
Thymus as an Endocrine Gland
Developmental (absence Hyperplasia
Autoimmune problems Tumors
Autoimmune
Heart surgery has found a bunch
DiGorge Syndrome Thymic Hyperplasia
Absence or hypoplasia Lots of autoimmune Faulty conditions Parathyroid Myasthenia Gravis development RA Lack of T-cell immunity Grave’s Branchial arch SLE deformities. Systemic sclerosis Great vessel deformities PA
33 Thymoma
Thymoma
34