Endocrine Flashcards
Thyroid embryology
Thyroid diverticulum arises from floor of primitive pharynx and descends into neck. Connected to tongue by thyroglossal duct, which normally disappears but may persist as pyramidal lobe of thyroid.
Foramen cecum is normal remnant of thyroglossal duct. Most common ectopic thyroid tissue site is the tongue
Thyroglossal duct cyst presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs persistent cervical sinus leading to brachial cleft cyst in lateral neck)
Adrenal cortex and medulla
Adrenal cortex (mesoderm) and medulla (neural crest)
1) Cortex
Zona Glomerulosa - regulates RAAS, secretes Aldosterone
Zona Fasiculata - regulates ACTH, CRH; secretes Cortisol, sex hormones
Zona Reticularis - regulates ACTH, CRH; secretes Sex hormone (androgens)
2) Medulla
Chromaffin Cells - regulate preganglionic sympathetic fibers; secrete catecholamines (Epi, NE)
Pheochromocytoma - most common tumor of the adrenal medulla in adults - episodic HTN
Neuroblastoma - most common tumor of the adrenal medulla in children - rarely causes HTN
Anterior Pituitary (adenohypophysis)
Secretes: FLAT PiG FSH LH ACTH TSH Prolactin GH
Acidophils secrete GH, prolactin
Basophils secrete the rest of them
Melanotropin (MSH) is secreted by intermediate lobe of pit - derived from oral ectoderm (Rathke Pouch)
- Alpha subunit - hormone subunit common to TSH, LH, FSH, and hCG
- Beta subunit - determines hormone specificity
Posterior Pituitary (neurohypophysis)
Secretes:
Vasopression (ADH)
Oxytocin
Made in hypothalamus (supraoptic - ADH, and paraventricular - oxy nuclei) and transported to posterior pituitary via neurophysins (carrier proteins)
Derived from neuroectoderm.
Endocrine pancreas cell types
Islets of Langerhans are collections of alpha, beta, and delta endocrine cells. Islets arise from pancreatic buds
a = glucagon (peripheral) B = insulin (central) d = somatostatin (interspersed)
Insulin synthesis
Preproinsulin (synthesized in RER) becomes proinsulin after cleavage of a “presignal”
Proinsulin (stored in secretory granules) is cleaved and then insulin + C-peptide are exocytosed equally
Insulin and C peptide are both elevated in insulinoma and sulfonylurea use, whereas exogenous insulin lacks C peptide
Source of insulin
Pancreatic Beta cells
Insulin function
Binds insulin receptors (tyrosine kinase activity), inducing glucose uptake (carrier-mediated transport) into insulin-dependent tissue and gene transcription
Anabolic effects of insulin:
1) Increased glucose transport in skeletal muscle and adipose tissue
2) Increased glycogen synthesis and storage
3) Increased triglyceride synthesis
4) Increased Na retention (kidneys)
5) Increased protein synthesis (muscles)
6) Increased cellular uptake of K and amino acids
7) Decreased glucagon release
Unlike glucose, insulin does NOT cross the placenta
Insulin-dependent glucose transporters:
GLUT4: adipose, striated muscle (exercise can also increase GLUT4 expression)
Insulin-independent transporters:
GLUT1 - RBCs, brain, cornea
GLUT2 - (bidirectional) - B islet cells, liver, kidney, SI
GLUT3 - brain
GLUT5 - (fructose) - spermatocytes, GI tract
Brain utilizes glucose for metabolism normally and ketone bodies during starvation. RBCs always utilize glucose bc they lack mitochondria for aerobic metabolism
BRICK L - insulin independent glucose uptake
Brain, Rbcs, Intestine, Cornea, Kidney, Liver
Regulation of Insulin
Glucose is a major regulator of insulin release.
GH (causes insulin resistance leading to increased insulin release)
B2 agonists lead to increased insulin
Glucose enters B cells leading to increased ATP generated from glucose metabolism.
This increased ATP closes K channels (target of sulfonylureas) and depolarizes B cell membrane
Voltage gated Ca channels open leading to Ca influx and stimulation of insulin exocytosis.
Glucagon
Made by alpha cells of pancreas
Function:
Catabolic effects of glucagon -
1) Glycogenolysis, gluconeogenesis
2) Lipolysis and ketone production
Regulation:
Secreted in response to hypoglycemia.
Inhibited by insulin, hyperglycemia, and somatostatin*
Hypothalamic-pituitary hormones (7)
1) CRH
Increases ACTH, MSH, B-endorphin
Lower CRH in chronic exogenous steroid use
2) Dopamine
Decreases prolactin
Dopamine antagonists (antipsychotics) can cause galactorrhea due to hyperprolactinemia
3) GHRH
Increases GH
Analog (tesamorelin) used to treat HIV-associated lipodystrophy
4) GnRH
Increases FSH and LH
Regulated by prolactin. Tonic GnRH suppresses HPA axis. Pulsatile GnRH leads to puberty and fertility.
5) Prolactin
Decreases GnRH
Pituitary prolactinoma leads to amenorrhea, osteoporosis, hypogonadism, galactorrhea
6) Somatostatin
Decreases GH and TSH
Analogs used to treat acromegaly
7) TRH
Increases TSH and prolactin
Prolactin source and function
Secreted by anterior pit
1) Stimulates milk production in breast
2) Inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release
Excessive amounts of prolactin is associated with decreased libido
Prolactin regulation
Prolactin secretion from anterior pit is tonically inhibited by dopamine from hypothalamus
Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus
TRH increases prolactin secretion (in primary or secondary hypothyroidism)
Dopamine agonists (bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma
Dopamine antagonists (most antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion
Growth hormone (somatotropin) source and function
Secreted by anterior pit
Stimulates linear growth and muscle mass through IGF-1 (somatomedin C) secretion
Increases insulin resistance (diabetogenic)
Growth hormone (somatotropin) regulation
Released in pulses in response to growth hormone-releasing hormone (GHRH)
Secretion is higher during exercise and sleep
Secretion inhibited by glucose and somatostatin release via negative feedback by somatomedin
Excess secretion of GH (pituitary adenoma) may cause acromegaly (adults) or gigantism (children)
Appetite regulation: Ghrelin
Stimulates hunger (orexigenic effect) and GH release (via GH secretagog receptor)
Produced by stomach.
Increases with sleep loss and Prader-Willi Syndrome
Appetite regulation: Leptin
Satiety hormone
Produced by adipose tissue.
Decreases during starvation.
Mutation of leptin gene leads to congenital obesity
Sleep deprivation lowers leptin production
Appetite regulation: Endocannabinoids
Stimulate cortical reward centers leading to increased desire for high-fat foods
ADH
Made in hypothalamus (supraoptic nuclei), released by posterior pit
regulates serum osmolarity (V2 receptors) and blood pressure (V1 receptors)
Primary function is serum osmolarity regulation (ADH lowers serum osmolarity, increases urine osmolarity) via regulation of aquaporin channel insertion in principal cells of renal collecting duct
ADH levels are decreased in central diabetes insipidus, normal or elevated in nephrogenic DI
Nephrogenic DI can be caused by mutation in V2 receptor
Demopressin acetate (ADH analog) is a treatment for central DI
Regulation of ADH:
Osmoreceptors in hypothalamus (primary); hypovolemia (secondary)
17a-hydroxylase deficiency
Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)
Mineralocorticoids: Up
Cortisol: Down
Sex hormones: Down
BP: Up
Labs: Low androstenedione
Presentation: XY - pseudo-hermaphroditism (ambiguous genitalia, undescended testes) XX - lack secondary sexual development
21-hydroxylase deficiency
Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)
Mineralocorticoids: Down
Cortisol: Down
Sex hormones: Up
BP: Down
Labs: Higher renin activity. High 17-hydroxy-progesterone
Presentation: Most common one** Presents in infancy (salt wasting) or childhood (precocious puberty). XX - virilization
11B-hydroxylase deficiency
Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)
Mineralocorticoids: Low aldosterone, High 11-deoxycorticosterone (results in higher BP)
Cortisol: Down
Sex hormones: Up
BP: Up
Labs: Low renin activity
Presentation: XX - virilization
Cortisol source and function
From adrenal zona fasciculata - bound to corticosteroid-binding globulin
Functions: BIG GIB (Blood pressure, Insulin, Gluconeo, Fibroblast, Inflammatory/Immune, Bone)
1) Increases BP
- Upregulates a1-receptors on arterioles leading to higher sensitivity to NE and Epi
- At high concentrations, can bind to mineralocorticoid (aldosterone) receptors
2) Increases Insulin resistance (Diabetogenic)
3) Increases Gluconeogenesis, lipolysis, and proteolysis
4) Lowers Fibroblast activity (causes striae)
5) Lower inflammatory/immune responses
- Inhibits production of leukotrienes and prostaglandins
- Inhibits WBC adhesion leading to neutrophilia
- Blocks histamine release from mast cells
- Reduces eosinophils
- Blocks IL-2 production
6) Lower bone formation (lower osteoblast activity)
Cortisol regulations
CRH (hypothalamus) stimulates ACTH release (pit) leading to cortisol production in adrenal zona fasciculata
Excess cortisol lowers CRH, ACTH, and cortisol secretion
Chronic stress induced prolonged secretion
Calcium homeostasis
Plasma Ca exists in 3 forms
1) Ionized (45%)
2) Bound to albumin (40%)
3) Bound to anions (15%)
Increase in pH leads to increased affinity of albumin (increased negative charge) to bind to Ca
This leads to hypocalcemia (cramps, pain, paresthesias, carpopedal spasm)
Vitamin D
1) Source: D3 from sun exposure in skin. D2 ingested from plants. Both converted to 25-OH in liver and to 1,25-(OH)2 (active form) in kidney
2) Function:
- Increased absorption of dietary Ca and PO4
- Increased bone resorption leads to increased Ca and PO4
3) Regulation:
Increased PTH, low Ca, low PO4 all lead to increased 1,25-(OH)2 production
1,25-(OH)2 feedback inhibits its own production
Deficiency leads to rickets in kids, osteomalacia in adults. Caused by malabsorption, lower sunlight, poor diet, chronic kidney failure
24,25-(OH)2D3 is an inactive form of vitamin D.
PTH leads to increased Ca reabsorption and lower PO4 reabsorption in the kidney, whereas 1,25-(OH)2D3 leads to increased absorption of both Ca and PO4 in the gut
PTH source and function
Chief Cells of parathyroid
1) Increases bone resorption of Ca and PO4
2) Increased kidney reabsorption of Ca in DCT
3) Decreased reabsorption of PO4 in PCT
4) Increased 1,25-(OH)2D3 (calcitriol) production by stimulating kidney 1a-hydroxylase in PCT
PTH increases serum Ca and lowers serum PO4.
PTH increases urine PO4
Increased production of macrophage colony-stimulating factor and RANK-L (receptor activator of NF-kB ligand). RANK-L (ligand) secreted by osteoblasts and osteocytes binds RANK (receptor) on osteoclasts and their precursors to stimulate osteoclasts and increase Ca
Intermittent PTH release can stimulate bone formation
PTH = Phosphate Trashing Hormone
PTH-related peptide (PTHrP) functions like PTH and is commonly increased in malignancies
PTH regulation
Lower serum Ca leads to higher PTH secretion
High serum PO4 leads to higher PTH secretion
Low serum Mg leads to high PTH secretion
Very low serum Mg leads to lower PTH secretion
Common causes of lower Mg include diarrhea, aminoglycosides, diuretics, alcohol abuse
Calcitonin
1) Source: Parafollicular cells (C cells) of thyroid
2) Function: Lowers bone resorption of Ca
3) Regulation: Increased serum Ca leads to calcitonin secretion
Calcitonin opposes action of PTH. Not important in normal Ca homeostasis. CalciTONin TONes done Ca levels
Endocrine hormones utilizing cAMP signaling
FSH LH ACTH TSH CRH hCG ADH (V2 receptor) MSH PTH calcitonin GHRH glucagon
FLAT ChAMP + cgg
Endocrine hormones utilizing cGMP signaling
ANP
BNP
NO (EDRF)
Think vasodilation
Endocrine hormones utilizing IP3 signaling
GnRH Oxytocin ADH (V1 receptor) TRH Histamine (H1 receptor) Angiotensin II Gastrin
GOAT HAG
Endocrine hormones utilizing intracellular receptor signaling
Vitamin D Estrogen Testosterone T3/T4 Cortisol Aldosterone Progesterone
VETTT CAP
Endocrine hormones utilizing Intrinsic tyrosine kinase signaling
Insulin IGF-1 FGF PDGF EGF
MAP kinase pathway - think growth factors
Endocrine hormones utilizing receptor-associated tyrosine kinase signaling
Prolactin Immunomodulators (cytokines IL2, IL6, IFN) GH G-CSF Erythropoietin Thrombopoietin
JAK/STAT pathway - think acidophils and cytokines
PIGG(L)ET
Signaling pathway of steroid hormones
Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility
In men, increased sex hormone-binding globulin (SHBG) lowers free testosterone leading to gynecomastia
In women, lower SHBG raises free testosterone and leads to hirsutism
OCPs, pregnancy raise SHBG (free estrogen levels remain unchanged)
Thyroid hormones (T3/T4) source and function
Iodine-containing hormones that control the body’s metabolic rate
Source: Follicles of thyroid. Most T3 formed in target tissues
Functions:
1) Bone growth (synergism with GH)
2) CNS maturation
3) Increases B1 receptors in heart = Higher CO, HR, SV, contractility
4) Increases basal metabolic rate via N/K/ATPase activity leads to higher O2 consumption, RR, body temperature
5) Increases glycogenolysis, gluconeogenesis, lipolysis
T3 functions - 4 B's Brain maturation Bone growth B-adrenergic effects Basal metabolic rate goes up
Thyroxine-binding globulin (TBG) binds most T3/T4 in blood; only free hormone is active. Lower TBG in hepatic failure, steroids;
Increased TBG in pregnancy or OCP use (estrogen increases TBG)
T4 is major thyroid product; converted to T3 in peripheral tissue by 5’-deiodinase
T3 binds nuclear receptor with greater affinity than T4
Peroxidase is the enzyme responsible for oxidation and organification of iodide as well as coupling of monoiodotyrosine (MIT) and di-iodotyrosine (DIT)
Propylthiouracil inhibits both peroxidase and 5’deiodinase. Methimazole inhibits peroxidase only
Thyroid hormones (T3/T4) regulation
TRH (hypothal) stimulates TSH (pit), which stimulates follicular cells.
Negative feedback by free T3, T4 to anterior pit lowers sensitivity to TRH
Thyroid-stimulating immunoglobulins (TSH) stimulate follicular cells (Graves Disease)
Wolff-Chaikoff Effect - excess iodine temporarily inhibits thyroid peroxidase leading to lower iodine organification leading to low T3/T4 production
Cushing Syndrome Etiology
High cortisol due to a variety of causes
1) Exogenous corticosteroids - results in lower ACTH, bilateral adrenal atrophy. Most common cause.
2) Primary adrenal adenoma, hyperplasia, or carcinoma - result in lower ACTH, atrophy of uninvolved adrenal gland. Can also present with pseudohyperaldosteronism
3) ACTH-secreting pituitary adenoma (Cushing Disease*); paraneoplastic ACTH secretion (small cell lung cancer, bronchial carcinoids) - result in high ACTH, bilateral adrenal hyperplasia.
* Cushing disease is responsible for the majority of endogenous cases of Cushing Syndrome
Cushing Syndrome findings
HTN, weight gain, moon facies, truncal obesity, buffalo hump, skin changes (thinning, striae), osteoporosis, hyperglycemia (insulin resistance), amenorrhea, immunosuppression
Cushing Syndrome Diagnosis
Screening tests include:
1) Increased free cortisol on 24-hr urinalysis
2) Increased midnight salivary cortisol, and no suppression with overnight low-dose dexamethasone test
3) Measure serum ACTH. If low, suspect adrenal tumor. If high, distinguish between Cushing disease and ectopic ACTH secretion with a high dose (8mg) dexamethasone suppression test and CRH stimulation test.
Ectopic secretion will not decrease with dexamethasone bc the source is resistant to negative feedback; ectopic secretion will not increase with CRH bc pit ACTH is suppressed
Adrenal insufficiency - general
Inability of adrenal glands to generate enough glucocorticoids +/- mineralocorticoids for the body’s needs.
Symptoms include: weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI disturbances, sugar and/or salt cravings
Diagnosis involves measurement of serum electrolytes, morning/random serum cortisol and ACTH, and response to ACTH stimulation test
Alternatively, can use metyrapone stimulation test: metyrapone blocks last step of cortisol synthesis (11-deoxycortisol becomes cortisol). Normal response is decreased cortisol and compensatory increased ACTH.
In adrenal insufficiency, ACTH remains low after test.
Adrenal insufficiency - Primary
Deficiency of aldosterone and cortisol production due to loss of gland function leading to hypotension (hyponatremic volume contraction), hyperkalemia, metabolic acidosis, skin and mucosal hyperpigmentation (due to MSH, a byproduct of increased ACTH production from pro-opiomelanocortin)
Acute - sudden onset (due to massive hemorrhage) - may present with shock in acute adrenal crisis
Chronic - aka Addison Disease. Due to adrenal atrophy or destruction by disease (e.g. autoimmune, TB, metastasis)
Primary Pigments the skin/mucosa.
Autoimmunity most common cause of primary chronic adrenal insufficiency in Western world. Associated with autoimmune polyglandular syndromes
Waterhouse-Friderichsen Syndrome - acute primary adrenal insufficiency due to adrenal hemorrhage associated with septicemia (usually N. Meningitides), DIC, endotoxic shock
Adrenal insufficiency - secondary
Seen with lower pituitary ACTH production
No skin/mucosal hyperpigmentation, no hyperkalemia (aldosterone synthesis preserved)
Secondary Spares the Skin/mucosa
Adrenal insufficiency - tertiary
Seen in patients with chronic exogenous steroid use, precipitated by abrupt withdrawal. Aldosterone synthesis unaffected
Tertiary from Treatment
Neuroblastoma
Most common tumor of the adrenal medulla in children, usually less than 4 years old.
Originates from neural crest cells; Homer-Wright rosettes characteristic
Occurs anywhere along the sympathetic chain. Most common presentation is abdominal distension and a firm, irregular mass that can cross the midline (vs Wilms Tumor, which is smooth and unilateral)
Can also present with opsoclonus-myoclonus syndrome (“dancing eyes-dancing feet”).
Homovanillic acid (HVA; a breakdown product of dopamine) and vanillylmandelic acid (VMA; a breakdown product of NE) are increased in urine
Bombesin and neuron-specific enolase (+).
Less likely to develop HTN.
Associated with overexpression of N-myc oncogene
Pheochromocytoma etiology and symptoms
Most common tumor of the adrenal medulla in adults
Derived from chromaffin cells (arise from neural crest)
Rule of 10’s
10% malignant 10% bilateral 10% extra-adrenal 10% calcify 10% kids
Symptoms:
Most tumors secrete Epinephrine, NE, and dopamine, which can cause episodic HTN
Associated with neurofibromatosis type 1, von Hippel-Lindau disease, MEN 2A and MEN 2B
Symptoms occur in “spells” - relapse and remit
Episodic hyperadrenergic symptoms (5 Ps)
Pressure (higher BP) Pain (HA) Perspiration Palpitations (tachycardia) Pallor
Pheochromocytoma Findings and Tx
Increased catecholamines and metanephrines in urine and plasma
Tx = Irreversible alpha-antagonists (phenoxybenzamine) followed by B-blockers prior to tumor resection. Alpha blockade must be achieved before giving B-blockers to avoid a hypertension crisis
Hypothyroidism - general
Cold intolerance (lower heat production)
Weight gain, lower appetite
Hypoactivity, lethargy, fatigue, weakness
Constipation
Lower reflexes
Myxedema (facial/ periorbital)
Dry, cool skin; coarse, brittle hair
Bradycardia, dyspnea on exertion
Labs: High TSH (sensitive test for primary hypothyroidism)
Low free T3 and T4
Hypercholesterolemia (due to lower LDL receptor expression)
Hyperthyroidism - general
Heat intolerance (higher heat production)
Weight loss, increased appetite
Hyperactivity
Diarrhea
Higher reflexes
Pretibial myxedema (Graves), periorbital edema
Warm, moist skin; fine hair
Chest pain, palpitations, arrhythmias, increased number and sensitivity of B-adrenergic receptors
Labs: Low TSH (if primary)
High free or total T3 and T4
Hypocholesterolemia (due to increased LDL receptor expression)
Hashimoto thyroiditis
Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder (anti-thyroid peroxidase, antimicrosomal and antithyroglobulin antibodies).
Associated with HLA-DR5
Increased risk of NH Lymphoma
May be hyperthyroid early in course due to thyrotoxicosis during follicular rupture
Histologic findings: Hurthe cells, lymphoid aggregate with germinal centers
Findings: moderately enlarged, nontender thyroid
Congenital hypothyroidism (Cretinism)
Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agensis, thyroid dysgenesis (most common cause in US), iodine deficiency, dyshormonogenetic goiter
Findings = 6Ps
Pot-bellied, Pale, Puffy-faced child with Protruding umbilicus, Protuberant tongue, and Poor brain development
Subacute thyroiditis (de Quervain)
A hypothyroidism
Self-limited disease often following a flu-like illness
May be hyperthyroid early in course, followed by hypothyroidism
Histology: granulomatous inflammation
Findings: Increased ESR, jaw pain, early inflammation, very tender thyroid
dequerVAIN = PAIN
Riedel thyroiditis
A hypothyroidism
Thyroid replaced by fibrous tissue (hypothyroid)
Fibrosis may extend to local structures (airway), mimicking anaplastic carcinoma
Considered a manifestation of IgG4 related systemic disease (autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis)
Findings: fixed, hard (rock-like) painless goiter
Other causes of hypothyroidism
Iodine deficiency
Goitrogens
Wolff-Chaikoff effect (thyroid gland downregulation in response to increased iodine)
Graves Disease
Most common cause of hyperthyroidism. Autoantibodies (IgG) stimulates TSH receptors on thyroid (hyperthyroidism, diffuse goiter), retro-orbital fibroblasts (exophthalmos: proptosis, extraocular muscle swelling), and dermal fibroblasts (pretibial myxedema)
often presents during stress (childbirth)
Toxic multinodular goiter
A hyperthyroidism
Focal patches of hyperfunctioning follicular cells working independently of TSH due to mutation in TSH receptor.
Increased release of T3 and T4. Hot nodules are rarely malignant
Thyroid storm
Hyperthyroidism cause
Stress-induced catecholamine surge seen as a serious complication of thyrotoxicosis due to disease and other hyperthyroid disorders
Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause of death)
May see increased ALP due to increased bone turnover.
Treat with 3Ps = B blockers (Proranolol), Propylthiouracil, corticosteroids (prednisolone)
Jod-Basedow phenomenon
Hyperthyroidism cause
Thyrotoxicosis if a patient with iodine deficiency goiter is made iodine replete
Thyroid cancer - general Tx and risk of Tx
Thyroidectomy is an option for thyroid cancers and hyperthyroidism. Complications of surgery include hoarseness (due to recurrent laryngeal nerve damage), hypocalemia (due to removal of parathyroid glands), and transection of recurrent and superior laryngeal nerves (during ligation of inferior and superior laryngeal arteries respectively)
Papillary carcinoma
Most common thyroid cancer, excellent prognosis
Empty-appearing nuclei with central clearing (“Orphan Annie” eyes), psammoma bodies, nuclear grooves.
Lymphatic invasion common
Increased risk with RET and BRAF mutations, childhood irradiation
Follicular carcinoma
Thyroid cancer
Good prognosis, invades thyroid capsule (unlike follicular adenoma), uniform follicles
Medullary carcinoma
Thyroid cancer
From parafollicular “C Cells”
Produces calcitonin, sheets of cells in an amyloid stroma, hematogenous spread common
Associated with MEN 2A and 2B (RET mutations)
Undifferentiated/Anaplastic Carcinoma
Thyroid cancer
Older patients
Invades local structures (airway)
Very poor prognosis
Lymphoma - Thyroid
Associated with Hashimoto thyroiditis
Hypoparathyroidism
Due to accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge
Findings = hypocalcemia, tetany
Chvostek sign - tapping of facial nerve (tap the Cheek) leads to contraction of facial muscles
Trousseu sign - occlusion of brachial artery with BP cuff (cuff the Triceps) leads to carpal spasm
Pseudohypoparathyroidism
“Albright hereditary osteodystrophy”
Unresponsiveness of kidney to PTH. Hypocalcemia, shortened 4th/5th digits, short stature
Autosomal dominant
Familial hypocalciuric hypercalcemia
Defective Ca sensing receptor on parathyroid cells
PTH cannot be suppressed by an increase in Ca level
This causes mild hypercalcemia with normal to increased PTH levels
Hyperparathyroidism - Primary
usually due to parathyroid adenoma or hyperplasia
Hypercalcemia, hypercalciuria (renal STONES), hypophosphatemia, increased PTH, ALP, cAMP in urine.
Most often asymptomatic. May present with weakness and constipation (“groans”), abdominal/flank pain (kidney stones, acute pancreatitis), depression (“psychiatric overtones”
Stones, groans, and psychiatric overtones
Osteitis fibrosa cystica - cystic BONE spaces filled with brown fibrous tissue (“brown tumor” consisting of deposited hemosiderin from hemorrhages; causes bone pain)
Stones, bones, groans and psych overtones
Hyperparathyroidism - secondary
Secondary hyperplasia due to low Ca absorption and/or high PO4, most often in chronic renal disease (causes hypovitaminosis D leading to low Ca absorption)
Hypocalcemia, hyperphosphatemia in chronic renal failure (vs hypophosphatemia with most other causes), high ALP, high PTH
Renal Osteodystrophy - bone lesions due to secondary or tertiary hyperparathyroidism due in turn to renal disease.
Hyperparathyroidism - tertiary
Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease. HUGE increase in PTH, high Ca
Renal Osteodystrophy - bone lesions due to secondary or tertiary hyperparathyroidism due in turn to renal disease.
Pituitary adenoma
Most commonly prolactinoma (benign).
Adenoma may be functional (hormone producing) or nonfunctional (silent.
Nonfunctional tumors present with mass effect (bitemporal hemianopia, hypopituitarism, HA)
Functional tumor presentation is based on the hormone produced (prolactinoma: amenorrhea, galactorrhea, low libido, infertility; somatotropic adenoma: acromegaly)
Tx for prolactinoma = dopamine agonists (bromocriptine or cabergoline), transsphenoidal resection
Acromegaly
Excess GH in adults. Typically caused by pituitary adenoma
Findings: Large tongue with deep furrows, deep voice, large hands and feet, coarse facial features, impaired glucose tolerance (insulin resistance)
Increased risk of colorectal polyps and cancer
Dx: Increased serum IGF-1; failure to suppress serum GH following oral glucose tolerance test; pituitary mass seen on brain MRI
Tx: Pit adenoma resection: If not cured, treat with octreotide (somatostatin analog) or pegvisomant (GH receptor antagonist)
Increased GH in children leads to gigantism (increased linear bone growth). HF most common cause of death
Diabetes insipidus
Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH (central) or failure of response to circulating ADH (nephrogenic)
1) Central DI
Cause: Pit tumor, autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic
Findings:
Low ADH
Urine specific gravity 290 mOsm/kg
Hyperosmotic volume contraction
Water deprivation test (No water intake for 2-3 hrs followed by hourly measurements of urine volume and osmolarity and plasma Na concentration and osmolarity. ADH analog - desmopressin acetate - is administered if normal values are not clearly reached)
> 50% increase in urine osmolality only after administration of ADH analog
Tx: Intranasal desmopressin acetate. Hydration.
2) Nephrogenic DI
Cause: hereditary (ADH receptor mutation), secondary to hypercalcemia, lithium, demeclocycline (ADH antagonist)
Findings:
Normal ADH levels
Urine specific gravity 290 mOsm/kg
Hyperosmotic volume contraction
Water deprivation test:
Minimal change in urine osmolality, even after administration of ADH analog
Tx: HCTZ, indomethacin, amiloride. Hydration.
SIADH
Syndrome of Inappropriate ADH secretion
Excessive free water retention
Euvolemic hyponatremia with continued urinary Na excretion
Urine osmolality > Serum osmolality
Body responds to water retention with reduced aldosterone (hyponatremia) to maintain near-normal volume status. Very low serum Na levels can lead to cerebral edema, seizures.
Correct slowly to prevent osmotic demyelination syndrome (formerly known as central pontine myelinolysis)
Causes include: Ectopic ADH (small cell lung cancer) CNS disorder/head trauma Pulmonary disease Drugs (cyclophosphamide)
Tx: Fluid restriction, IV hypertonic saline, conivaptan, tolvaptan, demeclocycline
Hypopituitarism
Undersecretion of pituitary hormones due to:
1) Nonsecreting pituitary adenoma, craniopharyngioma
2) Sheehan Syndrome - ischemic infarct of pituitary following postpartum bleeding; usually presents with failure to lactate, absent menstruation, cold intolerance
3) Empty Sella Syndrome - atrophy or compression of pituitary, often idiopathic, common in obese women
4) Pituitary apoplexy - sudden hemorrhage of pituitary gland, often in the presence of an existing pituitary adenoma
5) brain injury
6) Radiation
Tx: hormone replacement therapy (corticosteroids, thyroxine, sex steroids, human growth hormone)
Diabetes Mellitus - acute manifestations
Insulin deficiency or insensitivity (and glucagon excess) leads to:
1) Decreased serum glucose uptake. This leads to hyperglycemia, glycosuria, osmotic diuresis, electrolyte depletion. All this leads to dehydration +/- acidosis. Finally this can cause coma, death.
2) Increased protein catabolism leading to increased plasma amino acids, nitrogen loss in urine. This leads to hyperglycemia, glycosuria, osmotic diuresis, electrolyte depletion. All this leads to dehydration +/- acidosis. Finally this can cause coma, death.
3) Increased lipolysis (insulin deficiency only). This leads to increased plasma FFAs, ketogenesis, ketonuria, ketonemia. This all leads to dehydration +/- acidosis. Finally this can cause coma, death.
Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2)
Rarely, can be caused by unopposed secretion of GH and Epinephrine. Also seen in patients on glucocorticoid therapy (steroid diabetes)
Diabetes mellitus - chronic complications
1) Nonenzymatic glycation:
- small vessel disease (diffuse thickening of basement membrane) leads to retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules leads to progressive proteinuria and arteriolosclerosis leading to HTN; both lead to chronic renal failure)
- Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene leading to limb loss, cerebrovascular disease. MI most common cause of death
2) Osmotic damage (sorbitol accumulation in organs with aldose reductase and low or absent sorbitol dehydrogenase):
Neuropathy (motor, sensory, and autonomic degeneration)
Cataracts
Diabetes mellitus Dx
Fasting serum glucose, oral glucose tolerance test, HbA1C (reflects avg blood glucose over prior 3 months)
Type 1 vs Type 2 Diabetes mellitus
1) Type 1
Primary defect = Autoimmune destruction of B cells
Insulin necessary in Tx? Always
Age: Less than 30
Association with obesity? No
Genetic predisposition? Relatively weak (50% concordance in identical twins), polygenic
Association with HLA system? Yes (HLA-DR3 and DR4)
Glucose intolerance: Severe
Insulin sensitivity: High
Ketoacidosis: Common
B-cell numbers in the islets: Low
Serum insulin: Low
Classic symptoms of polyuria, polydipsia, polyphagia, weight loss: Common
Histology: Islet leukocytic infiltrate
2) Type 2
Primary defect = Increased resistance to insulin, progressive pancreatic B cell failure
Insulin necessary in Tx? Sometimes
Age: Over 40
Association with obesity? Yes
Genetic predisposition? Relatively strong (90% concordance in identical twins), polygenic
Association with HLA system? No
Glucose intolerance: Mild to moderate
Insulin sensitivity: Low
Ketoacidosis: Rare
B-cell numbers in the islets: Variable (with amyloid deposits)
Serum insulin: Variable
Classic symptoms of polyuria, polydipsia, polyphagia, weight loss: Sometimes
Histology: Islet amyloid polypeptide (IAPP) deposits
Diabetic ketoacidosis
One of the most feared complications of diabetes. Usually due to increased insulin requirements from increased stress (infection). Excess fat breakdown and increased ketogenesis from increased free fatty acids, which are then made into ketone bodies (B-hydroxubutyrate > acetoacetate). Usually occurs in type 1 diabetes, as endogenous insulin in type 2 diabetes usually prevents lipolysis.
Signs/Symptoms: Kussmaul respirations (rapid/deep breathing), nausea/vomiting, abdominal pain, psychosis/delirium, dehydration. Fruity breath odor (due to exhaled acetone)
Labs: Hyperglycemia, increased H, Low HCO3 (higher anion gap metabolic acidosis), increased blood ketone levels, leukocytosis. Hyperkalemia, but depleted intracellular K due to transcellular shift from low insulin insulin (therefore total body K is depleted)
Complications: Life-threatening mucormycosis (usually Rhizopus infection), cerebral edema, cardiac arrhythmias, heart failure
Tx: IV fluids, IV insulin, and K (to replete intracellular stores); glucose if necessary to prevent hypoglycemia
Glucagonoma
Tumor of pancreatic alpha cells leading to overproduction of glucagon
Presents with dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia), DVT, and depression
Insulinoma
Tumor of pancreatic B cells leading to overproduction of insulin leading to hypoglycemia.
May see Whipple triad: Low blood glucose, symptoms of hypoglycemia (lethargy, syncope, diplopia), and resolution of symptoms after normalization of glucose levels.
Symptomatic patients have low blood glucose and increased C peptide levels (vs exogenous insulin use).
Tx = surgical resection
Carcinoid Syndrome
Rare syndrome caused by carcinoid tumors (neuroendocrine cells), especially metastatic small bowel tumors, which secrete high levels of 5-HT (serotonin)
not seen if tumor is limited to GI tract (5HT undergoes first-pass metabolism in liver)
Results in recurrent diarrhea, cutaneous flushing, asthmatic wheezing, right-sided valvular disease
Increased 5-hydroxyindoleacetic acid (5-HIAA) in urine
Niacin deficiency (pellagra)
Tx = surgical resection, somatostatin analog (octreotide)
Zollinger-Ellison syndrome
Gastrin-secreting tumor (gastrinoma) of pancreas or duodenum
Acid hypersecretion causes recurrent ulcers in duodenum and jejunum
Presents with abdominal pain (peptic ulcer disease, distal ulcers), diarrhea (malabsorption). Positive secretin stimulation test: Gastrin levels remain elevated after administration of secretin, which normally inhibits gastrin release.
May be associated with MEN 1
MEN 1
Auto Dom
3 P’s
Parathyroid tumors
Pituitary tumors (prolactin or GH)
Pancreatic endocrine tumors - Zollinger-Ellison Syndrome, insulinomas, VIPomas, glucagonomas (rare)
Associated with mutation of MEN1 gene (menin, a tumor suppressor)
MEN 2A
Auto Dom
2 P’s
Parathyroid hyperplasia
Pheochromocytoma
Medullary thyroid carcinoma (secretes calcitonin)
Associated with marfanoid habitus; mutations in RET gene (codes for receptor tyrosine kinase)
MEN-2B
Auto Dom
Only 1 P now
Pheochromocytoma
Medullary thyroid carcinoma (secretes calcitonin)
Oral/intestinal ganglioneuromatosis (mucosal neuromas)
Associated with marfanoid habitus; mutations in RET gene
