endocrine pathologyobjectives •describe the pathways of feedback for hormone secretion in the...
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Endocrine PathologyHypothalamus
Pituitary
AdRenal
THYROID
parathyroid
Endocrine Pancreas
Lisa Lopez, Md
with sincere gratitude to
Clare McCormick-baw, md
Objectives
• Describe the pathways of feedback for hormone secretion in the neural axis.
• Describe the pathologic conditions that can arise from neuronal axis dysfunction.
• Discuss the laboratory testing and diagnosis for endocrine diseases and neoplasms within the pituitary gland, adrenal glands, thyroid gland, parathyroid glands and pancreas
Hypothalamus and Pituitary
Hypothalamic-Pituitary Axis
Hypothalamus
• Inducers/Stimulators:• TRH – Thyrotropin Releasing Hormone
• TSH secretion Thyroid gland
• CRH – Corticotropin Releasing Hormone• ACTH secretion Adrenal gland
• GHRH – Growth Hormone Releasing Hormone• GH secretion Systemic (bone, muscle, etc)
• GnRH – Gonadotropin Releasing Hormone• FSH, LH Testis or Ovaries
• Suppressors:• Somatostatin
• Downregulates GH
• Dopamine• Downregulates Prolactin
Hypothalamic-Pituitary Axis Regulation
Pituitary Gland Hormones
Anterior Pituitary Cell Types – Acidophils
• Somatotrophs• GH producing
• 50% of hormone producing cells in the pituitary
• Lactotrophs• Prolactin producing
Anterior Pituitary Cell Types – Basophils
• Corticotrophs• POMC producing
• ACTH
• MSH
• Lipotropin
• Beta-endorphin
• Gonadotrophs• FSH, LH producing
• Thyrotrophs• TSH producing
Posterior Pituitary Cell Types
• Pituicytes• Modified glial cells
• Store already synthesized peptide hormones
• Secrete:• ADH (vasopressin)
• Oxytocin
Dysfunction
Hyper
Neoplasm
Primary
Ectopic
Failed Feedback
Exogenous
Endogenous
Hypo
Neoplasm Iatrogenic
Surgery
Radiation
Injury
Ischemia
Infectious
Inflammatory
Pituitary Neoplasms
• Adenoma• Most common cause of hyperpituitarism
• + Hormone producing• Prolactin prolactinoma (30%)
• GH gigantism/acromegaly (15%)
• ACTH Cushing disease (15%)
• - Hormone producing• Null cell adenoma (25-30%)
• Description: Monomorphic population, sheets and cords of cells, sparse support network. Usually few or no mitoses.
• If numerous mitoses likely p53 mutations atypical adenoma
• Use reticulin stain to demonstrate distorted architecture of the support network
Clinical Manifestations of Pituitary Adenoma
• Prolactinemia• Signs and Symptoms:
• Galactorrhea
• Secondary amenorrhea
• Infertility
• Laboratory Diagnosis:• Prolactin Level
• Immunoassay
Clinical Manifestations of Pituitary Adenoma
• GH Excess• Acromegaly/Gigantism
• Signs and Symptoms:
• Failure for growth plates to close (kids)
• Diffuse enlargement of soft tissue and organs
• Laboratory Diagnosis:
• Screening test: IGF-1 level
• > than expected for age/gender
• Confirmatory test: Oral glucose tolerance test
• + test if: GH level is > 1 ng/ml at any blood draw
Screening test
Confirmatory Test Target
Clinical Manifestations of Pituitary Adenoma
• ACTH-Secreting Adenoma• Cushing Disease
Hypothalamic-Pituitary-Adrenal Axis
Cushing Syndrome
Diagnosis of Cushing Disease
Clinical Manifestations of Pituitary Adenoma
• Gonadotroph Adenoma• Paradoxically causes secondary hypogonadism
• Secrete hormone inefficiently or variably
• Signs and symptoms:• Fatigue, decreased libido (men) ↓ LH ↓ testosterone
• Secondary amenorrhea (women) ↓ LH
• Thyrotroph Adenoma• Rare (~1%)
• Cause of hyperthyroidism due to increased TSH secretion
Pituitary Carcinoma
• Rare <1%
• Commonly functional:• Prolactin
• ACTH
• Craniospinal or systemic metastasis
Clinical Manifestation of Pituitary Adenoma
• Null cell adenoma• No syndrome or symptoms from hormone secretion
• Can cause hypopituitarism!
• All come from one or more cell origins• Frequently will stain with hormone antibodies
• Typically present with mass effect symptoms:• Visual disturbance
• Headache
• Diplopia
• Apoplexy – acute hemorrhage within a micro/macroadenoma
Hypopituitarism
Hypo
Neoplasm
Pituitary Adenoma
Craniopharyn-gioma
Rathke cleft cyst
Metastatic Carcinoma
Iatrogenic
Surgery
Radiation
Malformation
Empty Sella
Congential
Injury
Ischemia
Sheehan Syndrome
Hemorrhage
Subarachnoid
Apoplexy
Infectious
TB
Inflammatory
Sarcoidosis
Pituitary Gland Hormones Gone Wrong
Rathke Cleft Cyst
• Mucinous thin-walled, cyst• Ciliated, cuboidal epithelium
• Incidental finding
Craniopharyngioma
• Hypothalamus (Suprasellar)• Rathke pouch remnants
• Two kinds:• Adamantinomatous – children
• See calcifications radiologically
• Peripheral palisading of squamous epithelium
• Spongy reticulum in the internal layers
• “wet keratin”
• Papillary – adults
• Solid sheets and papillae
• Rarely see calcifications, keratin or cysts
• No peripheral palisading and no spongy reticulum
AdamantinomatousCraniopharyngioma
Posterior Pituitary Gland Hormones
• ADH• Maintain osmotic homeostasis
• Anti-diuretic Hormone
• Keep water!!!!!
• Oxytocin• Uterine contractions
• Myoepithelial cell contraction in the breast
Diabetes Insipidus
• Neurogenic• ↓ ADH – causes increased urination and plasma osmolality
• Nephrogenic• Renal resistance to the effect of ADH – same effect as above
• Diagnosis: Water Deprivation Test
Syndrome of Inappropriate ADH Secretion• Euvolemic hyposomolar
hyponatremia
• Hyperosmolar urine
• Diagnosis of exclusion!
• Diagnosis: Water Load Test• Normal:
• 80-90% of water administered within 4 hours.
• Uosm to < 100 mOsm/kg
Adrenal Gland
Adrenal Gland Histology
• Zona glomerulosa • Mineralocorticoids
• Aldosterone – encourages Na reabsorption increased water uptake
• Zona fasciculata• Glucocorticoids
• Cortisol – stress hormone, immune regulator, metabolism mediator
• Zona reticularis• Sex steroids
• Androgens
• Dehydroepiandrosterone sulfate
• Medulla • Catecholamines
• Epinephrine
• Norepinephrine
Disease
Excess
Tumor
Primary Ectopic
Congenital ExogenousHormonal
Dysfunction
Deficiency
Injury
Mass effect Ischemia Inflammation Infection
TumorHormone
Dysfunction
Adrenal Cortical Adenoma
• Frequent incidental finding on CT or at autopsy
Adrenocortical Carcinoma
• Difficult to distinguish with adenoma
• Unencapsulated
• Nuclear Pleomorphism
• Mitoses
• Necrosis
• Invasion – either local invasion or distant metastasis
Adrenocortical Carcinoma
Adrenocortical Carcinoma
• Modified Weiss criteria:• Mitotic rate >5 per 50 high-power fields
• Cytoplasm (clear cells comprising 25% or less of the tumor)
• Abnormal mitoses
• Necrosis
• Capsular invasion
• Score: mitotic rate criterion + clear cytoplasm criterion + abnormal mitoses + necrosis + capsular invasion
• Each criterion is scored 0 when absent and 1 when present in the tumor
• Score ≥ 3 suggests malignancy
Hyperaldosteronism
• Primary (Conn Syndrome)• Hyperplasia
• Most common cause (60%)
• Pathology unclear
• Adenoma
• Primary familial hyperaldosteronism• Chimeric gene: CYP11B1 and CYP11B2
• Hybrid steroid hormones that have both mineralo- and glucocorticoid effects
• Gene under the influence of ACTH
• Secondary
Secondary Hyperaldosteronism
• Occurs as a consequence of ACTIVITY of Renin-Angiotensin system:• Too much renin
• Conditions:• Decreased renal perfusion
• Arteriolar nephrosclerosis
• Renal artery stenosis
• Arterial hypovolemia and edema
• CHF
• Cirrhosis
• Nephrotic syndrome
• Pregnancy
Clinical Manifestation
• Signs and Symptoms:• HYPERTENSION
• Hypokalemia (BUT not necessary)
• Laboratory Diagnosis:• Aldosterone:Renin ratio
• Confirmatory test: Aldosterone suppression test
Hypercortisolism
• Signs and Symptoms of Cushing’s Syndrome:
• Psychiatric
• General body changes
• Musculoskeletal
• Skin changes
• Metabolism changes• Hyperglycemia
• Hypertension
• Osteoporosis
Laboratory Diagnosis of Cushing’s Syndrome
• Screening tests for Cushing’s:• Salivary cortisol
• 24 hour urine free cortisol
• Overnight dexamethasone suppression test.
24 hour Urine Free Cortisol
• Urinary Free Cortisol• Methodology – HPLC-MS
• Sensitivity of 100%
• Specificity of 98%
• Reference ranges varies but >4x the normal is diagnostic for Cushing’s syndrome
• Pros• Provides an integrated profile of cortisol secretion over a 24 hr period.
• Assay creatinine for adequacy (quality control variable built-in)
• Levels are unaffected by hepatic metabolism of cortisol.
• Cons• Need normal kidneys though!
• Other times to beware: pregnancy, water loading, topical steroids, and starvation
Overnight Dexamethasone Suppression Test
• How it is done…• Patient takes 1 mg of dexamethasone between 11p-12a
• Plasma cortisol is drawn between 8-9a• If suppression FAILS, then positive result
• Needs to suppress to <1.8 ug/dL (50 nmol/L)
• Pros• Easier than collecting urine for 24 hours
• False negative results <2%
• Cons• False + rate can be as high as 30%
• Multiple reasons: took meds at the wrong time, interfering medicines (that accelerate steroid metabolism), malabsorption, alcoholism, pregnancy, people on exogenous estrogens
Confirmatory Testing
Dexamethasone Suppression Test Low dose DST
2 day test
UFC is taken for two consecutive days to establish baseline level
At 9 am, patient receives 0.5 mg dexamethasone q 6 hrs for 48 hrs
On day 2, another 24 hr urine is collected for UFC
Response:
• Normal: decrease in UFC to < 10 on day 2
Or, serum cortisol can be measured at baseline 9am on day 1 and 48 hrs later
Response:
• Normal: decrease to 1.8 ug/dL
Source of Hypercortisolism
High dose DST Good at distinguishing ectopic versus adrenal Cushing’s
Baseline 24 hr UFC
Day 1: 2 mg dexamethasone q 6 hr for 48 hrs
UFC collected Day 1 and Day 2
OR…plasma cortisol can be measured before, during and after steroid administration
Suppression of UFC/plasma cortisol by > 50% from baseline: CUSHING’S DISEASE
If not suppressed, more likely a functional adenoma, carcinoma or ectopic ACTH producing syndrome.
Hyperandrogenism
• Too much androgen hormone
• Arises from either:• Adrenal carcinoma
• Congenital adrenal hyperplasia• 21-hydroxylase deficiency (90%)
• Salt wasting syndrome
• Simple virilizing adrenogenital syndrome (no salt wasting)
• Nonclassic adrenogenital syndrome
• 17-hydroxylase deficiency
• 11-hydroxylase deficiency
21-hydroxylase deficiency
• ↑ sex hormones• ↓ cortisol• ↓ mineralocorticoids• ↑ plasma renin• ↓ volumeHypotension, Hyperkalemia, HyponatremiaMASCULINIZATION, Pseudohermaphroditism
17 alpha hydroxylase deficiency↑ mineralocorticoids↓ cortisol↓ sex hormones
Hypertension, HypokalemiaPhenotypically F – NO MATURATION
11 beta hydroxylase deficiency↑ sex hormones↓ cortisol↓ Aldosterone, Corticosterone
HypertensionMASCULINIZATION
Pheochromocytoma
• Catecholamine-producing tumor
• <1% of secondary hypertension
Pheochromocytoma
• 80-90% sporadic
• 10-20% associated with:• MEN2A or 2B
• Von Hippel Lindau
• Neurofibromatosis type 1
• Familial paraganglioma
• Occurs outside of the adrenal gland Paraganglioma
• Signs and Symptoms:• Episodic hypertension
• Anxiety
• Diaphoresis
• Weight loss
Laboratory Testing for Pheochromocytoma
Adrenal Insufficiency
• Primary insufficiency• Increased ACTH (>50-100 pg/ml)
• Secondary, tertiary• Low ACTH (< 10 pg/ml)
Waterhouse-Friderichsen Syndrome
Causative agent?
Neisseria meningitidis
Congenital Adrenal Hyperplasia
Laboratory Testing for Adrenal Insufficiency
• Basal hormone measurement: Cortisol <3ug/dl at 8am
• ACTH stimulation test: • Take baseline cortisol level 250ug cosyntropin cortisol at 30, 60
minutes post• Should get cortisol increase to >18-20 ug/dl
Adrenal Myelolipoma
• Benign neoplasm composed of:• Mature Fat (lipoma)
• Bone Marrow (myelo)
• Found incidentally on radiography or at autopsy
• Rare
• Obese adults
• Mean age 50 y
• Follow up or surgical excision if symptomatic
Adrenal Myelolipoma