Endocrine PathologyObjectives •Describe the pathways of feedback for hormone secretion in the...
Transcript of 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
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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
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Hypothalamus and Pituitary
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Hypothalamic-Pituitary Axis
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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
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Hypothalamic-Pituitary Axis Regulation
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Pituitary Gland Hormones
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Anterior Pituitary Cell Types – Acidophils
• Somatotrophs• GH producing
• 50% of hormone producing cells in the pituitary
• Lactotrophs• Prolactin producing
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Anterior Pituitary Cell Types – Basophils
• Corticotrophs• POMC producing
• ACTH
• MSH
• Lipotropin
• Beta-endorphin
• Gonadotrophs• FSH, LH producing
• Thyrotrophs• TSH producing
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Posterior Pituitary Cell Types
• Pituicytes• Modified glial cells
• Store already synthesized peptide hormones
• Secrete:• ADH (vasopressin)
• Oxytocin
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Dysfunction
Hyper
Neoplasm
Primary
Ectopic
Failed Feedback
Exogenous
Endogenous
Hypo
Neoplasm Iatrogenic
Surgery
Radiation
Injury
Ischemia
Infectious
Inflammatory
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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
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Clinical Manifestations of Pituitary Adenoma
• Prolactinemia• Signs and Symptoms:
• Galactorrhea
• Secondary amenorrhea
• Infertility
• Laboratory Diagnosis:• Prolactin Level
• Immunoassay
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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
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Screening test
Confirmatory Test Target
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Clinical Manifestations of Pituitary Adenoma
• ACTH-Secreting Adenoma• Cushing Disease
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Hypothalamic-Pituitary-Adrenal Axis
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Cushing Syndrome
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Diagnosis of Cushing Disease
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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
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Pituitary Carcinoma
• Rare <1%
• Commonly functional:• Prolactin
• ACTH
• Craniospinal or systemic metastasis
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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
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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
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Pituitary Gland Hormones Gone Wrong
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Rathke Cleft Cyst
• Mucinous thin-walled, cyst• Ciliated, cuboidal epithelium
• Incidental finding
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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
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AdamantinomatousCraniopharyngioma
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Posterior Pituitary Gland Hormones
• ADH• Maintain osmotic homeostasis
• Anti-diuretic Hormone
• Keep water!!!!!
• Oxytocin• Uterine contractions
• Myoepithelial cell contraction in the breast
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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
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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
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Adrenal Gland
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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
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Disease
Excess
Tumor
Primary Ectopic
Congenital ExogenousHormonal
Dysfunction
Deficiency
Injury
Mass effect Ischemia Inflammation Infection
TumorHormone
Dysfunction
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Adrenal Cortical Adenoma
• Frequent incidental finding on CT or at autopsy
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Adrenocortical Carcinoma
• Difficult to distinguish with adenoma
• Unencapsulated
• Nuclear Pleomorphism
• Mitoses
• Necrosis
• Invasion – either local invasion or distant metastasis
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Adrenocortical Carcinoma
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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
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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
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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
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Clinical Manifestation
• Signs and Symptoms:• HYPERTENSION
• Hypokalemia (BUT not necessary)
• Laboratory Diagnosis:• Aldosterone:Renin ratio
• Confirmatory test: Aldosterone suppression test
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Hypercortisolism
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• Signs and Symptoms of Cushing’s Syndrome:
• Psychiatric
• General body changes
• Musculoskeletal
• Skin changes
• Metabolism changes• Hyperglycemia
• Hypertension
• Osteoporosis
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Laboratory Diagnosis of Cushing’s Syndrome
• Screening tests for Cushing’s:• Salivary cortisol
• 24 hour urine free cortisol
• Overnight dexamethasone suppression test.
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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
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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
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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
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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.
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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
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21-hydroxylase deficiency
• ↑ sex hormones• ↓ cortisol• ↓ mineralocorticoids• ↑ plasma renin• ↓ volumeHypotension, Hyperkalemia, HyponatremiaMASCULINIZATION, Pseudohermaphroditism
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17 alpha hydroxylase deficiency↑ mineralocorticoids↓ cortisol↓ sex hormones
Hypertension, HypokalemiaPhenotypically F – NO MATURATION
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11 beta hydroxylase deficiency↑ sex hormones↓ cortisol↓ Aldosterone, Corticosterone
HypertensionMASCULINIZATION
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Pheochromocytoma
• Catecholamine-producing tumor
• <1% of secondary hypertension
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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
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Laboratory Testing for Pheochromocytoma
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Adrenal Insufficiency
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• Primary insufficiency• Increased ACTH (>50-100 pg/ml)
• Secondary, tertiary• Low ACTH (< 10 pg/ml)
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Waterhouse-Friderichsen Syndrome
Causative agent?
Neisseria meningitidis
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Congenital Adrenal Hyperplasia
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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
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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
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Adrenal Myelolipoma