endocrine pathologyobjectives •describe the pathways of feedback for hormone secretion in the...

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

Questions/Concerns?Lisa.Lopez@bswhealth.org

Office: 254-724-3690