The Endocrine System

Pituitary Gland Clinical manifestations of pituitary disease Pituitary adenomas and hyperpituitarism

Prolactinomas Growth hormone cell (somatotroph) adenomas ACTH (corticotroph) adenomas Other anterior pituitary adenomas

Hypopituitarism Posterior pituitary syndromes Hypothalmic suprasellar tumors

Pituitary GlandAnterior pituitary

Somatotrophs – GH

Lactotrophs – prolactin

Corticotrophs – ACTH, POMC, MSH

Thryotrophs – TSH

Gonadotrophs – FSH, LH

Posterior pituitary – axonal processes from hypothalamus:

Oxytocin

ADH

Clinical – Hyperpituitarism, Hypopituitarism, local mass effects – radiographic abnormalities of the sella turcica, visual field abnormalities, elevated intracranial pressure, pituitary apoplexy

Pituitary GlandHyperpituitarism – pituitary adenoma

Most common cause is adenoma arising in the anterior pituitary

Classified based on the hormone produced

Functional or nonfunctional

Microadenoma < 1 cm

Macroadenoma > 1 cm

Usually soft, well-circumscribed

30% invasive adenomas – no capsule

Cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma

Atypical adenomas – p53 mutations, aggressive

Pituitary GlandProlactinomas

Most frequent hyperfunctioning adenoma

Amenorrhea, galactorrhea, loss of libido, infertility

Tend to undergo dystrophic calcification

Any mass in the suprasellar department may disturb the normal inhibitory influence of the hypothalamus (via dopamine secretion) on prolactin secretion resulting in hyperprolactinemia

Pituitary GlandSomatothroph adenoma

Second most common

GH stimulates the hepatic secretion of IGF-1 (somatomedin C)

Gigantism or acromegaly

Failure to suppress GH production in response to a glucose challenge is one of the most sensitive tests for acromegaly

Pituitary GlandCorticotroph adenoma

Cushing disease

Nelson syndrome

Gonotroph adenoma

Thyrotroph adenoma

Nonfunctioning pituitary adenoma

Pituitary carcinoma ( <1% of all pituitary tumors)

Pituitary GlandHypopituitarism

Decreased secretion of pituitary hormones

Hypofunction when > 75% of pituitary is lost or absent

Causes – Tumors and other mass lesions, traumatic brain injury, subarachnoid

hemorrhage, pituitary surgery or irradiation, pituitary apoplexy, ischemic

necrosis and Sheehan syndrome, Rathke cleft cyst, empty sella syndrome, genetic defects, hypothalamic lesions, inflammatory or infections

Pituitary GlandPosterior pituitary syndromes

DI

SIADH

Hypothalamic suprasellar tumors

Gliomas

Craniopharygiomas

Thyroid Gland Hyperthyroidism Hypothyroidism

Cretinism Myxedema

Thyroiditis Hashimoto thyroiditis Subacute (granulomatous) thyroiditis Subacute lymphocytic (painless) thyroiditis

Graves disease Diffuse and multinodular goiters

Diffuse nontoxic (simple) goiter Multinodular goiter

Neoplasms of the thyroid Adenomas Carcinomas

Pathogenesis Papillary carcinonoma Follicular carcinoma Anaplastic (undifferentiated) carcinoma Medullary carcinoma

Congenital anomalies

Thyroid Gland Hyperthyroidism

Hypermetabolic state caused by elevated circulating levels of free T3 and T4

Thyrotoxicosis

Most common forms:

Diffuse hyperplasia associated with Graves disease ( 85%)

Hyperfunctional multinodular goiter

Hyperfunctional adenoma of the thyroid

Thyroid GLandClinical manifestations of hyperthyroidism

Hypermetabolic state

Overactivity of the sympathetic nervous system

Warm, flushed skin

heat intolerance

Sweating

Weight loss despite increased appetite

Cardiac- tachycardia, palpitations, cardiomegaly, arrhythmias,CHF,cardiomyopathy

Neuromuscular – tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, insomnia, myopathy

Ocular – wide staring gaze, lid lag

Osteoporosis

Thyroid storm

Apathetic hyperthyroidism

Thyroid GlandHypothyroidism

Causes-

Primary – Thyroid dysgenesis, Thyroid hormone resistance syndrome, postablative, Hashomoto’s thyroiditis, Iodine deficiency, drugs,

dyshormonogenetic goiter

Penred syndrome (+hearing loss)

Secondary – Pituitary failure, Hypothalamic failure

Thyroid GlandClinical manifestations:

Cretinism – infancy or childhood, impaired development of the skeletal system and CNS, short stature and mental retardation

Myxedema- older child or adult, slowing of physical and mental activity, fatigue, apathy, mental sluggishness, decreased sympathetic activity, non-pitting edema due to accumulation of matrix substances, decreased cardiac output

Thyroid glandThyroiditis

Infectious- acute or chronic

Hashimoto – autoimmune; anti- thyroglobulin, anti-thyroid peroxidase antibodies, Painless enlargement with hypothyroidism in a middle- aged woman, inflammatory infiltrate, germinal centers, Hurthle cells

Subacute (granulomatous or DeQuervain) - triggered by a viral infection, painful enlargement, transient

Subacute lymphocytic (painless) – also post- partum, variant of Hashimoto

Riedel – extensive fibrosis of thyroid and contiguous structures

Thyroid GlandGraves disease

Hyperthyroidism

Infiltrative ophthalmopathy exothalmos

Localized, infiltrative dermopathy pretibial myxedema

Antibodies: Thyroid-stimulating immunoglobulin, thyroid growth-stimulating immunoglobulin, TSH-binding inhibitor immunoglobulin

Diffuse hypertrophy and hyperplasia with tall, crowded follicular cells

Thyroid GlandDiffuse nontoxic (simple) goiter- colloid goiter, iodine deficiency, clinically euthyroid, sporadic usually related to substances that interfere with thyroid hormone synthesis, mass effects from enlarging size

Multinodular goiter- recurrent hyperplasia and involution from a long-standing simple goiter, mistaken for neoplasia, mass effects, occasionally toxic - hyperthyroidism

Thyroid glandNeoplasms

Adenoma

Carcinoma

Papillary

Follicular

Anaplastic

Medullary

Congenital anomaly – Thyroglossal duct or cyst

Thyroid Gland Solitary nodules, in general, are likely to be neoplastic than are

multiple nodules Nodules in younger patients are more likely to be neoplastic

than are those in older patients Nodules in males are more likely to be neoplastic that are

those in females A history of radiation treatment to the head and neck region is

associated with an increased incidence of thyroid malignancy Functional nodules that take up radioactive iodine in imaging

studies (hot nodules) are significantly more likely to be benign than malignant

Thyroid Gland Adenomas

Follicular, capsule, functioning autonomy, TSH receptor signaling pathway mutations in toxic ademonas

Unilateral painless mass – usual presentation

Thyroid Gland Carcinomas

Papillary – 85% of cases, associated with prior radiation, Orphan Annie eyes nuclei, papillae, psammoma bodies

Follicular Anaplastic Medullary - MEN syndromes, calcitonin

Parathyroid Gland PTH

Increases renal tubular reabsorption of calcium, thereby conserving free calcium

Increases the conversion of vitamin D to its active dihydroxy from in the kidneys

Increases urinary phosphate excretion, thereby lowering serum phosphate levels

Augments gastrointestional calcium absorption Malignancy is the most common cause of clinically apparent

hypercalcemia Hyperparathyroidism is the most common cause of asymptomatic

hypercalcemia

Parathyroid Glands Hyperparathyroidism

Primary – adenoma ( 85-95%), hyperplasia, carcinoma Familial forms – MEN-1, MEN-2, Familial hypocalciuric hypercalcemia Cyclin D1gene inversions MEN1 mutations Clinical – “painful bones, renal stones, abdominal groans, psychic moans” Table 24-5 Causes of Hypercalcemia

Secondary – renal failure is most common Hypoparathyroidism – surgically induced, autoimmune, Ad, FIH,

congenital absence, tetany, Chvostek and Trousseau signs, mental status changes, intracranical calcifications, Prolonged QT, dental

Pseudohypoparathyroidism

The Endocrine Pancreas Diabetes mellitus

Diagnosis Classification Glucose homeostasis Pathogenesis of type 1 DM Pathogenesis of type 2 DM Monogenic forms of diabetes Pathogenesis of late complications of DM Morphology of diabetes and its late complications Clinical features of DM

Diabetes Mellitus Diagnosis

A random glucose > 200mg/d l, with classical signs and symptoms

Fasting glucose concentration > 126 mg/dl Abnormal oral glucose tolerance test ( glucose >200mg.dL 2

hours after a standard carbohydrate load “pre-diabetes”

Diabetes Mellitus Classification – Table 24-6 Glucose homeostasis

Glucose production in the liver Glucose uptake and utilization by peripheral tissues (primarily

muscle) Actions of insulin and counter-regulatory hormones

Most important stimulus for insulin synthesis and release is glucose itself

Insulin is the most potent anabolic hormone, increase the rate of glucose transport into certain cells in the body – striated muscles including cardiac and adipose, other cells – uptake is insulin dependent

Diabetes Mellitus Pathogenesis of Type I

Autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous Beta-cell antigens

HLA-DR3 or HLA-DR4 Viral infections Failure of self-tolerance in T cells Clinical manifestations begin after > 90% Beta cells are

destroyed

Diabetes Mellitus Pathogenesis of Type 2

Decreased response of the peripheral tissues to insulin Beta-cell dysfunction – manifested as inadequate insulin

secretion in the face of insulin resistance and hyperglycemia Obesity

Nonesterified fatty acids Adiokines Inflammation Peroxisome proliferator-activated receptor gamma Intrinsic predisposition to Beta-cell failure

Pathogenesis of Complications of DM Macrovascular disease – accelerated atherosclerosis Microvascular disease – retinopathy, nephropathy,

neuropathy Persistent hyperglycemia – Hemoglobin A1C

Pormation of advanced glycation end products Activation of protein kinase C Intracellular hyperglycemia and disturbances in polyol pathways

Morphology of DM and Complications Pancreas

Reduction in number and size of islets Leucocytic inflitrates in the islets Amyloid deposition , reduction in islet cell mass ( type 2) Increase in number and size of islets ( IDM)

Macrovascular disease Endothelial dysfunction, MI – most common cause of death, gangrene, hyaline arteriolosclerosis

Diabetic microangiopathy Diffuse thickening of basement membranes, leaky capillaries

Diabetic nephropathy Glomerular lesions – Thickening of GBM, increase in mesangial matrix, intercapillary

glomerulosclerosis ( Kimmelstiel-Wilson) Renal vascular Pyelonephritis

Diabetic ocular complications – chapter 29 Diabetic neuropathy – chapter 27

Clinical Features of DM Type 1

Polyuria, polydipsia, polyphagia Honeymoon period Catabolic state – glucose, fats, proteins DKA Table 24-7 Type 1 vs Type 2 DM

Clinical Features Type 2

Hyperosmolar nonketotic coma Complications

MI, Renal vascular insufficiency, strokes End-stage renal disease Visual impairment Distal symmetric polyneuropathy of lower extremities Autonomic neuropathy Increased susceptibility to infections: skin, TB, pneumonia,

pyelonephritis

The Endocrine Pancreas Pancreatic Endocrine Neoplasms

Hyperinsulinism (insulinoma) – persistent hypoglycemia Zollinger-Ellison syndrome (gastrinomas) – peptic ulceration Other rare pancreatic endocrine neoplasms

Alpha –cell tumors – increase glucagon Delta-cell tumors – somatostatinomas VIPoma Carcinoid

Adrenal Glands Adrenal cortex

Adrenocortical hyperfunction (hyperadrenalism) Hypercortisolism (Cushing syndrome) Primary hyperaldonsteronism Adrenogenital syndromes

Adrenocortical insufficiency Primary acute adrenocortical insufficiency Waterhouse-Friderichsen syndrome Primary chronic adrenocortical insufficiency (Addison disease) Secondary adrenocortical insufficiency

Adrenocortical neoplasms Other lesions of the adrenal

Adrenal medulla Pheochromocytoma

Adrenal Cortex Hypercortisolism ( Cushing syndrome)

Clinical features – Table 24-9 Any condition that produces elevated glucocorticoid levels Exogenous – administration of gluocorticoids Endogenous – ACTH-dependent, ACTH –independent

Table 24-8 Cushing disease – ACTH-producing pituitary microadenoma Secretion of ectopic ACTH Adrenal neoplasms

Adrenal Cortex Primary Hyperaldosteronism

Resultant suppression of renin-angiotensin system Decreased levels of renin Bilateral idipathic hyperaldosteronism Adrenocortical neoplasm Glucocorticoid-remediable hyperaldosteronism Hypertension – endothelial dysfunction Secondary caused by activation of renin-angiotensin system,

increased renin

Adrenal Cortex Adrenogenital syndrome

Neoplasms Congenital adrenal hyperplasia

21-hydroxylase deficiency Salt-wasting Simple virilizing ( ambiguous genitalia) Nonlassic or late-onset adrenal virilism

Adrenal Cortex Adrenocortical Insufficiency – Table 24-10 Acute adrenal cortical insufficiency

Crisis precipitated by any form of stress Rapid withdrawal of steroids or failure to increase dose with

acute stress Massive adrenal hemorrhage Weaknees, fatigue, hyperpigmentation (primary ), hyperkalemia,

hypomatremia, volume depletion, hypotension

Adrenal Medulla Paraganglion system Pheochromocytomas

Rule of 10s – sort of Extra-adrenal Bilateral Malignant No hypertension Familial

Multiple Endocrine Neoplasia Syndromes Multiple Endocrine Neoplasia, type 1 (Wermer syndrome)

Parathyroid, pancreas, pituitary, also gastrinomas Multiple Endocrine Neoplasia, type 2

MEN-2A (Sipple syndorme) Pheochromocytoma, medullary carcinoma, parathyroid hyperplasia

MEN -2B Neuromas, marfanoid habitus, similar to 2A withouf

hyperparathyroidism Familial Medullary thyroid cancer -RET mutations, prophylactic

thyroidectomy

Pineal Gland Pinealomas Germinomas