The Endocrine System

1. The Endocrine System

2. 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 • Hypothalmicsuprasellar tumors

3. Pituitary Gland Anterior 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 sellaturcica, visual field abnormalities, elevated intracranial pressure, pituitary apoplexy

4. Pituitary Gland Hyperpituitarism – 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

5. Pituitary Gland Prolactinomas 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

6. Pituitary Gland Somatothroph 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

7. Pituitary Gland Corticotroph adenoma Cushing disease Nelson syndrome Gonotroph adenoma Thyrotroph adenoma Nonfunctioning pituitary adenoma Pituitary carcinoma ( <1% of all pituitary tumors)

8. Pituitary Gland Hypopituitarism 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

9. Pituitary Gland Posterior pituitary syndromes DI SIADH Hypothalamic suprasellar tumors Gliomas Craniopharygiomas

10. 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

11. 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%) Hyperfunctionalmultinodular goiter Hyperfunctional adenoma of the thyroid

12. Thyroid GLand Clinical 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

13. Thyroid Gland Hypothyroidism 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

14. Thyroid Gland Clinical 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

15. Thyroid gland Thyroiditis 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

16. Thyroid Gland Graves 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

17. Thyroid Gland Diffuse 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

18. Thyroid gland Neoplasms Adenoma Carcinoma Papillary Follicular Anaplastic Medullary Congenital anomaly – Thyroglossal duct or cyst

19. 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

20. Thyroid Gland • Adenomas • Follicular, capsule, functioning autonomy, TSH receptor signaling pathway mutations in toxic ademonas • Unilateral painless mass – usual presentation

21. Thyroid Gland • Carcinomas • Papillary – 85% of cases, associated with prior radiation, Orphan Annie eyes nuclei, papillae, psammoma bodies • Follicular • Anaplastic • Medullary - MEN syndromes, calcitonin

22. 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

23. Parathyroid Glands • Hyperparathyroidism • Primary – adenoma ( 85-95%), hyperplasia, carcinoma • Familial forms – MEN-1, MEN-2, Familial hypocalciurichypercalcemia • 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

24. 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

25. 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”

26. 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

27. 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

28. 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

29. 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

30. Morphology of DM and Complications • Pancreas • Reduction in number and size of islets • Leucocyticinflitrates 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, intercapillaryglomerulosclerosis ( Kimmelstiel-Wilson) • Renal vascular • Pyelonephritis • Diabetic ocular complications – chapter 29 • Diabetic neuropathy – chapter 27

31. 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

32. 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

33. 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

34. 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

35. 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

36. Adrenal Cortex • Primary Hyperaldosteronism • Resultant suppression of renin-angiotensin system • Decreased levels of renin • Bilateral idipathichyperaldosteronism • Adrenocortical neoplasm • Glucocorticoid-remediable hyperaldosteronism • Hypertension – endothelial dysfunction • Secondary caused by activation of renin-angiotensin system, increased renin

37. Adrenal Cortex • Adrenogenital syndrome • Neoplasms • Congenital adrenal hyperplasia • 21-hydroxylase deficiency • Salt-wasting • Simple virilizing ( ambiguous genitalia) • Nonlassic or late-onset adrenal virilism

38. 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

39. Adrenal Medulla • Paraganglion system • Pheochromocytomas • Rule of 10s – sort of • Extra-adrenal • Bilateral • Malignant • No hypertension • Familial

40. Multiple Endocrine Neoplasia Syndromes • Multiple Endocrine Neoplasia, type 1 (Wermer syndrome) • Parathyroid, pancreas, pituitary, also gastrinomas • Multiple Endocrine Neoplasia, type 2 • MEN-2A (Sipplesyndorme) • Pheochromocytoma, medullary carcinoma, parathyroid hyperplasia • MEN -2B • Neuromas, marfanoid habitus, similar to 2A withouf hyperparathyroidism • Familial Medullary thyroid cancer -RET mutations, prophylactic thyroidectomy

41. Pineal Gland • Pinealomas • Germinomas