Autocrine Paracrine Endocrine In endocrine signaling, the secreted molecules ( hormones) act on target cells that are distant from their site of synthesis. An endocrine hormone is frequently carried by the blood from its site of release to its target.

 Hormones that trigger biochemical signals upon interacting with cell-surface receptors Growth hormone and insulin  Hormones that diffuse across the plasma membrane and interact with intracellular receptors Steroids (e.g., estrogen, progesterone, and glucocorticoids), and thyroxine.progesterone

 Diseases of underproduction or overproduction of hormones and their resulting biochemical and clinical consequences  Diseases associated with the development of mass lesions. (nonfunctional, or overproduction or underproduction of hormones).

 Pituitary  Thyroid  Parathyroid  Adrenal

 The anterior pituitary, or adenohypophysis, constitutes about 80% of the gland:  Somatotrophs, producing (GH): acidophilic cells constitute half of all the hormone-producing cells in the anterior pituitary.  Lactotrophs (mammotrophs): acidophilic cells prolactin  Corticotrophs: basophilic cells (ACTH), (POMC), (MSH), endorphins, and lipotropin.  Thyrotrophs: pale basophilic cells (TSH).  Gonadotrophs: basophilic cells (FSH),(LH).

 Posterior pituitary, or neurohypophysis -  hypothalamus, through the pituitary stalk to the posterior lobe: anti-diuretic hormone (ADH, vasopressin ) and oxytocin. vasopressin oxytocin  In contrast to the anterior lobe, the posterior lobe of the pituitary is supplied by an artery and drains into a vein.  The pituitary has a dual circulation, composed of arteries and veins and a portal venous system linking the hypothalamus and the anterior lobe.

 The thyroid gland consists of two bulky lateral lobes connected by a relatively thin isthmus, usually located below and anterior to the larynx.  The thyroid gland is one of the most responsive organs in the body and contains the largest store of hormones of any endocrine gland.

 Graves : 1835 : "violent and long continued palpitations in females" associated with enlargement of the thyroid gland.  Graves disease  Hyperthyroidism owing to hyperfunctional, diffuse enlargement  Infiltrative ophthalmopathy (exophthalmos)  Localized, infiltrative dermopathy (pretibialmyxedema)

 Graves disease is an autoimmune disorder : (autoantibodies to the TSH receptor are central to disease pathogenesis):  LATS IgG antibody : anti-TSH receptor  Coexistence of stimulating and inhibiting immunoglobulins in the serum of the same patient, a finding that could explain why some patients with Graves disease spontaneously develop episodes of hypothyroidism.

 Thyroiditis: inflammation of the thyroid gland  Acute illness with severe thyroid pain (e.g., infectious thyroiditis, subacutegranulomatousthyroiditis)  Disorders : little inflammation,thyroid dysfunction (subacute lymphocytic thyroiditis and fibrous [Reidel] thyroiditis).

 Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient.  Gradual thyroid failure by autoimmune destruction of the thyroid gland

 Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens. The feature of Hashimoto thyroiditis is progressive depletion of thyroid epithelial cells (thyrocytes), replaced by mononuclear cell infiltration and fibrosis.

 Solitary nodules : neoplastic  Nodules in younger patients : neoplastic  Nodules in males : neoplastic  A history of radiation : neoplastic  Nodules radioactive iodine (hot nodules) : benign

 Adenomas of the thyroid are typically discrete, solitary masses. ( follicular adenomas)  Degree of follicle formation and the colloid content of the follicles:  Simple colloid adenomas (macrofollicular adenomas)  A common form recapitulate stages in the embryogenesis of the normal thyroid (fetal or microfollicular, embryonal or trabecular).

 Carcinomas of the thyroid : 1.5%  Papillary carcinoma (75% to 85% of cases)  Follicular carcinoma (10% to 20% of cases)  Medullary carcinoma (5% of cases)  Anaplastic carcinoma (<5% of cases)

 Follicular Thyroid Carcinomas: mutations in the RAS family of oncogenes (HRAS, NRAS, and KRAS) NRAS mutations being the most common.NRAS mutations being the most common.  Papillary Thyroid Carcinomas. rearrangements of the tyrosine kinase receptors RET or NTRK1  Medullary Thyroid Carcinomas: Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2) RET protooncogene mutation  Anaplastic Carcinomas: Inactivating point mutations in the p53 tumor suppressor gene are rare in well-differentiated thyroid carcinomas but common in anaplastic tumors.  Environmental Factors. The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation

 Papillary structures  Orphan Annie nuclei  Psammoma bodies  Pseudoinclusions  Grooved nuclei

 Tall cell variant  Hyalinizingtrabecular tumors ( ret/PTC gene rearrangement)  Follicular  Encapsulated  Diffuse sclerosing

 Minimally invasive  Widely invasive

 Medullary carcinomas of the thyroid are neuroendocrineneoplasms derived from the parafollicular cells, or C cells, of the thyroid.

 Polygonal to spindle cells  Amyloid deposition  Bilaterality  Multicentricity  Necrosis  Hemorrhage

 Anaplastic carcinomas of the thyroid are undifferentiated tumors of the thyroid follicular epithelium.  Arising from a more differentiated carcinoma (papillary)  Lethal (100%)  Older age group > 65year

 Highly anaplastic cells:  (1) large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells  (2) spindle cells with a sarcomatous appearance  (3) mixed spindle and giant cells  (4) small cells

 The parathyroid glands are derived from the developing pharyngeal pouches that also give rise to the thymus.  The four glands normally lie in close proximity to the upper and lower poles of each thyroid lobe  10% of individuals have only two or three glands.

 The adrenal glands: paired endocrine organs: cortex and medulla: 4  Three layers in the cortex:  zonaglomerulosa  zonareticularis abuts the medulla.  Intervening is the broad zonafasciculata (75%) of the total cortex.  Three types of steroids:  (1) glucocorticoids (principally cortisol) zonafasciculata  (2) mineralocorticoids (aldosterone) zonaglomerulosa  (3) sex steroids (estrogens and androgens) zonareticularis.  The adrenal medulla chromaffin cells- catecholamines, mainly epinephrine

 Three basic types of corticosteroids (glucocorticoids, mineralocorticoids, and sex steroids)  (1) Cushing syndrome, characterized cortisol  (2) Hyperaldosteronism  (3) Adrenogenital or virilizing syndromes caused by an excess of androgens Overlapping

 Primary Hyperaldosteronism  Hyperaldosteronism (excess aldosterone secretion)  Sodium retention and potassium excretion  Primary aldosteronism (autonomous overproduction of aldosterone) with resultant suppression of the renin- angiotensin system and decreased plasma renin activity  Adrenocortical neoplasm(Adenoma) (Conn Syndrome).F/M (2:1) Adrenocortical neoplasm(Adenoma) (Conn Syndrome).F/M (2:1)  Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism), characterized by bilateral nodular hyperplasia (Cushing Syndrome) Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism), characterized by bilateral nodular  Glucocorticoid-remediable hyperaldosteronism (primary hyperaldosteronism) Respond to dexamethasone, ACTH induced

 In secondary hyperaldosteronism, in contrast, aldosterone release occurs in response to activation of the renin-angiotensin system  Increased levels of plasma renin Increased levels of plasma renin  Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)  Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome) Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)  Pregnancy (due to estrogen-induced increases in plasma renin substrate). Pregnancy (due to estrogen-induced increases in plasma renin substrate).

 Aldosterone-producing adenomas  solitary  small (<2 cm in diameter)  well-circumscribed lesions left > right  thirties and forties  women more often than in men  buried within the gland and do not produce visible enlargement  bright yellow on cut section  cortical cells (fasciculata cells than glomerulosa cells) (the normal source of aldosterone) cortical cells (fasciculata cells than glomerulosa cells) (the normal source of aldosterone)  the cells tend to be uniform in size (mature cortical cells) the cells tend to be uniform in size (mature cortical cells)  eosinophilic, laminated cytoplasmic inclusions( spironolactone bodies)after spironolactone eosinophilic, laminated cytoplasmic inclusions( spironolactone bodies)after spironolactone

 Loss of cortex  Congential adrenal hypoplasia  X-linked adrenal hypoplasia ( DAX-1 gene on Xp21)  "Miniature" type adrenal hypoplasia (unknown cause)  Adrenoleukodystrophy ( ALD gene on Xq28)  Autoimmune adrenal insufficiency  Autoimmune polyendocrinopathy syndrome type 1 ( AIRE-1 gene on 21q22)  Autoimmune polyendocrinopathy syndrome type 2 (polygenic)  Isolated autoimmune adrenalitis (polygenic)  Infection  Acquired immune deficiency syndrome  Tuberculosis  Fungi  Acute hemorrhagic necrosis ( Waterhouse-Friderichsen syndrome)  Amyloidosis, sarcoidosis, hemochromatosis  Metastatic carcinoma  Metabolic failure in hormone production  Congenital adrenal hyperplasia (cortisol and aldosterone deficiency with virlization)  Drug- and steroid-induced inhibition of adrenocorticotropic hormone or cortical

 Primary Chronic Adrenocortical Insufficiency (Addison Disease)  1855, Thomas Addison:  "general languor and debility  remarkable feebleness of the heart's action  change in the color of the skin”  Addison disease, or chronic adrenocortical insufficiency, is an uncommon disorder resulting from progressive destruction of the adrenal cortex( 90%) of the adrenal cortex has been compromised.  Addison disease (such as autoimmune adrenalitis) whites, women Addison disease (such as autoimmune adrenalitis) whites, women

 PHEOCHROMOCYTOMA  Pheochromocytomas(chromaffin cells ) catecholamines  (similar to aldosterone-secreting adenomas) give rise to surgically correctable forms of hypertension.  0.1% to 0.3%( fatal )  Other peptides –Cushing etc…

 Pheochromocytomas  "rule of 10s":  10% of pheochromocytomas arise in association with one of several familial syndromes MEN-2A and MEN-2B syndromes. MEN-2A and MEN-2B syndromes  10% of pheochromocytomas are extra-adrenal.  10% of nonfamilial adrenal pheochromocytomas are bilateral; this figure may rise to 70% in cases that are associated with familial syndromes.  10% of adrenal pheochromocytomas are biologically malignant  10% of adrenal pheochromocytomas arise in childhood ( male preponderance)( adults between 40 and 60 years of age, with a slight female preponderance)

 Syndrome Components  MEN, type 2AMedullary thyroid carcinomas and C-cell hyperplasia,Pheochromocytomas and adrenal medullaryhyperplasia,Parathyroid hyperplasia  MEN, type 2BMedullary thyroid carcinomas and C-cell hyperplasia,Pheochromocytomas and adrenal medullaryhyperplasia,Mucosalneuromas,Marf anoid features

 von Hippel-Lindau  Renal, hepatic, pancreatic, and epididymalcysts,Renal cell carcinomas,Angiomatosis,Cerebellarhemangio blastomas  von Recklinghausen Neurofibromatosis  Café au lait skin spots,Schwannomas, meningiomas, gliomas  Sturge-Weber:Cavernoushemangiomas of fifth cranial nerve distribution

 Small to large hemorrhagic  Well demarcated  Polygonal to spindle shaped(chromaffin,chief cells)  Sustentacular small cells  Together, Zellballen nests

 The endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets of Langerhans. The first evidence of islet formation in the human fetus is seen at 9 to 11 weeks.

 Diabetes mellitus (DM) is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both.  More than 140 million people suffer from diabetes,the most common noncommunicable diseases.  The number of affected individuals with diabetes is expected to double by The countries with the largest number of diabetics are India, China, and the United States.

 DIAGNOSIS  Blood glucose values are normally maintained in a very narrow range, usually 70 to 120 mg/dL.glucose values are normally maintained in a very narrow range, usually 70 to 120 mg/dL.  The diagnosis of diabetes is established by noting elevation of blood glucose by any one of three criteria: The diagnosis of diabetes is established by noting elevation of blood glucose by any one of three criteria:  A random glucose > 200 mg/dL A random glucose > 200 mg/dL  A fasting glucose > 126 mg/dL on more than one occasion A fasting glucose > 126 mg/dL on more than one occasion  An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200 mg/dL 2 hours after a standard carbohydrate load An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200 mg/dL 2 hours after a standard carbohydrate load

 1.Type 1 diabetes  2.Type 2 diabetes  3.Genetic defects of β -cell functionMaturity-onset diabetes of the young (MODY)  4.Genetic defects in insulin processing or insulin  5.Exocrine pancreatic defectsChronicpancreatitisPancreatectomyNeoplasiaCysticfibro sisHemachromatosisFibrocalculouspancreatopathy  6.EndocrinopathiesAcromegalyCushing  7.InfectionsCytomegalovirusCoxsackie virus B  8. Drugs Glucocorticoids  9.Genetic syndromes associated with diabetesDownsyndromeKleinfeltersyndromeTurner syndrome  10.Gestational diabetes mellitus

 The long-term complications in kidneys, eyes, nerves, and blood vessels are the same, as are the principal causes of morbidity and death.

 Several mechanisms contribute to β cell destruction:..  (1) CD4+ T cells (1) CD4+ T cells  (2) CD8+ cytotoxic T lymphocytes, which directly kill β cells and also secrete cytokines that activate macrophages. In the rare cases in which the pancreatic lesions have been examined at the early active stages of the disease, the islets show cellular necrosis and lymphocytic infiltration. This lesion is called insulitis. (2) CD8+ cytotoxic T lymphocytes, which directly kill β cells and also secrete cytokines that activate macrophages. In the rare cases in which the pancreatic lesions have been examined at the early active stages of the disease, the islets show cellular necrosis and lymphocytic infiltration. This lesion is called insulitis.

 The pathogenesis of type 2 diabetes remains enigmatic. Environmental factors, such as a sedentary life style and dietary habits  G enetic factors are even more important than in type 1 diabetes. Among identical twins, the concordance rate is 50% to 90%, while among first-degree relatives with type 2 diabetes (and in fraternal twins), the risk of developing the disease is 20% to 40%, compared to 5% to 7% in the population at large.  The disease is not linked to genes involved in immune tolerance and regulation,no autoimmune factors

 Large- and medium-sized muscular arteries ( macrovascular disease), as well as capillary dysfunction in target organs (microvascular disease).  Macrovascular disease(atherosclerosis )-   Myocardial infarction  Stroke  Gangrene.  Microvasculardisease  Retina  Kidneys  Peripheral nerves: (retinopathy, nephropathy, and neuropathy)

 Extracellular Matrix Components  Abnormal matrix-matrix and matrix-cell interactions  Cross-linking of polypeptides of same protein (e.g., collagen)  Trapping of nonglycated proteins (e.g., LDL, albumin)  Resistance to proteolytic digestion

 Intracellular and Plasma Proteins  AGE receptor ligation leads to generation of reactive oxygen species and NF- κ B activation  Target cells (endothelium, mesangial cells, macrophages) respond by:  Cytokines and growth factor secretion  Induction of procoagulant activity  Increased vascular permeability  Enhanced ECM production

 Pancreas  Type 1>type 2 diabetes.  Reduction in the number and size of islets.  InsulitisT lymphocytes..  Eosinophilic infiltrates Eosinophilic infiltrates  β -cell degranulation. β -cell degranulation.  Amyloid replacement of islets in type 2 diabetes Amyloid replacement of islets in type 2 diabetes  Fibrosis Fibrosis

 Myocardial Infarction  Gangrene  Stroke  Hyaline changes

 Diabetic Microangiopathy.  One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes.  Diabetic retinopathy  Diabetic nephropathy  Diabetic neuropathy

 (1) glomerularlesions  (2) renal vascular lesions, principally arteriolosclerosis  (3) pyelonephritis, including necrotizing papillitis.

Mes CL RBC US

 Diabetic Ocular Complications:  Retinopathy  Cataract formation  Glaucoma

 Diabetics are plagued by enhanced susceptibility to infections of the skin

 The eye:Thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body is a reliable histologic marker of diabetes mellitus in the eye  The retinal vasculopathy of diabetes mellitus may be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy

 Diabetes is more than one disease.