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AutocrineParacrineEndocrine
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.
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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.
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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).
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Pituitary Thyroid Parathyroid Adrenal
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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).
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Posterior pituitary, or neurohypophysis -hypothalamus, through the pituitary stalk to the posterior lobe: anti-diuretic hormone (ADH, vasopressin) and 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.
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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.
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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)
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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.
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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).
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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
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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.
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Solitary nodules : neoplastic Nodules in younger patients : neoplastic Nodules in males : neoplastic A history of radiation : neoplastic Nodules radioactive iodine (hot nodules) :
benign
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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).
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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)
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Follicular Thyroid Carcinomas: mutations in the RAS family of oncogenes (HRAS, NRAS, and KRAS) 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
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Papillary structures Orphan Annie nuclei Psammoma bodies Pseudoinclusions Grooved nuclei
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Tall cell variant Hyalinizingtrabecular tumors ( ret/PTC
gene rearrangement) Follicular Encapsulated Diffuse sclerosing
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Minimally invasive Widely invasive
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Medullary carcinomas of the thyroid are neuroendocrineneoplasms derived from the parafollicular cells, or C cells, of the thyroid.
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Polygonal to spindle cells Amyloid deposition Bilaterality Multicentricity Necrosis Hemorrhage
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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
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Highly anaplastic cells: (1) large, pleomorphicgiant cells,
including occasional osteoclast-like multinucleate giant cells
(2) spindle cells with a sarcomatous appearance
(3) mixed spindle and giant cells (4) small cells
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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.
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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
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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
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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)
Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism), characterized by bilateral nodular hyperplasia (Cushing Syndrome)
Glucocorticoid-remediable hyperaldosteronism (primary hyperaldosteronism) Respond to dexamethasone, ACTH induced
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In secondary hyperaldosteronism, in contrast, aldosterone release occurs in response to activation of the renin-angiotensin system
Increased levels of plasma renin Decreased renal perfusion (arteriolar nep
hrosclerosis, renal artery stenosis) Arterial hypovolemia and edema (congest
ive heart failure, cirrhosis, nephrotic syndrome)
Pregnancy (due to estrogen-induced increases in plasma renin substrate).
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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) the cells tend to be uniform in size (mature cortical c
ells) eosinophilic, laminated cytoplasmic inclusions( spiro
nolactone bodies)after spironolactone
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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
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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
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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…
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Pheochromocytomas "rule of 10s": 10% of pheochromocytomas arise in association
with one of several familial 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)
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Syndrome Components MEN, type 2A Medullary thyroid
carcinomas and C-cell hyperplasia,Pheochromocytomas and adrenal medullaryhyperplasia,Parathyroid hyperplasia
MEN, type 2B Medullary thyroid carcinomas and C-cell hyperplasia,Pheochromocytomas and adrenal medullaryhyperplasia,Mucosalneuromas,Marfanoid features
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von Hippel-Lindau Renal, hepatic, pancreatic, and
epididymalcysts,Renal cell carcinomas,Angiomatosis,Cerebellarhemangioblastomas
von Recklinghausen Neurofibromatosis Café au lait skin spots,Schwannomas,
meningiomas, gliomas Sturge-Weber:Cavernoushemangiomas of
fifth cranial nerve distribution
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Small to large hemorrhagic Well demarcated Polygonal to spindle
shaped(chromaffin,chief cells) Sustentacular small cells Together, Zellballen nests
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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.
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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 2025.
The countries with the largest number of diabetics are India, China, and the
United States.
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DIAGNOSIS Blood
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:
A random glucose > 200 mg/dL A fasting glucose > 126 mg/dL on more than
one occasion An abnormal oral glucose tolerance test (OG
TT), in which the glucose is > 200 mg/dL 2 hours after a standard carbohydrate load
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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
defectsChronicpancreatitisPancreatectomyNeoplasiaCysticfibrosisHemachromatosisFibrocalculouspancreatopathy
6. EndocrinopathiesAcromegalyCushing
7. InfectionsCytomegalovirusCoxsackie virus B 8. Drugs Glucocorticoids 9. Genetic syndromes associated with
diabetesDownsyndromeKleinfeltersyndromeTurner syndrome
10. Gestational diabetes mellitus
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The long-term complications in kidneys, eyes, nerves, and blood vessels are the same, as are the principal causes of morbidity and death.
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Several mechanisms contribute to β cell destruction:.
(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.
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The pathogenesis of type 2 diabetes remains enigmatic. Environmental factors, such as a sedentary life style and dietary habits
Genetic 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
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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)
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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
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Intracellular and Plasma Proteins AGE receptor ligation leads to generation
of reactive oxygen species and NF-κB activation
Target cells (endothelium, mesangial cells, macrophages) respond by:
Cytokines and growth factor secretion Induction of procoagulant activity Increased vascular permeability Enhanced ECM production
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Pancreas Type 1>type 2 diabetes. Reduction in the number and size of
islets. InsulitisT lymphocytes. Eosinophilic infiltrates β-cell degranulation. Amyloid replacement of islets in type 2 di
abetes Fibrosis
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Myocardial Infarction Gangrene Stroke Hyaline changes
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Diabetic Microangiopathy. One of the most consistent
morphologic features of diabetes is diffuse thickening of basement membranes.
Diabetic retinopathy Diabetic nephropathy Diabetic neuropathy
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(1) glomerularlesions (2) renal vascular lesions, principally
arteriolosclerosis (3) pyelonephritis, including
necrotizing papillitis.
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Mes
CL RBC
US
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Diabetic Ocular Complications: Retinopathy Cataract formation Glaucoma
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Diabetics are plagued by enhanced susceptibility to infections of the skin
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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.22
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Diabetes is more than one disease.