Transcript ENDOCRINE pathology

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.
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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 reninangiotensin 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
nephrosclerosis, renal artery stenosis)
Arterial hypovolemia and edema (congestive 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 cells)
eosinophilic, laminated cytoplasmic inclusions(
spironolactone 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,Marf
anoid features
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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
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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 (OGTT), 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
defectsChronicpancreatitisPancreatectomyNeoplasiaCysticfibro
sisHemachromatosisFibrocalculouspancreatopathy
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
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(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
diabetes
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.
US
CL
RBC
Mes
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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.