Lecture #19Endocrine 2

Parathyroid gland

Four glands, embedded within the thyroid lobes Can show different number and location,"some people

have 5 glands but generally they are 5 in number". Composed of: 1-Chief cells, light or dark pink, secret parathyroid

hormone (PTH) 2-Oxyphil cell, larger, acidophilic cytoplasm, contain

numerous mitochondria"similar to the Herbal cell in Hashimoto's disease".

PT is controlled by blood level of free ionized calcium PTH activates osteoclasts, to mobilizes calcium from

bone matrix into blood PTH increases absorption of calcium from enterocytes PTH increases reabsorption of calcium in kidney,

activates Vitamin D and enhances phosphate secretion

Primary hyperparathyroidism:Features:

Manifests as hypercalcemia Mostly silent, asymptomatic Symptoms of hypercalcemia: bone pain, kidney stones,

constipation, seizure, psychosis Associated with high Parathyroid hormone

Causes:

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(1 ) adenoma, 80%, most coomon,a single gland is enlarged and secretes PTH aberrantly

Note: almost diseases of pituitary and thyroid glands are related to adenoma

(2) hyperplasia, 15%, the four glands are enlarged and secret PTH

(3) carcinoma, 5%

Pathobiology:Genetic mutation in two genes:(1) Parathyroid adenomatosis gene (PRAD1); its produces Cyclin-D1 protein, which normally activates cell cycle. There is over expression of Cyclin-D1 in PTH adenoma and hyperplasia(2) Multiple Endocrine Neoplasia gene (MEN1); a tumor suppressor gene, mutant gene produces inactive protein

Morphology Normally, the weight of parathyroid gland is very

small about 0.1 ,but in adenoma it reach from 0.5 to 5 g, its weight is important in diagnosis of adenoma

Microscopically, adenoma appears encapsulated, predominantly contains chief cells and absent fat cells, absent of oxophilic cell. The background normal cells outside the capsule are atrophic

PT hyperplasia: all gland are enlarged "this the only difference from adenoma.

PT carcinoma: chief cells invade adjacent structures and into blood vessels

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Normally we see 2 types of the cell but because of neoplastic we just can identify one type which is chief cell "

Solitary chief-cell parathyroid adenoma revealing clear delineation from the residual gland below. B, High-power detail of chief-cell parathyroid adenoma. There is slight variation in nuclear size and tendency to follicular formation

Secondary hyperparathyroidism Here the problem is not in parathyroid but something

else stimulating the gland.CAUSES:

Secondary to chronic renal failure

Chronic hypocalcemia, "we considered about free calcium in the blood not bounded one "and hyperphosphatemia stimulate secretion of PTH

With time, all parathyroid glands become enlarged , REMEMBER :ENLARGEMENT OF 4 GLANDS IS

HYPERPLASIA.

Bone changes:

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Parathyroid hormone increases osteoclast activity, causes bone resorption, bone trabeculae becomes thin

By continues resorption our body try to compensate it by bone remodeling,which is mean New bone formation takes place

With repeated episodes; fibrosis, hemorrhage and masses of multinucleated giant cells accumulate and form what is called: Brown tumor of hyperparathyroidism .

Brown tumor: is secondary to hyperparathyroidism, characteristic by presence of many osteoclastic cells ,fibrosis and hemorrhage in tissue ,it might be seen in the jaw .

Hypoparathyroidism Rare Mostly secondary to surgical removal Also associated with immobility Causes hypocalcaemia

Endocrine Pancreas Islets of Langerhans that responsible on endocrine

function of pancreas α: Glucagon" elevate glucose level in the blood,

glycogenolysis " β: Insulin, anabolic, increases synthesis and reduced

degradation of glycogen, lipid, and protein. Also has several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation

δ: Somatostatin, inhibitory

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PP (pancreatic polypeptide): Vasoactive intestinal peptide (VIP), secretary, immobility

Diabetes Milletus Group of diseases share the persistence of

hyperglycemia Can result from: 1-Impaired insulin synthesis,beta cell destruction

defines as type1 2-Impaired insulin action,type 2 which is more difficult 3-both Chronic hyperglycemia causes diseases in almost all

organs, especially the vessels, kidneys, retina and nerves

Diagnosis:1. Random blood glucose level > 200 mg/dL in the presence

of symptoms,"if we test the suger after eating shoudnt elevate more than 200 OR,

2. Fasting level > 126 twice or more reading

Type 1 DM: 10% of DM cases

Absolute deficiency in insulin synthesis either by genetic factor "more in family than other ,as in identical twins" or environmental" viruses attack beta cell and destoy them or by cross rxn in which immune system will destroy the cells

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Destruction to β-cells, secondary to autoimmune process and genetic predisposition

Common in children Needs insulin replacement Similar picture is seen in chronic pancreatitis, pancreatic

carcinoma, pancreatectomy

Type 2 DM 90% of cases,the most common Insulin secreted by beta ell but there is peripheral a

resistance for insulin Increased cellular resistance to insulin Inability of β-cells to secret more insulin to counter this

resistance More common in adults Genetic and environmental factors (obesity, sedentary

life) Similar picture is seen in acromegaly, Cushing syndrome,

hyperthyroidism, pheochromocytoma, steroid treatment

Note :insulin work alone but there are 5 hormones work against it 1-GH 2- thyroid 3-cortisol 4-adrenals 5- steroid ,(1:5)

If any of these hormone increase because of any related disease it will overcome insulin function and the pt will suffer from diabetes mellitus

Slide 17:

Tissues in the body differ in respond to insulin Most of the body are fat and musculoskeletal ,the

constitute about 2l3 of body weight "75%"

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These tissues are insulin dependent need insulin to uptake glucose , so in diabetic patient they are the most important to cause disease

Brain insulin independent

Complications1) - non enzymatic glycosylation:

Direct deposition of glucose onto proteins without the aid of enzymes

Proportional to the level of blood glucose, used to assess the degree of disease (glycosylated hemoglobin السكر(التراكمي

Glycosylated extracellular proteins undergo permanent physical and chemical changes, such as cross linking and trapping circulating lipoproteins, accelerating atherosclerosis and vasculopathy and glomerulopathy

Vasculopathy: disease of the vessels in the limbs cause ulcers>>>gangrene >>>ischemia and infection end with amputation "secondary to no enzymatic glycosylation"

2) Activation of protein kinase C Hyperglycemia activates PKC, which produces vascular

endothelial growth factor VEGF promotes angiogenesis and increased synthesis of

extracellular matrix This causes retinal damage and blindness Hyperglycemia increases blood viscosity, stagnation and

promotes thrombosis, augmenting retinopathy

Hyperglycemia>>>activates PKC>>>produces VEGF>>> increase synthesis and growth of small blood vessels ,for

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example, in the retina cause damage and blindness which is called retinopathy.

3) Intracellular hypeglycemia occur in insulin independent tissues

Examples:Nerves, lens, kidney and vessels are insulin independent in glucose uptake

Hyperglycemia is associated with intracellular hyperglycemia

Accumulated glucose is metabolized to sorbitol, a potent osmotic factor, causing water influx and cell damage

Sorbitol consumes cellular anti-oxidants, leaving cells more susceptible to damage

Important mechanism in diabetic neuropathy (pain, parasthesia, palsy, loss of pain, impotence

• Insulitis (autoimmune diabetes) is seen in type 1 human diabetes. Islets are destructed by lymphocytes

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Pancreatic Endocrine Neoplasia :related to islets of pancreas Rare, 2% of pancreatic tumors Heterogeneous: Single or multiple Functional or non Benign or malignant Little correlation between morphology and biologic

behavior for these reasons it called neoplasia Metastasis defines malignant tumor

Types:1. Insulinoma: β-cell tumor, the most common type, most

are benign and functional, causing severe hypoglycemia, confusion and loss of consciousness, precipitated by exercise

2. Gastrinoma: tumor of Gastrin-secreting cells, 50% are malignant, increased gastrin production causes multiple severe gastric ulcers

Note :Gastrin activates the G-cell in gastic gland to produce acid .

• Pancreatic endocrine tumor ("islet cell tumor"). The neoplastic cells form sheets instead of normal islets. They are monotonous and demonstrate minimal pleomorphism or mitotic activity.

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Adrenal Gland :

Cortex: (1) Granulosa: miniralocorticoids (aldosteron),increase

retention Na and water inside the cell and increase secretion K out side .

(2) Fasciculata: glucocorticoids (cortisol),retention of Na inside and secretion K out side ,but less specific than aldosteron,inaddition cortisol is catabolic hormone work in the whole body and neutralize insulin and growth hormone.

(3) Reticularis: sex steroids (estrogens and androgens)

Medulla: chromaffin cells, secrete catecholamines (epinephrine)

Cushing syndrome (Hypercortisolism):increae cortisol in the blood

Exogenous glucocorticoid administration is the most common cause (adrenal atrophy)

Endogenous causes:

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(1) pituitary corticotrph adenoma ,increase ACTH,(bilateral enlarged adrenal glands, activation both glands,called Cushing disease)

(2) Ectopic ACTH secretion by a malignant neoplasm (lung carcinoma)

(3) Primary cortical hyperplasia (familial, bilateral, rare) (4) Adrenocortical adenoma (unilateral), atrophic second

gland (5) Adrenocortical carcinoma (unilateral), very large size 3,4,5 contitute 10-20% of Cushing syndromes, low ACTH

The first one is normal But the second is hyperplasia, bilateral ,as we see diffuse enlargement of gland it couid be secondary for pituitary disease or benign familial

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aAdrenocortical denoma:tumor"mass"

- Small remenant glands- If it enlarge more,it will turn into carcinoma

Clinical features Hypertension"increase Na and water retention" Weight gain Fat redistribution "collection of fat in the center of the

body ": moon face, buffalo hump, central obesity Hyperglycemia Osteoporosis Immune suppression (infection) Depression, psychosis Muscle wasting

Conn syndrome (Hyperaldosteronism)

Adrenocortical adenoma, producing aldosteron Suppresses renin secretion from kidneys, but not ACTH Patients have hypertention and hypokalemia Treatment: surgical removal

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Adrenal Insufficiency Primary: adrenal gland disease, normal pituitary, can be

acute or chronic,more important Secondary: normal adrenal gland but no ACTH (pituitary

adenoma, Sheehan syndrome). Low cortisol and ACTH levels, responds well to exogenous ACTH administration

Primary Adrenal insufficiencyAcute: secondary to:

(1 )severe bacterial infection ,the most important ,(meningiococcous),causes sever hemorrhage in adrenal gland

(2 )sudden withdrawal of exogenous glucocorticoid administration

(3 )acute stress on top of chronic insuffiency It is a life-threatening condition, patients develop severe hypotension and cardiac arrest

Acute adrenal insufficiency caused by severe bilateral adrenal hemorrhage in an infant with overwhelming sepsis. At autopsy the adrenals were grossly hemorrhagic and shrunken; microscopically, little residual cortical architecture is discernible.

Chronic adrenal insufficiency

Gradual and progressive4 causes:(1) autoimmune (Addison disease), 70%,most common

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(2) Tuberculosis(3) Metastatic cancer,breast cancer (4) AIDS (secondary to repeated infections)

Clinical Features: Progressive weakness Weight loss Nausea and vomitting Hypoglycemia Hyperkalemia, hyponatremia Hypotension,most important one

Pheochromocytoma Tumor of adrenal medulla Synthesizes and release catecholamines “10% disease”: familial, bilateral, functional, malignant,

extra-adrenalExtra adrenal: Pheochromocytoma in other organ than adrenal gland with same features

90% unilateral Patients complain of intractable, paroxysmal

hypertension, vasoconstriction in all body vessels , resulting in renal injury, heart failure, myocardial infarction and cerebrovascular attacks that can kill the patients

Done by Tasneem ziad

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