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ParathyroidParathyroid
AdrenalAdrenal
PancreasPancreas
PTH
• Hypocalcemia is main stimulus (9-10.5 mg/dl)• Antagonize Calcitonin
35-50 mg
Parathyroid Gland – note small dark staining chief cells and larger, eosinophilic oxyphil cells
PARATHYROID DISORDERS
• Primary Hyperparathyroidism – Adenoma: 85% to 95% – Primary hyperplasia (diffuse or nodular): 5% to 10% – Parathyroid carcinoma: 1%∼
• Secondary Hyperparathyroidism- (LOW CA++ of Renal Failure)
• Hypoparath-: Surgical, congenital, familial, idiopathic• Pseudo - hypoparath.
– (end organ resistance)
Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma revealing clear delineation from the residual gland below. B, High-power detail of a chief cell parathyroid adenoma. some slight tendency to follicular formation
HYPER-PARATHYROIDISM
– Bone pain, fractures– Nephrolithiasis– Constipation, ulcers, gallstones– Depression, lethargy– Weakness, fatigue– Calcifications, esp. Lung, VALVES
HYPO-PARATHYROIDISM
– Neuromuscular irritability– Mental status change– Parkinsonism like effects– Widened QT interval– Defective, carious, teeth
MEN-1, Wermer Syndrome (3 P’s)
• HYPERPARATHYROIDISM, chiefly hyperplasia
• Pancreatic endocrine tumors• Pituitary adenoma, usually prolactinoma
MEN-2
• MEN-2A (SIPPLE): Pheochromo, Medullary Thyroid CA., Parathyroid hyperplasia
• MEN-2B: NO hyperparathyroidism, but neuromas present
• Familial Medullary Thyroid CA
ADRENAL CORTEX
• Glomerulosa (Salt), mineralocorticoids– ALDOSTERONE
• Fasciculata (Sugar), glucocorticoids– CORTISOL
• Reticularis (Sex), gonadocorticoids– ANDROGENS, ESTROGENS
4 g.
Adrenal Cortex
Zona Glomerulosa
(clumps, cords, and follicle like structures
Zona Fasciculata
(cords of spongiocytes)
SALT
SUGAR
SEX
STRESSSTRESS
HYPERADRENALISM
• HYPERALDOSTERONISM (G).• CUSHING SYNDROME (CORTISOL) (F).• ADRENOGENITAL (VIRILIZING)
SYNDROME (R).
CUSHING SYNDROME
• Exogenous steroid (90%)***• ACTH-DEPENDENT ** - pituitary adenoma; - Ectopic corticotropin syndrome (ACTH-secreting
pulmonary small-cell carcinoma, bronchial carcinoid)
• Adrenal adenoma• Adrenal Carcinoma• Hyperplasia.
CUSHING SYNDROME
• CENTRAL OBESITY
• MOON FACIES• WEAKNESS• HYPERTENSION• DIABETES• OSTEOPOROSIS• HIRSUTISM• STRIAE
CUSHING SYNDROME
MOON FACIES BUFFALO HUMP
STRIAE
Cushing syndrome
• Depending on the cause of the hypercortisolism the adrenals have one of the following abnormalities:
• (1) cortical atrophy,• (2) diffuse hyperplasia, • (3) macronodular or micronodular hyperplasia, • (4) an adenoma or carcinoma.
Diffuse hyperplasia of the adrenal contrasted with normal adrenal gland
Cushing syndrome
Dx: • (1) Increased the 24-hour urine free-cortisol
concentration.• (2) loss of normal diurnal pattern of cortisol
secretion.
Cushing syndrome
• Dx the cause of Cushing syndrome depends on;
• Serum ACTH and • Dexamethasone suppression test;
Measurement of urinary steroid excretion after administration of dexamethasone.
PRIMARY HYPERALDOSTERONISM(Conn’s Syndrome)
• Na+ RETENTION• K+ EXCRETION• HYPERTENSION
Secondary hyperaldosteronism
• Activation of the renin-angiotensin system, (increased plasma renin)
• In the following conditions: • Decreased renal perfusion (arteriolar nephrosclerosis, renal
artery stenosis) • Arterial hypovolemia and edema (CHF, cirrhosis, nephrotic
syndrome) • Pregnancy (due to estrogen-induced increases in plasma
renin substrate)
SECONDARY HYPERALDOSTERONISM
• DECREASED RENAL PERFUSION
• EDEMA (HEART, LIVER, KIDNEY)
• PREGNANCY
ADRENOGENITAL SYNDROME
• VIRILIZATION/feminization• CORTICAL NEOPLASM• CORTICAL HYPERPLASIA• 21-Hydroxylase Deficiency
ADRENAL INSUFFICIENCY
• PRIMARY ACUTE (ADRENAL CRISIS)• PRIMARY CHRONIC (auto-immune ADDISON
DISEASE)• SECONDARY (PITUITARY)
• hyperkalemia, hyponatremia, volume depletion, and hypotension
PRIMARY ACUTE
• Rapid withdrawal of steroid• Massive adrenal hemorrhage - Newborns with difficult delivery - Anticoagulant RX - Postsurgical DIC patient - MASSIVE ADRENAL HEMORRHAGE
(WATERHOUSE-FRIDERICHSEN, if it follows infection and shock)
Waterhouse-Friderichsen Syndrome septicemia , shock,DIC, adrenocortical insufficiency with bilateral adrenal hemorrhage
PRIMARY CHRONIC
• Most of Addison disease is auto-immune adrenalitis• INFECTIONS (Tuberculosis, fungal)• METASTASES (adrenals are preferred site for early lung
carcinoma metastases)• AIDS• Acute hemorrhagic necrosis (Waterhouse-Friderichsen
syndrome) • Amyloidosis, sarcoidosis, hemochromatosis,
lymphoma. • GENETIC DISORDERS
Autoimmune adrenalitis.
NEOPLASMS• ADENOMAS of ADRENAL CORTEX
• CARCINOMAS of ADRENAL CORTEX
Adrenocortical adenomas; a well-circumscribed, nodular lesion up to 2.5 cm expands the adrenal.Most are clinically silent
Adrenocortical Adenoma
Adrenocortical Adenoma
Carcinoma of the adrenal cortex
Carcinoma of the adrenal cortex
Low magnification of the Adrenal Gland
Medulla
Cortex
Adrenal Medulla
ADRENAL MEDULLA
• PHEOCHROMOCYTOMAS, “rule of 10s”. Primary tumors of adrenal medulla
– 10% arise in an MEN setting– 10% are EXTRA-adrenal– 10% are bilateral– 10% are malignant– 10% are not associated with hypertension,
(hypertension in 90%).– 10% are in childhood– can only call them malignant if they metastasize.
PHEO
TWO crucially important points specific for endocrine tumors:
• 1. FUNCTIONING carcinomas are very RARE in ANY endocrine gland.
• 2. Benign adenomas may have extremely bizarre nuclei, but are most usually BENIGN!!!
MEN-1, Wermer Syndrome (3 P’s)
• HYPERPARATHYROIDISM, chiefly hyperplasia
• Pancreatic endocrine tumors• Pituitary adenoma, usually prolactinoma
MEN-2
• MEN-2A (SIPPLE): Pheochromo, Medullary Thyroid CA., Parathyroid hyperplasia
• MEN-2B: Pheochromo, Medullary Thyroid CA., neuromas, NO hyperparathyroidism.
ENDOCRINEENDOCRINE
PANCREASPANCREAS
High mag of an Islet – note Beta cells and more eosinophilic Alpha2 cells
Acini
Alpha Cells
Exocrine
Endocrine
Islets
Alpha Cells
Beta Cells
Delta Cells (suppress insulin and glucagon)
Pancreatic Polypeptide (PP) cells
Epsilon Cells make gherlin, which causes hunger
Glucagon Insulin
Immunohistochemistry of a pancrearic Islet of Langerhans
• β cell produces insulin, • α cell secretes glucagon,• δ cells contain somatostatin, which suppresses both
insulin and glucagon• PP cells contain pancreatic polypeptide that exerts
secretion of GIT enzymes and inhibits its motility. • D1 cells elaborate vasoactive intestinal polypeptide
(VIP), that induces glycogenolysis and hyperglycemia; • Enterochromaffin cells synthesize serotonin and are
the source of pancreatic tumors that cause the carcinoid syndrome
Pancrearic Islet of Langerhans
DIABETES MELLITUS• 16 Million in the USA• 1 Million/yr
How to Diagnose Dm:
• Glucose >200• Or…………….• Fasting glucose >126 trice• Or…………….• Post-prandial glucose > 200, 2 hrs AFTER standard
OGTT (Oral Glucose Tolerance Test)
Classification of Diabetes MellitusAmerican Diabetes Association
1. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) Immune – mediated Idiopathic
2. Type 2 diabetes (combination of insulin resistance and β-cell dysfunction)
3. Genetic defects of β-cell function; Maturity-onset diabetes of the young (MODY)4. Exocrine pancreatic defects5. Endocrinopathies6. Genetic defects in insulin action7. Infections8. Drugs9. Gestational diabetes mellitus10.Genetic syndromes associated with diabetes
TWO* Types of DM
•1• Genetic• Autoimmune• Childhood (juvenile) onset• Antibodies to beta cells• Beta cell depletion• NON-OBESE patients
•2• Genetic, but diff. from Type 1• NOT autoimmune• Adult, or maturity onset, e.g.,
40’s, 50’s• Insulin may be low, BUT,
peripheral resistance to insulin is the main factor
• OBESE patients
Type 1 Diabetes Mellitus Type 2 Diabetes MellitusCLINICAL
Onset: usually childhood and adolescence
Onset: usually adult; increasing incidence in childhood and adolescence
Normal weight or weight loss preceding diagnosis
Vast majority are obese (80%)
Progressive decrease in insulin levels
Increased blood insulin (early); normal or moderate decrease in insulin (late)
Circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512)
No islet auto-antibodies
Diabetic ketoacidosis in absence of insulin therapy
Nonketotic hyperosmolar coma more common
GENETICS Major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs
No HLA linkage; linkage to candidate diabetogenic and obesity-related genes (TCF7L2, PPARG, FTO, etc.)
PATHOGENESIS Dysfunction in regulatory T
cells (Tregs) leading to breakdown in self-tolerance to islet auto-antigens
Insulin resistance in peripheral tissues, failure of compensation by β- cells
Multiple obesity-associated factors (circulating nonesterified fatty acids, inflammatory mediators, adipocytokines) linked to pathogenesis of insulin resistance
PATHOLOGY Insulitis (inflammatory
infiltrate of T cells and macrophages)
No insulitis; amyloid deposition in islets
β-cell depletion, islet atrophy
Mild β-cell depletion
Dm• POLY-• POLY-• POLY-
Metabolic actions of insulin
PATHOGENESIS• 1• T-Lymphocytes
reacting against poorly defined beta cell antigens
• Inflammatory inflitrate, chronic, i.e., “INSULITIS”
• 2• Diet• Life Style• Obesity• INSULIN RESISTANCE• Beta cells UN-able to
adapt to the “long term demands of insulin resistance”
MODY (Maturity Onset Diabetes of the Young)
• Multiple types• 2-5% of diabetics• Primary beta cell defects• Multiple genetic mechanisms, especially
GLUCOKINASE mutations
PANCREAS in Dm
PANCREAS in Dm
COMPLICATIONSMORPHOLOGY
• (MACRO-vascular) Atherosclerosis• MICRO-vascular
– Retinopathy– Nephropathy- glomerular, vascular, KW– Neuropathy (most common cause of
neuropathy)
• Infections
ATHEROSCLEROSIS
ATHEROSCLEROSIS
Diabetic Nephropathy• Renal failure is second only to MI as a cause of death from
DM. • Three lesions are encountered: (1) Glomerular lesions; capillary BM thickening, diffuse
mesangial sclerosis, and nodular glomerulosclerosis (2) vascular lesions, arteriolosclerosis; (3) PN, including necrotizing papillitis.
NEPHROPATHYGBM thickening
NEPHROPATHY
Kimmelstiel-Wilson (KW) Kidneys
Is…………
“Nodular” glomerulosclerosis
Diffuse and nodular diabetic glomerulosclerosis (PAS stain). Note the diffuse increase in mesangial matrix and characteristic acellular PAS-positive nodules.
Severe renal hyaline arteriolosclerosis
NEPHROPATHYNEPHROSCLEROSIS
RETINOPATHY in DmShows microaneurysms,
areas of hemorrhage,
cotton wool spots,
hard exudates,
venous beading,
neovascularization,
retinal detachment,
vitreous detachment,
pre retinal hemorrhage
INFECTIONS in Dm• SKIN• TUBERCULOSIS• PNEUMONIA• PYELONEPHRITIS• CANDIDA
NEOPLASMS of the Endocrine Pancreas
• Islet cell tumors– Beta cells INSULINOMAS (NOT rare)– Alpha cells GLUCAGONOMAS (rare)– Delta cells SOMATOSTATINOMAS (rare)
– GASTRINOMAS, producing ZOLLINGER-ELLISON SYNDROME, consisting of increased acid and ulcers
The Adrenal Glands
Pineal Body
The Seat of the Soul
The Third Eye
PINEAL “GLAND”
• PINEALOMAS– PINEOBLASTOMAS– PINEOCYTOMAS
Pineal Gland
N – neuroglia
P –pinealocytes
S – Brain Sand