Chapter 24: Endocrine Flashcards
Define microadenoma of the pituitary
<1 cm
Features of diabetes insipidus
- deficiency of ADH
- inability of kidney to reabsorb water -> polyuria
- causes: head trauma, tumors, etc (central)
- nephrogenic results from non-responsiveness of renal tubules to circulating ADH
Features of SIADH
- hyponatremia from excessive water reabsorption with cerebral edema
- causes: ectopic ADH from non-pituitary tumors, drugs, CNS disorders
Two variants of craniopharyngioma
Adamantinomatous: usually children
-stratified squamous epithelium with peripheral palisading in a spongy reticulum with wet keratin formation
-dystrophic calcs, fibrosis, cyst formation
Papillary: usually adults
-sheets and papillae of squamous epithelium
-usually no calcs, keratin or cysts
-no peripheral palisading
Cardiac effects of hyperthyroidism
Palpitations and arrhythmia (esp. A fib)
Myocardial lymphocytes and eosinophils with fibrosis and fatty infiltration, sometimes resulting in LV dysfunction
What is cretinism?
- congenital/early childhood hypothyroidism
- less common with supplementation of iodine
- impaired CNS and skeletal development
Pathogenesis of Hashimoto thyroiditis
- loss of self-tolerance to thyroid autoantigens
- patients have circulating anti-thyroglobulin and thyroid peroxidase antibodies
- CD8 cytotoxic cell death and cytokine mediated cell death in addition to antibody mediated effects
Etiology of subacute (granulomatous/deQuervain) thyroiditis
Viral trigger usually
-stimulation of cytotoxic T cells that attack thyroid follicular cells
Histology of subacute thyroiditis
- patchy involvement of the gland
- early: neutrophilic destruction of follicles
- later: lymphocytes, macrophages, giant cells and granulomas
- even later: fibrosis
Biochemical/radioactive iodine findings in subacute thyroiditis?
Increased T3 and T4 and decreased TSH
Decreased uptake of radioactive iodine
Histologic findings of Graves disease
- diffuse hypertrophy and hyperplasia of follicular cells
- tall, crowded follicular cells, sometimes forming micropapillae
- pale, scalloped colloid
- lymphoid infiltrates and germinal centres
Features associated with higher likelihood of a thyroid nodule being neoplastic
- younger age
- history of radioactive iodine
- male gender
- solitary nodule
- cold nodules more likely malignant than hot nodules
Pathogenesis of follicular thyroid carcinoma
PI3/AKT signalling pathway mutations
- includes RAS gain of function and PTEN loss of function
- end result is activating of oncogenic pathway
t(2;3) found in some follicular carcinomas: PAX-PPARG fusion gene
Special features of tall cell variant of PTC
- older patients, more aggressive
- most have BRAF mutations, some with RET/PTC translocations in addition, which may account for more aggressive behaviour
Special features of the diffuse sclerosing variant of PTC
- younger patients including children
- papillary growth but with extensive fibrosis
- no BRAF mutations; some have RET/PTC
Histologic features of follicular thyroid carcinoma
- often well circumscribed proliferations of small follicles with or without colloid
- sometimes Hurthle cell dominant
- vascular invasion: either in or outside the capsule
- capsular invasion
- no nuclear features of PTC
What are the contents of oxyphil and chief cells?
Chief cells: parathyroid hormone secretory granules
Oxyphil cells: mitochondria and glycogen granules but no PTH granules
Functions of parathyroid hormone
- increased gut absorption of calcium
- increases renal conversion of Vit D to its active form
- increases renal reuptake of calcium
- increases urinary phosphate excretion
Causes of primary hyperparathyroidism and their frequencies
Adenoma (85%)
Hyperplasia (5-10%)
Carcinoma (1%)
Familial syndromes with primary hyperparathyroidism
MEN1: 11q13; both adenomas and hyperplasias
-mutations in MEN1 can also be found in sporadic adenomas
MEN2A: RET mutations chr 10
Familial hypocalciuric hypercalcemia::
-inactivating mutations in calcium sensing receptor gene (CASR) (3q)
Molecular defects identified in sporadic parathyroid adenomas
CyclinD1
MEN1
Features of parathyroid adenoma
- 0.5-5 gm
- other glands are normal weight
- peripheral rim of normal thyroid tissue
- may see endocrine atypia but usually no mitoses
Pathologic features of parathyroid carcinoma
- may exceed 10 gm in weight
- usually uniform cells often not distinguishable from adenoma
- diagnosis of malignancy rests of invasion of surrounding tissues and metastasis
Extra-parathyroid manifestations of hyperparathyroidism
Osteitis fibrosa cystica: thinned bone cortex with marrow replaced by cysts and fibrosis due to increased osteoclastic activity
Brown tumors
Nephrolithiasis
Metastatic calcification in other tissues
Cause of secondary hyperparathyroidism?
Usually, chronic renal failure
-impaired urinary phosphate excretion leads to hyperphosphatemia that depresses serum calcium levels and thereby increases PTH secretion
Tertiary hyperparathyroidism?
Parathyroid activity becomes autonomous such that it doesn’t require stimulation from low serum calcium to produce PTH. May require parathyroidectomy.
Product and function of pancreatic alpha cells?
Glucagon secretion
Causes hyperglycemia
Product and function of pancreatic delta cells?
Somatostatin secretion
Inhibits both insulin and glucagon release
What cell types secrete VIP and serotonin, respectively?
VIP: D1 cells
Serotonin: Enterochromaffin cells
Main pathology of type I diabetes
- destruction of beta cells resulting in absolute lack of insulin
- loss of self-tolerance with putative antigens being insulin, glutamic acid decarboxylase, and islet cell autoantigen 512
Main pathology of type II diabetes
- peripheral resistance to insulin action and an inadequate response by beta cells (relative insulin deficiency)
- no autoimmune factors have been implicated in the pathogenesis
Genetic factors in type I DM
HLA type, especially DR3 and DR4
-other implicated genes include ‘insulin’, CTLA4 and PTPN22
Which probably has a larger genetic contribution, type I or type II DM?
Probably type II, with higher concordance in monozygotic twins
Factors by which obesity negatively influences insulin resistance
- adipokines
- nonesterified fatty acids
- inflammation
- peroxisome-proliferator activated receptor gamma
Monogenic causes of diabetes
- genetic defects in beta cell function (MODY; 6 different genes have been implicated)
- genetic defects in insulin action (mutations of the insulin receptor)
Metabolic pathways implicated in the deleterious effects in diabetes
- formation of advanced glycation end products: causes inflammation, ROS production, proliferation of vascular smooth muscle and procoagulant effects
- activation of protein kinase C: pro-angiogenic, pro-fibrogenic, and pro-inflammatory effects
- intercellular hyperglycemia and disturbances in polyol pathways
Macrovascular disease in diabetes
- results from endothelial dysfunction
- accelerated atherosclerosis: myocardial infarction, gangrene of extremities
Other systemic changes in DM
- hyaline arteriolosclerosis (also associated with hypertension, but more prevalent in diabetics)
- diabetic microangiopathy (basement membrane thickening with leaky capillaries: underlies diabetic retinopathy, nephropathy and neuropathy
Features of diabetic nephropathy
- glomerular lesions
- vascular lesions (hyaline arteriolosclerosis)
- pyelonephritis and papillary necrosis
Features of glomerular lesions in DM
- diffuse mesangial matrix increase
- diffuse basement membrane thickening
- nodular glomerulosclerosis (Kimmelstiel-Wilson nodules, PAS positive) with fibrin caps (in capillary loops) and capsular drops (adherent to Bowman’s capsule)
Most common causes of mortality in DM?
Myocardial infarction, renal insufficiency, cerebrovascular accidents
Features of gastrinoma
- over 50% malignant
- may arise in duodenum, pancreas or peripancreatic soft tissues
- produce ZE syndrome: pancreatic tumor, gastric acid hypersecretion and peptic ulceration
- 25% associated with MEN1
What is the gross feature of adrenal glands in Cushing disease?
Nodular cortical hyperplasia
Features of adrenal carcinomas
- more often functional than adenomas; often associated with virilization
- large, invasive tumors
- variegated, hemorrhagic and necrotic cut surface
- may be well differentiated or composed of monster cells
Features of MEN1
- hyperparathyroidism: both adenomas and hyperplasias
- pancreatic endocrine tumors
- pituitary adenomas (prolactinoma most common)
-also, duodenal gastrinomas, carcinoid tumors, thyroid and adrenal adenomas, lipomas
What is the mutation in MEN1
- germline mutation in MEN1 (menin)
- normal menin activates some cell cycle inhibitors such as p16
What syndromes are associated with pituitary tumors?
Carney complex (PRKAR1A)
Pituitary adenoma predisposition syndrome (mutations of AIP)
MEN1 (menin)
MEN1-like syndrome (CDKN1B/p27)
What are features of autoimmune polyendocrine syndromes types 1 and 2?
APS1: mutations in autoimmunre regulator gene (AIRE)
-autoimmune hypoparathyroidism, mucocutaneous candidiasis, primary adrenal insufficiency, idiopathic hypogonadism, pernicious anemia and ectodermal dysplasia; absence of AIRE compromises central tolerance to peripheral antigens, resulting in autoimmunity
APS2: adrenal insufficiency and autoimmune thyroiditis without other signs of ASP1 (more common, more heterogenous genetically)
What are candidate genes for type 2 DM?
- TCF7L2
- PPARG
- FTO
What are the main causes of primary hyperaldosteronism?
- idiopathic bilateral (most common)
- adrenocortical adenoma or carcinoma
- glucocorticoid remediable hyperaldosteronism due to ACTH (rare)
What are clinical features of hyperaldosteronism?
- hypertension
- hypokalemia (causing weakness, paesthesia, visual disturbance, tetany)
What’s the most common enzyme deficiency in congenital adrenal hyperplasia?
21 hydroxylase deficiency; may have salt wasting forms or simple virilizing forms
-adrenals are hyperplastic because of stimulation by ACTH, but glucocorticoids can’t be made
What are most common causes of primary chronic adrenocortical insufficiency?
- autoimmune adrenalitis (60-70%), due to autoantibodies to steroidogenic enzymes
- tuberculosis
- AIDS
- metastatic cancer
What are clinical features of Addison disease?
- weakness and fatigability
- GI distrubances
- hyperpigmentation due to increased levels of POMC (a precursor of ACTH - not seen in adrenocortical insufficiency caused by a primary pituitary or hypothalamic disease)
- hyperkalemia
- hyponatremia
- volume depletion
- hypotension
What underlying pathogenic mechanism do the SDHB C and D syndromes and VHL have in common?
All probably lead to stabilization of HIF1 alpha
What is catecholamine cardiomyopathy?
- a consequence of paroxysms of hypertension seen in pheochromocytoma
- acute CHF, pulmonary edema, myocardial infarction, arrhythmia, etc.
