Endocrine Part II Flashcards
What is the Incretin effct?
oral intake of food leads to secretion of multiple hormones that play a role in glucose homeostasis & satiety
what are the hormones released during Incretin effect and where are they secreted from?
Glucose-dependent insulinotropic polypeptide - K cells in the proximal small intestine
Glucagon-like peptide-1 = L cells in the distal ileum and colon
What mediates glucose u[tale by GLUT4 to the plasma membrane?
AKT - principle effector of the PI3K pathway
CBL - direct phosphorylation target of the Insulinr eceptor
What are the chances of u developing DM with first-degree relatives with DM?
5 to 10 fold higher risk
What are adipokines that decrease blood glucose by INC insulin sensitivity in peripheral tissues?
Leptin & Adiponectin
What adipokine is reduced in obesity thus contributing to insulin resistance?
Adiponectin
What can happen when there is an excessive FFA?
impedes insulin signaling directly within peripheral tissues or indirectly through the release of pro-inflammatory cytokines
what happens if there is excess FFAs within macrophages and B cells?
Activates Inflammasome –> secretion of the cytokine IL-1B
What is the function of IL-1B and IL-1?
IL-1B = mediates secretion additional pro-inflammatory cytokines
IL-1 and other cytokines = released into the circulation and act on the major sites of Insulin action to promote Insulin resistance
What are diff mechanisms that promote B cell dysfunction?
- Excess FFA compromising B cell function and Insulin release
- Impact of chronic hyperglycemia
- Abnormal “incretin effect” which leads to reduced secretion of GIP & GLP-1
- Amyloid deposits in the islets
- Genetics
what are the monogenic forms of DM?
Genetic defects in B cell function
Genetic defects in Insulin action
What are the genetic defects in Insulin action?
Type A insulin resistance = Acanthosis nigricans
Lipoatrophic DM = hyperglycemia w/ loss of adipose tissue
What are the 4 harmful effects of persistent hyperglycemia?
- Formation of advanced glycosylation end product
- Activation of protein kinase C
- Oxidative stress and disturbances in the polyol pathway
- Hexosamine pathway and formation of fructose-6-phosphate => exacerbates end organ damage
What is the histological presentation in DM type I & II?
Type I = INC in # of Islet cells, leukocytic infiltrates in the islets
Type II = Subtle reduction in islet cell mass, amyloid deposit in the islets –> expression of B cell exhaustion
What happens in diabetic macrovascular disease?
Endothelial dysfunction
- Accelerated atherosclerosis = Coronary artery (MI)
- Hyaline atherosclerosis: arterioles in Small BVs in the kidney
What histologic presentation is seen in diabetic microangiopathy disease?
Diffuse thickening of the BM –> capillaries of skin, skeletal muscle, retina, glomeruli, renal medulla
What are the 3 lesions formed from diabetic nephropathy?
- Glomerular lesion
- Renal vascular lesion
- Pyelonephritis
What is Kimmelstiel-Wilson lesion?
nodular glomerulosclerosis
What happens if renal vascular lesion & pyelonephritis progress?
Renal vascular lesion = arteriosclerosis
Pyelonephritis= necrotizing papilitis
What condition in the kidneys can occur if there is long standing DM? WHat does it look like (gross)?
Nephrosclerosis
- Diffuse granular transformation of the surface
- marked thinning of the cortical tissue
- irregular depression
- incidental cortical cyst
What are the different diabetic ocular complications?
Cataract –> disturbance of polyol pathway
Glaucoma
Retinal vasculopathy of DM
What are the complications of diabetic peripheral neuropathy?
diabetic foot
ulceration
gangrene –> ischemia –> infection –> necrotic –> amputation
What are the clinical manifestation of chronic disease?
Macrovascular complication –> MI, renal vascular insufficiency, CVA
Visual impairment –> total blindness
Neuropathy –> distal symmetrical neuropathy
Autonomic neuropathy –> neurogenic bladder
INC susceptibility to infection
What are the different pancreatic endocrine tumors?
Hyperinsulinism (Insulinomas)
Zollinger-Ellison syndrome (Gastrinomas)
What are the presentation of Insulinomas?
Solitary tumors w/ amyloid deposits –> Focal or diffuse hyperplasia of the Islets
Hypoglycemia
What is the presentation of Zollinger-Ellison syndrome?
Gastrin-producing tumors –> gastric acid hypersecretion & peptic ulceration
What are other rare pancreatic neuroendocrine tumors?
a-cell tumors (Glucagonomas) –> produce Glucagon
Delta-cell tumors (Somatostatinomas) –> produces Somatostatin
VIPomas –> watery diarrhea, hypokalemia, achlorhydria/WDH syndrome
Pancreatic carcinoids -> produces Serotonin
what are the clinical manifesations of Cushing syndrome?
Truncal obesity, moon facies, and accumulation of fat in the posterior neck & back (buffalo hump)
What are the lab tests done to diagnose Cushing syndrome?
Increased 24-h urine free-cortisol concentration
Loss of normal diurnal pattern of cortisol secretion
What is a cell pathognomonic to Cushing’s dynrome?
Pituitary-Crooke’s hyaline change
In what type of CUshing syndrome can we see diffuse hyperplasia?
ACTH-dependent Cushing syndrome
What type of hyperplasia are seen in the adrenal glands?
Macronodular hyperplasia - lipid-poor & lipid-rich cells
Micronodular hyperplasia - w/ atrophic intervening areas
What can cause Cushing syndrome to be malignant or benign?
Primary adrenococortical neoplasms
WHat are the histological features of an adrenal cortical adenoma?
Neoplatic cells are vacuolated bcos of the presence of intracytoplasmic lipids
There is mild nuclear pleomorphism
Mitotic activity & necrosis are not seen
What are the 2 kinds of hyperaldosteronism?
Primary & Secondary hyperalodsteronism
What is the cause of primary hyperalosteronism?
Autonomous overproduction of aldosterone with resultant suppression of the RAAS & DEC plasma renin activity
What causes secondary hyperaldosteronism?
Aldosterone release occurs due to activation of RAAS —> INC levels of plasma renin —> DEC renal perfusion, Arterial hypovolemia & edema, Pregnancy
What is the most common manifestation of primary hyperaldosteronism?
BP Elevation
What is the most common underlying cause of primary hyperaosteronism?
Bilateral idiopathic hyperaldosteronism w/ bilateral nodular hyperplasia
What condition cayses Adrenocortical neoplasm?
Conn syndrome
Aka solitary aldosterone-secreting adenoma
What is an uncommon cause of primary familial hyperalodsoteronism?
Glucocorticoid-remediable hyperalodsteronism
What is the gross morphology of Aldosterone-producing adenomas?
Solitary small, well-circumscribed lesions, mroe often found on the L than on the R
Buried within the gland, is not visibly enlarged
What are the special cells seen in Aldosterone-producing adenomas?
Lipid-laden cortical cells
WHat is a characteristic feature of aldosterone-producing adenomoas?
Spironolactone bodies
What is the most important clinical consequence of hyperaldosteronism?
Hypertension
What are the long-term effects of hyperaldosteronism-induced HTN?
CV compreomise, stroke, MI
What confirms diagnosis of primary hyperaldosteronism?
Elevated ratios of plasma aldosterone concentration to plasma renin activity
What are different adrenogenital syndrome?
C-21 hydroxylase deficiency
21-Hydroxylae deficiency - impaired synthesis of both cortisol & aldosterone
What are the cause sof C21 hydroxylase deficiency?
Adrenocortical neoplasms
Congenital adrenal hyperplasia
What causes congenital adrenal hyperplasia? What is its effect?
Autusomal recessive inherited metab errors
Effect: INC production of androgens (virilization), INC secretion of ACTH
What is the msot common cause of congenital adrenal hyperplasia & what are its 3 primary features?
21 hydroxylase deficiency
- Salt losing adrenogenitalism - salt-wasting, hyponatremia, and hyperkalemia (acidosis, HTN, CV collapse, death)
- Simple virilizing adrenogenitalism syndrome w/o salt-wasting - ambigous genitalia
- Nonclassic or late onset adrenal virilism - more common & partial def of 21-hydroxylase function
What are the 3 conditions caused by adrenocortical hypofunction?
Primary & Secondary adrenal insufficiency
Addison’s disease (Primary chronic adrenocortical insufficiency)
What conditions cause primary adrenal insufficiency?
- rapid withdrawal of steroids
- massive adrenal hemorrhae (Waterhouse-Friederichson syndrome)
- loss of cortical cells
- metab failure in hormone production
What are cause sof secondary adrenal insufficiency?
Hypothalami pituitary disease = neoplasm, inflammation
Hypothalamic pitutiary suppression = long-term steroid administration, steroid-producing neoplasms
What are diff conditions that can cause Addison’s disease?
Autoimmune adrenalitis
TB, AIDS infections
Metastastic tumors
Genetic causes: CAH, Adrenoleukodystrophy
What are conditionc of Primary Chronic Adrenocortical insufficiency/Addison’s dis?
Autoimmune polyendocrine syndrome type 1
Autoimmune polyendocrine syndrome type 2
In 90% of Addison’s dis, what is the secondary condtion?
Tuberculous adrenalitis
What causes skin pigmentation in Addison’s dis?
Elevated levels of Pro-opiomelanocortin
What are the 3 grps of autonomic NS found in extra-adrenal paraganglia?
Branchiomeric
Intravagal
Aortico-sympathetic
What are neoplasms derived from chromaffin cells?
Pheochromocytoma
What are the clinical manifestations of Pheochromocytoma?
Extra-adrenal -> Paragangliomas
Sporadic
Bilateral Sporadic adrenal pheochromocytoma
Malignant adrenal pheochromocytoma
What are Paragangliomas?
Pheochromocytomas that develop in extra-adrenal parganglia
What is the gross morphology of Pheochromocytoma?
Small, circumscribed lesions condined to the adrenal medulla, to large hemorrhagic mass
Well-demarcated large tumors
WHat is the histologic morphology of Pheochromocytoma?
CLusters of polygonal to SPINDLE-shaped chromaffin cells or chief cells surrounded by supporting sutentanicular rash
“Salt & Pepper” chromatin
What cells in Pheochromocytoma are stained with antibodies against S-100?
Peripheral sustentacular cells
What is the definitive dx of malignancy of Pheochromocytoma?
Excusively on the presence of metastasis
What are endocine tumors arising in the contect of MEN syndromes? Wjat are the distinct features of this condition?
Multiple endocrine neoplasms
Distinct features:
- younger age
- arise in multiple endocrine organ syndronously/metachronously
- multifocal in one organ
- usually prceded by an asymptomatic stage of hyperplasia
What are the 3 multiple endocrione neoplasms?
MEN 1
MEN 2A
MEN 2B
WHat condition is aka Wemer’s syndrome & caused by germline mutations in the MEN1 tumor suppressor gene?
MEN 1
What does MEN1 do?
Encodes a protein called Menin
What is the purpose of Menin?
It blocks tracriptional activation by JunD when menin partners with JunD
What are the abnormalities of MEN1?
3Ps
PTG
Pancreas,
Pitutiary gland
WHat is the most common manifestation of MEN-1?
Primary hyperparathyroidism
What is the most commn site of gastrinomas in indiviudal with MEN-1?
Duodneum
What condition is aka Sipple syndrome tha thas Pheochromcytoma, Medullar carcinoma of the thyroid
Caused by germinal mutation in the RET proto-oncogene on chromosome 10q11.2?
Men-2A
What is a common presentation in MEN-2A?
Medullary carcinoma asosci w. foci of C-cell hyperplasia
What is the difference betw MEN-2A & MEN-2B?
Hyperparathyroidism is not present in MEN-2B
