P- Adrenal, Endocrine Pancreas, MEN Syndromes Flashcards
What are the 3 layers of the adrenal cortex?
What is the main product of each?
What are the histology findings for each?
- Zona Glomerulosa - aldosterone (salt) - pink vacuolated cells in homogenous small clusters
- Zona Fasciculata - corticosteroids (metabolism, anti-inflammatory) - clear vacuolated large cells in cords
- Zona Reticularis - androgens (sex) - pink ,granular in meshwork
What are the 3 types of adrenocortical hyperfunction?
- hyperaldosteronism [Conn’s]
- hypercortisolism [Cushing]
- adrenogenital syndrome
What is the #1 cause of Cushing syndrome today?
What are the serum levels of ACTH?
What do the adrenals look like?
Iatrogenic - exogenous administration of corticosteroids/drugs
The ACTH goes down by negative feedback and the adrenals will be atrophied [ZF,ZR]
What is the definition of Cushing syndrome?
Too much cortisol [with or without elevated ACTH]
What are the 3 main endogenous causes of Cushing syndrome?
- Cushing disease- pituitary ATCH secreting adenoma
- Primary adrenal neoplasm or hyperplasia
- non-endocrine ACTH-producing neoplasm [SSC of the lung]
What is Cushing disease?
What sex and age group is it most common in?
What are the 3 potential causes?
It is the overproduction of ACTH by the hypothalamus/pituitary
Females 20-40
- pituitary microadenoma > macroadenoma
- primary corticotroph cell hyperplasia [no mass]
- secondary corticotroph hyperplasia [hypothalamus secretes too much CRH]
With Cushing disease, what is the gross and histologic appearance of the adrenal cortex?
Gross:
- brown/yellow cortical thickening [excess lipid]
- diffuse, scattered nodules (.5-2.5cm), or mix of both
- BILATERAL enlargement
Histology:
- diffuse, nodular hyperplasia of ZR, ZF [larger, more vacuolated cells]
- flattening of ZG [not responsive to ACTH]
- unaffected medulla
What are the 2 types of ACTH-independent Cushing syndromes?
Which is more common?
What will serum ACTH and cortisol levels be?
- primary [bilateral] adrenal hyperplasia
- primary adrenal neoplasm - more common
Both have decreased ACTH from neg feedback and increased cortisol
Describe primary hyperplasia of the adrenal gland.
One gland or bilateral?
diffuse or nodular?
micro or macronodular?
It is bilateral and can be micronodular (less than 3mm) or macronodular (over 3mm)
What are three distinguishing features of micronodular primary adrenal hyperplasia?
- familial
- pigmented adrenal nodules
- large cortical cells
Describe the gross appearance of adrenocortical neoplasia.
- benign [adenoma] or malignant [carcinoma]
- unilateral
- 3cm, encapsulated tellow-black lesion
What are the types of non-endocrine neoplasms that can make ACTH?
- SCC of the lung ** most common
- medullary thyroid carcinoma
- pancreatic islet tumor
- carcinoid
- ovarian tumor
- thymic carcinoma
What are the clinical manifestations of hypercortisolism?
Group them by cortisol action.
Action on MR:
- hypertension, fluid retention/weight gain
- hypokalemia
Fat redistribution:
- truncal obesity
- moon facies
- humpback
Gluconeogenesis
Protein Catabolism:
- osteoporosis, fracture
- cutaneous stria
Atrophy of fast twitch and prox. limb weakness
Immunosuppression
Action on androgens:
- hirsutism
- depression/mood swings
Hyperpigmentation
A patient presents with high Na, low K, volume overload and new onset hypertension.
When looking at lab values you notice reduced AngII and renin.
What is the likely problem?
How would you treat this patient?
Primary hyperaldosteronism.
You know it is primary, because the volume had made a negative feedback on the renin and AngII reducing their levels.
If it was a secondary hyperaldosteronism, then renin/AngII would be elevated.
Treat the patient with unilateral adrenalectomy.
What are the 3 potential causes of primary hyperaldosteronism?
- adrenal mass [80% adenoma, 20% carcinoma]
- adrenal hyperplasia
- idiopathic
An aldosterone-secreting adenoma in the adrenal is known as ___________.
What sex and age group is this more common in?
What do ACTH levels show?
What does the adrenal gland look like?
It is Conn’s syndrome.
It affects women from 30-50.
ACTH levels are NOT suppressed because aldosterone is regulated renally, not by ACTH.
The adrenal gland does NOT show atropy or hypoplasia.
What patient would you expect to present with primary adrenocortical hyperplasia?
Is it unilateral or bilateral?
What zones are proliferating?
What is the current theory of what causes the hyperplasia?
- Children and young adults
- bilateral hyperplasia
- ZG and ZF
- Theory = overactivity of aldosterone synthase [CYP11B2 which converts deoxycortisone–> aldo]
What causes secondary hyperaldosteronism?
It occurs when there is perceived low flow to the kidney resulting in activation of RAAS:
- decreased flow [RA stenosis, nephrosclerosis]
- hypovolemia, edema
- pregnancy [estrogen stimulates renin]
Are production rates of aldosterone higher for primary or secondary hyperaldosteronism?
Secondary [RAAS stimulation]
What is made in the ZR?
- DHEA [dihydroepiandosterone]
2. androstenedione
What are the 3 causes for primary androgen excess?
- adrenal adenoma
- adrenal carcinoma
- adrenal hyperplasia
What is CAH?
What is the inheritance pattern?
What is thought to be defective?
Describe the pathogenesis.
It is congenital adrenal hyperplasia
AR disorder involving one of the many steroid biosynthesis genes most often : 21 hydroxylase [CYP21B] .
- hypocortisolemia–> stimulate pit. ACTH release
- ACTH stimulates cortisol production but due to the 21 hydroxylase deficiency, gets bottlenecked
- precursors are pushed down the androgen synthetic pathway–> virilization
What is the gross appearance of the adrenals in CAH?
- bilaterally enlarged (10x)
- nodular
- cells are lipid-depleted
When there is CAH 21 hydroxylase deficiency, what are the clinical manifestations:
- in infancy
- pubertal girls
- pubertal boys
- pseudohermaphroditism
- oligomenorrhea, hirsutism
- precocious puberty, genitalia enlargement
ALL may have mixed disorder with mineralocorticoid deficiency–> hyponatremia
What is the result of CAH 11-b- hydroxylase deficiency?
The steroid hormone precursors shunt down the mineralocorticoid path cause excess:
- hypernatremia
- high BP
What are the 3 main causes of acute primary adrenal insufficiency?
- hemorrhage into the adrenals
- Waterhouse Freiderichsen syndrome in kids
- anti-coagulant use in adults - excessive stress [trauma, infection, surgery] in setting of chronic adrenal insufficiency
- sudden cessation of prescribed cortisol
What is Waterhouse-Frederichsen syndrome?
What are the 4 most common causes?
It is massive hemorrhage into the adrenals in children caused by:
- meningococcal sepsis
- pseudomonas
- strep
- staph
What is the other name for chronic primary adrenal insufficiency?
What are the 4 common causes?
How much gland needs to be destroyed before symptoms present?
Addison’s disease - 90% of gland must be destroyed for symptoms. ACTH levels remain normal.
- Autoimmune - most commonly
- Infection- TB, granulomatous inflammation
- AIDS- CMV, Kaposi sarcoma, MAI
- Mets- from bronchigenic or breast
For autoimmune Addison’s what is thought to be the target of the autoantibodies?
- 21- hydroxylase
2. ACTH receptor
What is seen histologically in Addison’s disease?
lymphocytic infiltration of the adrenal gland
What is APS? What diseases are involved?
Autoimmune polyendocrinopathy syndrome.
- adrenal [Addisons]
- hashimotos thyroiditis
- pernicious anemia
- diabetes
- hypoparathyroidism
What symptoms are associated with Addison’s?
PRogressive loss of glucocorticoids and mineralocorticoids:
- hyperpigmentation [increased ACTH, POMC, MSH]
- hypoglycemia -> fatigue/weakness
- GI disturbances [nausea, anorexia, weight loss]
- Na wasting, hypovolemia, hyperkalemia, hypotension
What are the causes of secondary adrenocortical insufficiency?
How do the signs/symptoms differ from primary?
It can be caused by reduced pituitary output of ACTH due to :
- tumor
- infection
- infarction
It differs from primary because:
- Adrenal cortex is atrophic [esp. ZF, ZR]
- no hyperpigmentation [because reduced ACTH]
- no loss of aldosterone
Adrenal adenomas can be derived from __________ of the adrenal gland and can be associated with the production of _____,_________,_____________,________.
Adrenal adenomas can derive from any layer of the cortex of the adrenal glands.
They can produce:
- mineralcorticoids
- glucocorticoids
- estrogen
- androgen
Describe the gross appearance and histology of Cushing syndrome from adrenal adenoma.
Gross:
- over 60g, 3cm
- yellow due to lipid content
Histology:
- resemble fasciculata cells
- nests and cords
- adjacent adrenal is atrophic due to HP feedback
Describe the gross appearance and histology of an adrenal adenoma that is causing Conn’s syndrome.
Gross:
- less than 2cm, solitary
- unencapsulated and yellow
Histologically:
- cells resemble glomerulosa OR fasiculata
- glomerulosa is thickened
- adrenals are NOT atrophic
- Spironolactone bodies
What is the largest andrenal adenoma?
Describe the histology of this adenoma.
androgenital adenoma gets larger than the others and up to 500g.
Histology- estrogen, pink ovoid cells with solid trabecula
Describe non-functional adrenal nodules.
They are esp common in the elderly
- bilateral
- less than 2cm
- pigmented black
Secretions of what hormones are associated with adenocortical carcinomas?
What secretion is infrequent with adenocortical carcinoma?
Common:
- Cushing
- androgens
- estrogens
- non functional
Uncommon:
- aldosterone
Mixed syndromes are more common in ________ than _______________.
mixed is more common in carcinoma than adenoma
How do adenomas and carcinomas of the adrenal gland differ in terms of :
- size
- vessel invasion
- mitotic rate
- capsule invasion
- necrosis
- border of tumor
- mets
- A = 100
- C invades vessels and lymphatics
- C has high mitotic rate
- C invades capsule
- C has necrosis
- A is encapsulated, C is invasive
- C has mets
What percent of cortical carcinomas have mets when discovered?
Where do the mets most often go?
What is the median survival?
50% have mets
Most go to the lung
Median survival = 1yr
____________tumors are more common in the adrenals than _______tumors. Most often these malignancies arise in the ________ and _______.
Mets are more common than primary tumors.
They tend to come from lung and breast
What are the 4 types of adrenal cysts?
What symptoms are associated with each?
How are they discovered/confirmed?
All the adrenal cysts are asymptomatic and found incidentally on CT.
- cystic neoplasm - primary/met
- parasitic- echinococcal
- endothelial - dilated vascular structures
- pseudocysts- lymphoendothelial cysts w/o lining
Describe the structure of the normal adrenal medulla.
Where does the medulla derive from?
What 3 cell types are present?
What do the main cells secrete?
Adrenal medulla derives from neural crest cells
- pheochromocytes- secrete epi/norepi
- ganglion cells
- supporting cells
[nerves]
Pheochromocytes are arranged in tight clusters with invested capillaries.
The adrenal medulla can suffer from hyperplasia and what 4 tumors?
- pheochromocytoma
- ganglioneuroma
- neuroblastoma
- ganglioneuroblastoma
What patients are usually seen to have adrenal medulla hyperplasia?
MEN II and IIb patients
A patient presents with sudden, sporadic bouts of hypertension associated with tachycardia, headaches, sweating and tremors.
He says this usually occurs after some type of painful experience.
What do you think he has?
What is he at risk to develop?
How do you diagnose him?
What is treatment?
Pheochromocytoma
Risk for:
- MI, stroke
- renal injury
- sudden cardiac death
Diagnosis:
1. urine catecholamines, VMA and metanephrines
Treat :
- pre-surgery adrenergic blockers
- surgical resection of the tumor
What is the “rule of 10” for pheo?
10% familial [MEN, neurofibromatosis]
10% bilateral
10% malignant
10% extradrenal [carotid body, neural crest cells]
Describe the histology of pheo.
How can you tell the different btwn benign tumor and malignant?
- balls of blue cells “zellballen”
- encased by rich vascular network
- nuclear atypia
Benign and malignant can look the same histologically so you need to see if there are METS.
For pheochromocytoma, the ONLY reliable criteria for malignancy is what?
Mets usually to the lung or liver
Describe neuroblastomas histologically.
When do they arise? From what precursor?
What gene is amplified?
TNeuroblastomas are made of “small blue cell”
They present in infancy and derive from neuronal precursors.
there is an N-myc gene amplification
A tumor biopsy of the adrenal medulla has small blue cells and ganglion cells. What tumor is it?
ganglioneuroblastoma
A tumor presents in the adrenal medulla with mature ganglion cells and Schwann cells but NO small blue cells. What is the tumor called?
ganlioneuroma
In the endocrine pancreas what is the product of:
- alpha
- beta
- delta
- pp cells
- glucagon
- insulin
- somatostatin
- vasoactive intestinal polypeptide
What type of diabetes is more common?
Type II is 10x more common than type 1
[type II = insulin resistant, type I = autoimmune]
What is thought to be the cause of type 1 diabetes?
It is an absolute deficiency in insulin secretion due to ongoing autoimmune destruction of B-cells in the pacreas.
Autoantibodies are directed against:
- insulin
- glutamic acid decarboxylase [GAD]
- protein tyrosine phosphatase
What does histology of type 1 diabetes show?
- lymphocytic infiltrate of islets
- CD4 T cell, and macrophages they activate
- CD8 cytotoxic cells
- IFNg from T cells, IL2 from macrophages - foci of apoptotic B-cells
What is the “overload hypothesis” for type 1 diabetes?
What are competing theories?
“overload hypothesis” says sedentary lifestyle and overeating in children puts a high demand on B-cells resulting in increased apoptosis making them more prone to autoimmune attack
Other evidence suggest viral/bacterial infections trigger onset of autoimmunity.
HLADR3, DR4
What is the cause/pathogenesis of type 2 diabetes?
In type 2, the person is making insulin, however the target tissues are resistant to the effect [liver, muscle, adipose].
At first B cells hypersecrete insulin to “keep up” but then after years, they fail.
What are 3 proposed reasons for why obesity can lead to type 2 DM?
- intracellular FFA and TGs inhibit insulin signaling in skeletal muscle and liver
- adipocytes secrete adipokines into blood which promote insulin resistance
- Fat cells have TF PPARg which promotes insulin sensitivity. Mutations in PPAR –>insulin resistance
What is seen histologically for type 2 DM?
Elevated glucose and FFA are toxic to B cells so you see:
- islet degeneration
- amyloid replacing the parenchyma
There is a set of 3 criteria to be diagnosed with diabetes. What are they?
How many of the criteria need to be met to be considered diabetic?
- random glucose >200mg/dl and signs of diabetes
- fasting glucose >125 mg/dl on more than 1 occasion
- abnormal glucose tolerance test [give the person 75mg glucose, wait 2 hrs then measure glucose level. If >200, it is abnormal]
What is the pathological mechanism by which diabetes causes complications in organs?
Excess glucose binds to proteins by glycosylation. The glycosylated proteins undergo more changes to form “advanced glycosylated end product” [AGE].
- atherosclerosis- glycosylation of collagen in vessels–>protein crosslinking that entraps lipoproteins
- thick capillary basement membranes [kidney]
- circulating plasma proteins–> endothelial cells, macrophages, glom mesangial cells
How does diabetes contribute to atherosclerosis?
Glycosylation and crosslinking of proteins in the vessel wall can trap lipoproteins and lead to atherosclerosis
How does diabetes contribute to increased cell permeability, coagulopathy, increased ECM production and cytokine release?
circulating proteins are glycosylated and bind endothelial cells, macrophages, and glom. mesangial cells
How does diabetes contribute to angiogenesis, coagulation abnormalities and increased ECM?
hyperglycemia activated protein kinase C signaling pathway
What are the 3 classic symptoms of type 1 AND 2 diabetes?
Why do they occur?
- polyuria
- polyphagia
- polydipsia
Low insulin prevents glucose from being taken up in liver, skeletal muscle. Increased serum glucose overwhelms renal reabsorption and sugar/water spills in urine [polyuria]. The large water loss leads to thirst [polydipsia]
No insulin = catabolism instead of anabolism. gluconeogenesis breaks down proteins and fat to make sugar. This stimulates more eating [polyphagia]
A patient presents with nausea, vomiting, and tachypnea. They have recently run out of insulin. What are you suspicious of?
What besides running out of insulin could have triggered this?
What will the blood glucose level be?
What are the effects?
DKA- results from physiological stress, running out of insulin, altered diet.
Blood glucose reaches 500-700mg/dl bc of unopposed glucagon AND gluconeogenesis.
Urine–>osmotic diuresis–> volume depletion
Cell lipids break down to FFA secondary to insulin loss, go to the liver and get oxidized to ketones which leads to a ketoacidosis [gap acidosis]
Effects could be alter consciousness, coma, death
What acute exacerbation of diabetes is seen in type 2?
What age patient does this occur in? What is the impetus?
Hyperosmolar nonketotic coma cand occur in obese type 2 diabetic over 40.
The coma develops in response to severe dehydration [due to hyperosmotic diuresis
A type 2 diabetic presents with altered mental status, seizures and severe dehydration. What is your concern?
Hyperosmolar nonketotic coma
What cardiovascular changes are associated with diabetes?
- MI, stroke
- renal vascular disease
- atherosclerosis is aorta, large/med vessels
- hyaline arteriolosclerosis
- microangiopathy
Diabetics are 3-7x more likely to die of cardiovascular disease than non-diabetics
What histological changes are seen in the kidneys of a diabetic?
Which is pathognemonic for diabetes?
- glomerular BM thickening
- mesangial proliferation
- increased mesangial matrix
- aff/eff arteriole hyaline arteriolosclerosis
- Kimmelsteil-Wilson nodules [hyaline btw capillary loops] *** pathognemonic
Describe the progression of kidney failure as diabetes progresses.
1, microproteinuria [30-300mg/day]
2. macroproteinuria [ >300, nephrotic syndrome]
Also they can have:
- RA stenosis –> increased BP
- acute/chronic inflammation [pylonephritis]
- necrotizing papillitis
Describe the peripheral and autonomic neuropathy associated with DM.
Peripheral:
- stocking glove distribution
- numb, paresthesia, pain, proprioception
- pain worse at night
Autonomic:
- GI - lack of motility
- bladder- lack of contraction
- penile ED
What 4 things are thought to contribute to the development of diabetic neuropathy?
- microangiopathy–> ischemia
- increased capillary permeability
- glycosylation of axon proteins
- oxidative stress from increased sorbitol
What 3 problems are associated with diabetic eyes?
- cataracts
- glaucoma
- retinal damage
What are the 2 forms of diabetic retinopathy?
Non-proliferative:
- microaneurysms
- exudates
- minute hemorrhage, venous dilation, edema, microangiopathy
Proliferative:
- vitreal and retinal neovascular fronds
- bleeding
- fibrosis
Proliferative can lead to retinal detachment and blindess.
Why are diabetic more likely to get infections?
What are specific infections they get?
More likely to get infections because:
- reduced blood flow
- abnormal leukocyte function
More common infections:
- malignant otitis media [pseudomonas]
- mucormycosis [mucor or rhizopus fungi]- nose eroding up into the brain vessels
- emphysematous cholecystitis [clostridium]
- emphysematous pyelonephritis
What are the types of PET?
What is the most common?
Which are more likely to be benign? MAlignant?
- Insulinoma- most common, 90% benign
The rest are 60% malignant
- gastrinoma
- VIPoma
- glucagonoma
- somatostatinoma
For islet cell tumors, what size is usually benign? Malignant?
How does functionality of the tumor affect malignancy?
Less than 2cm is benign, over 2cm is malignant.
Non-functional pancreatic tumors have aggressive behavior
What is whipple’s triad?
What type of tumor is it for?
B-cell Insulinomas
- hypoglycemic attacks [glucose below 50]. EPISODIC, AUTONOMOUS
- stupor, confusion, loss of consciousness, coma
- brought on by fasting/exercise, relieved by eating
A patient presents with episodic hypotension. They have arrythmia, palpitations, diaphoresis, pallor and irritability. What PET are you nervous about?
Insulinoma
How is the diagnosis of insulinoma confirmed?
- serum insulin levels are elevated when fasting/hypoglycemic
- biopsy has trabecular pattern with salt/pepper chromatin and immunohistochemical stain to insulin
What is secreted in a gastrinoma?
What syndrome is associated with this?
What are the 3 locations these can arise?
They are gastrin secreting tumors that can lead to peptic ulcers.
Zollinger-Ellison syndrome
“gastrinoma triangle”
- duodenum
- peripancreatic soft tissue
- pancreas
A postmenopausal woman comes to see you. She has mild diabetes, necrolytic migratory erythema in high friction areas, and anemia. What is the likely problem?
Gastrinoma
A patient present with diabetes, gallstones, steatorrhea, and hypochlorhydria. What is the likely PET.
Somatostatinoma because it inhibits gastric secretions
A patient present with WDHA syndrome. What are the symptoms and what is the likely PET?
Water Diarrhea, Hypokalemia, Achlorhydria
VIPoma
What are the 5 characteristics of the MEN syndromes [Multiple Endocrine Neoplasia]?
AD inherited characterized by hyperplasia, adenomas, carcinomas in endocrine organs.
- young age
- multiple organs [synchronous or met]
- multifocal within the organ
- preceded by asymptomatic hyperplasia
- more aggressive/recurring tumors
What 3 organs are affected by MEN1?
- pancreas- endocrine tumors
- parathyroid- primary hyperparathyroidism, multigland hyperplasia
- pituitary- prolactin adenoma
What 3 organs are affected by MEN2a?
- Parathyroid- primary hyperparathyroidism
- adrenal - pheo
- thyroid- medullary thyroid cancer, C-cell
What 3 organs are affected by MEN2B?
- “other” - GI ganglioneuromas, Marfan habitus
- adrenal- pheo
- Thyroid - medullary thyroid cancer, C-cell
