Endocrinology - Adrenal, Diabetes Flashcards
where specifically does each zone of the adrenal cortex contain?
- Outer zone glomerulsa - aldosterone
- middle zona fasciulata - cortisol
- inner zone reticularis - androgens
- GFR - ACR
where in the adrenal glands is epinephrine produced?
chromaffin cells in the adrenal medulla
what is the function of mineralocorticoids function ?
aldosterone normally increase sodium absorption and K+/H+ excretion so high levels cause hypertension, hypokalemia, and alkalosis.
what is the function of glucocorticoids?
- cortisol stimulates lipolysis
- release of amino acid from muscles
- liver glucogenesis
- inhibits inflammatory process
- Inhibits T-cells and associated DTH and cell-mediated immunity\
- excess cortisol can stimulate mineralocorticoids and androgen receptors with a similar appearance to aldosterone excess (HTN, hypokalemia, alkalosis)
- It does not bind to androgen receptors.
what are the androgens produced by the adrenals?
DHEA and small amounts of testosterone.
what is the effect of excess adrenal androgens in a woman?
- during gestation - ambiguous genitalia
- Postnatally - excess hair and abnormal menses
Describe signs and symptoms of Cushing syndrome?
excessive adrenal glucocorticoid production causing:
- proximal muscle weakness and fatigue
- amenorrhea, hirsutism, acne
- easy bruising
- emotional liability/frank psychosis
what are the physical exam findings of Cushing syndrome?
facial plethora (redness of face/fullness due to increased blood flow)
thin skin with pink to purple striae
cervicodorsal fat pad
truncal obesity
moon facies
what are the comorbid conditions associated with Cushing syndrome?
DM2 and osteoperosis
what are the causes of cushing syndrome from most to least frequent?
- iatrogenic cortisol adminsitration
- ACTH - secretuing pituitary adenoma (cushing disease)
- ectopic ACTH secretuing tumor: (bronchogenic, pancreatic, thymic (if age>60), SCLC
- bilateral adrenal hyperplasia
- adrenal tumors
what would you expect to see on a BMP with cushing syndrome?
hypokalemia and metabolic alkalosis
what can mimic the phenotypic features of cushing’s syndrome? why is this important?
- obesity, alcoholism, and depression can mimic
- important as they can result in slightly increased 24-hour urine cortisol and/or abnormal low-dose suppression test
- this is called pseudo-cushing’s.
what does ACTH do again?
increases cortisol, androgens, and mineralocorticoids.
what is the difference between Cushing disease and Cushing syndrome?
- Cushing disease is a disease in the head, caused by a pituitary microadenoma which has increased ACTH stimulating the production of adrenal DHEA.
- Females can present with virilization (hirsitusim and acne)
what endocrinology labs would you expect to see with an adrenal adenoma that is producing cortisol?
ACTH and DHEA would be low.
what are the initial tests to get for Cushing syndrome workup?
- 24 hour urine free cortisol
- late-night salivary cortisol and/or
- low dose dexamethasone suppression test to confirm excess cortisol
- abnormal tests should be confirmed at least once.
- note that urinary cortisol reflects plasma free cortisol levels
how do you identify pseduo-Cushing’s?
elevated cortisol levels (urine) with suppression with low dose dexamethasone suppression of cortisol
what is your next step in working up Cushing’s syndrome if you have elevated cortisol with failure to suppress cortisol with low dose dexamethasone test?
- identify if this is ACTH dependent or ACTH independent disease by measuring ACTH.
- Normally, a high cortisol completely suppresses ACTH production
- Any measurable ACTH indicates ACTH dependent Cushing syndrome (Cushing disease or ectopic ACTH production)
- ACTH to low to be measured indicates ACTH independent Cushing syndrome - (nonpituitary adrenal hyperplasia or adrenal mass)
what if your next step if you have a high urinary cortisol, measurable ACTH?
- this is an ACTH dependent Cushing syndrome so either pituitary tumor (Cushing disease) or ectopic ACTH secreting tumor.
- Next step is to image the pituitary with a gadolinium-contrasted MRI
- Can also image chest/abdomen with high res CT.
what is the next step if you have high cortisol, low/unmeasurable ACTH ?
- this is likely ACTH independent cushing syndrome from an adrenal tumor (adenoma or carcinoma)
- Would measure DHEA and testosterone concentrations
- Adrenal adenomas have low ACTH and modest DHEA levels
- carcinomas have low ACTH and high DHEA and urine 17 ketosteroids.
- adrenal tumors do not usually suppress cortisol production in response to high dose dexamethasone test.
what is the difference between primary and secondary adrenal insufficiency in terms of labs?
- primary (abnormal cosyntropin stim, high ACTH, low aldosterone, hyponatremia, hyperkalemia,
- secondary (abnormal cosyntropin stim, low ACTH production by pituitary or withdrawal of glucocorticoids, normal aldosterone)
- all adrenal insufficiency does not respond to ACTH stimulation
why do you have hyperkalemia with primary adrenal insufficiency and not secondary?
primary AI would affect both the zona glomerulosa and zona fasiculata causing a hyperreninemic hypoaldosteronism.
what labs do you get to test for adrenal insufficiency?
- baseline cortisol, serum aldosterone, ACTH
- Cosyntropin stimulation test 0,30.60.
- If ACTH not >18-20, diagnostic.
what is the treatment for AI?
corticosteroids and mineralcorticoids like fludrocortisone
what is schmidt syndrome? what is the treatment?
- combination of primary adrenal insufficiency and hypothyroidism and often type I DM.
- Must replace cortisol first because giving thryoid replacement as this can increase metabolic demand and cause or worsen shock.
what is the function of aldosterone?
- increases sodium resorption and hence potassium and hydrogen excretion in distal tubules.
- Increase in sodium resorption means increased water retention and hypertension.
what is primary aldosteronism? associated diseases?
- too much aldosterone produced by adrenal gland.
- associated with hyporeninemia, hypertension, and hypokalemia
- associated with Cushing syndrome and licorice ingestion
what is secondary aldosteronism?
- overactivity of the RAAS in the kidney
- associated with high renin, increased aldosterone
- this causes decreased renal blood flow, increased renin, increased Ang II, increased aldosterone.
- See hypertension and hypokalemia
what conditions are associated with a PAC: PRA ratio?
- primary aldosteronism: PAC elevated, PRA supression, with elevated ratio. Think adrenal tumor or hyperplasia
- Secondary aldosteronism: PAC and PRA both icnreased with ratio<10. Think kidney disease (renoovascular or renal tumor)
- Cushing, and block licorice: PAC and PRA both decreased with PAC:PRA normal or elevated.
what is the most common cause of hypoaldosteronism?
- decreased production of renin in diabetic patients with mild renal failure
- this is hyporeninemic hypoaldosteronism
what lab findings do you see in hypoaldosteronism?
- hyperkalemia
- normal anion gap metabolic acidosis
- low renin and low aldosterone
what do you do for work up for hypoaldosteronism? treatment?
- exclude AI as a cause of hyperkalemia
- perform ACTH stimulation test.
- Low aldosterone response indicates primary hypoaldosteronism of the adrenals
- large response indicates secondary hypoaldosteronism
- Tx with mineralocorticoid (fludrocortisone( and/or furosemide
when do you suspect catecholamine-secreting tumor?
spells of headaches, sweating, chest palpitations
what is the most sensitive biochemical screening test for pheochromocytoma?
- fractioned metanephrines and catecholamines on 24 hour urine. Wean off TCA and cyclobenazprine 2 weeks before testing)
- plasma fractionated metanpehrines has a high sensitivity but low specificity.
- if concern for false positive with plasma metanephrine increase, can do clonidine suppression test.
- If after a dose of clonidine, plasma metanephrine levels fall, it is due to HTN.
- If after a dose of clonidine, plasma metanephrines still elevated, likely due to pheo.
what do you do after biochemical tets are positive for pheochromocytoma?
CT or MRI of abd/pelvis to find the tumor.
what is the treatment for pheochromocytoma?
- combined alpha and beta blockade preoperatively.
- phonoxybenzamine for 2 weeks prior to surgery, and 3 days before surgery beta-blocker.
- Never use beta-blocker first due to unopposed alpha stimulation and potential for HTN crisis.
what tests should patient have for adrenal incidentaloma?
- BP and potassium. Add PAC:PRA if HTN or hypokalemia present. testing for hyperaldosteronism
- 24 hour urinary free cortisol or low dose dex for Cushing
- plasma fractionated metanephrines for adrenal medulla for pheochromocytoma
- estrogens and androgens if feminization or virilization present.
what are the 3 indicatinos for adrenalectomy of incidentaloma?
- functioning tumor
- mass is >4-6cm
- imaging suspicious for malignancy
define primary amenorrhea? cause?
- lack of menstruation by age 16 or lack of development of secondary sex characteristics by age of 14.
- uterine outflow tract abnormality/absence or ovulatory abnormality.
what are the common causes of primary amenorrhea?
- if short stature, wide space nipples, web neck, decreased pubic and axillary hair, think turner (45,XO)
- if no palpable cervix and no uterus, androgen insensitivity (see elevated testosterone) or genetic absence of uterus.
define secondary amenorrhea?
absence of menses for 3-6 months
most common causes of secondary amenorrhea?
pregnancy
what are the initial labs do you want to get for secondary amenorrhea?
- pregnancy test, FSH, and LH
- If virilization, get serum total testosterone and DHEA.
what does increased FSH and LH levels tell you in the amenorrheic women?
- it tells you that the pituitary has lost negative feedback from the ovaries.
- this suggest ovarian failure either premature ovarian failure<40 like turner syndrome, galactosemia, or autoimmune polyglandular syndrome
what does decreased GSH and LH levels tell you in an amenorrheic woman?
it tells you that the pituitary is not making hormones either it is diseased or because the hypothalamus is not sending out GnRH.
what do you need to check on a amenorrheic women with low FSH and low LH?
- meds - antiepilpeitic or psychotropic meds - functional hypothalamic amenorrhea
- prolactin level
- TSH
- MRI
- If young patient, consider estrogen testing for functional hypothalamic amenorrhea from stress/athletes.
ddx for amenorrheic women with virilizing signs?
- PCOS
- adrenal or ovarian tumors
what is the MOA behind POCS?
- ovaries and adrenal produces excess androgen and estrogens
- continuous secretion of estrogen decreases FSH secretions but enhances LH so the LH:FSH ratio is more than 2.
- LH causes ovarian stromal hyperplasia (more theca cells) and more production of androgens.
what is the primary treatment for PCOS?
- First line treatment is education and weight loss.
- No hirsutism and no pregnancy: OCP or medroxypgrogesterone 1-3 months to induce withdrawal bleeding and to protect the endometrium from hyperplasia
- Hirsute and no desire for pregnancy: combined estrogen-progesteorne OCP, metformin
- Hrisute and describes pregnancy: induce ovulation with clomiphene with or without metformin.
define virilization? define hirsutism?
- clitoromegaly,
- voice deepending
- male pattern balding
- de-feminization (breast atrophy)
- Hirsutism - abnormal growth of hair
ddx for histutism?
- Cushing disease (central)
- adrenal cancer
- ovarian cancer (stromal)
- congenital adrenal hyperplasia
- PCOS
what labs with hirsutism are suggestive of PCOS?
- mild elevations of DHEA
- mild elevation of testosterone
- LH:FSH >2
what labs with hirsutism are suggestive of congenital adrenal hyperplasia?
- normal to mild testosterone level
- normal to mild DHEA or urinary 17 ketosteroids
- normal LH:FSH
what labs are suggestive of adrenal carcinoma with hirsutism?
- normal to mild testosterone
- very high DHEA or urinary 17 ketosteroids
- normal LH:FSH
what labs with hirsutism are suggestive of ovarian cancer (stromal)?
- elevated testosterone level
- normal to mild DHEA/urinary 17 ketosteroids
- normal LH:FSH
what labs with hirsutism is suggestive of Cushing disease (central)?
normal to mild testosterone
normal to mild DHEA level/urinary 17 ketosteroids
normal LH:FSH
what drugs are associated with hirsutism?
- minoxidil
- cyclosporine
- phenytoin
what does LH do?
stimulates Leydig cells (L stimulates L) to produce testosterone which inhibits FSH and LH secretion.
what does FSH do?
FSH stimulates sertoli cells to secrete inhibin B and androgen binding globulin which in turn binds to testosterone.
what is the most common cause of primary hypogonadism?
usually due to Klinefelter syndrome, which results in defective testosterone synthesis by the Leydig cells.
what is the gene mutation associated with klinefelter syndrome?
47XXY or mosaic 46XY/47,XXY
what labs are associated with klinefelters and treatment?
- low testosterone, high LH and high FSH
- tx is testosterone
what is the ddx of secondary hypogonadism?
- hyperprolactinemia (high prolactin)
- anabolic steroids
- cushing syndrome (excessive glucocorticoids)
- congenital gonadotropin deficiency (kallman syndrome)
- hemochromatosis (high ferritin)
what endocrine labs do you see with secondary vs primary hypogonadism?
- primary has defective testosterone synthesis, so low testosterone, high FSH and high LH
- secondary has low testosterone, low FSH and low LH
ddx of gynecomastia ? lab abnormalities likely to be seen?
- altered estrogen:androgen ratio
- advanced age
- obesity
- cirrhosis
- hyperthyroidism
- kleinfelters
- germ cell tumors
- meds
what does high cholesterol mean?
high LDL
what is the primary endpoint of lipid screening? Formula?
- LDL
- LDL = TC - HDL - VLDL
- LDL = TC - HDL - TGL/5 (provided TGL<400)
what is the secondary target once LDL target achieved for primary prevention of lipid screening? formula?
- non-HDL
- non-HDL = TC - HDL
lipid profile effect of changing diet to hydrogenated vegatable oils (trans)?
increase LDL, decrease HDL
lipid profile effect of changing diet to decreasing saturated fats?
decrease LDL, decrease HHDL, same or increase LDL/HDL ratio. Neutral/bad.
lipid profile effect of changing diet to change diet to polyunsaturated fats?
decrease LDL, decrease HDL, same or increase. this is bad.
lipid profile effect of changing diet to monounsaturated fats?
decrease LDL, may increase HDL, decrease LDL/HDL. This is good.
what are the 4 statin benefit groups? and which statin?
- age 21 with ASCVD. age<75 high intensity; age>75 - moderate staitn
- age 21 with LDL>190 - high intensity statin
- age 40-75 with DM and LDL 70-189; ASCVD<7.5% - moderate, ASCVD >7.5 - high intensity
- age 40-75 with no ASCVD or diabetes with ASCVD of 7.5% higher - moderate/high statin
if you can’t use a statin, what 3 drugs can you use that are not statins? (generally)
PCSK9 inhibitors, Ezetimibe, bile acid sequestrants
what is the adverse effect of statins?
myalgias, myositis, elevated transaminases
define MODY vs LADA?
- MODY is mature onset diabetes of the young and rare genetic defect in beta cells.
- LADA is latent autoimmune diabetes in adults is a late-onset of immune-mediated course in non-obese adults due to autoantibodies targeting pancreas
what are the components of whole blood, serum, and plasma?
- whole blood = cells + clotting factors + watery part of blood
- serum = watery part of blood - (cells + clotting factors)
- Plasma = (watery part + clotting factors) - cells
how do you diagnose prediabetes?
- One of the following:
- impaired fasting glucose between 100-125
- impaired glucose tolerance between 140-199 after 75gm oral glucose load. (more sensitive)
- A1c of 5.7-6.4 is supportive, but you need to retest patients with OGTT or FPG
how do you diagnose DM?
- FPG>126
- random plasma glucose>200 with symptoms
- A1c>6.5%
- 2 hour plasma glucose>200 after 75g OGTT
- confirm diagnose with the same test used initially
- the best test to diagnose overt T2DM is fasting plasma glucose
what diseases can lead to false value of HbA1c?
- anything that alters abnormal blood turnover.
- iron-deficiency anemia
- thalassemias
- hemolytic anemias
- hepatic or renal diseases
what autoantibodies are associated with Type I DM? which is the most important?
- islet cells
- insulin
- glutamic acid decarboxylase (most clinically useful)
- tyrosine phosphatases IA-2 and IA-2B
what autoimmune diseases are associated with T1DM? MHC?
- HLA Dr3 and DR4
- thyroid, adrenal celiac, vitiligo, b12 deficiency, and myasthenia
name the long acting insulins?
glargine (lantus) and detemir (levemir)
explain the honeymoon effect?
improvement of hyperglycemia after diagnosis and treatment for a short while, but eventually require reinstitution of treatment
explain the dawn phenomenon?
- increased blood glucose between 4 and 7 AM with no preceding hypoglycemia.
- The cause is transient, mild insulin resistance due to normal early-morning rise in cortisol and GH.
explain the Somogyi effect? treatment?
- nocturnal hypoglycemia stimulates adrenal to release glucocorticoids that increase early morning glucose.
- INCORRECT to reduce evening NPH
- delay the long evening acting insulin bedtime if NPH used
- or substitute NPH for a long-acting insulin analog
what conditions are associated with acanthosis nigricans? what is it?
- velvety dark rash on flexural surfaces
- associated with insulin-resistant conditions like PCOS, Cushing, acromegaly, meds like niacin or corticosteroids
- rapid onset of widespread acanthosis nigricans in older patients suggest GI malignancy
what are the oral meds associated with treatment of T2DM?
- BATS
- biguanide (metformin)
- alpha glucosidase inhibitors (acarbose, miglitol)
- Thiazolidinediones/glitazones
- secretagogues (sulfonyulureas, meglitinidies)
MOA, weight effect, mortality and disadvantage of insulin?
- MOA: decrease hepatic glucose production, increase peripheral glucose uptake, suppress ketogenesis
- increased weight gain
- hypoglycemia, weight gain, training,
- decrease in microvascular events.
MOA, weight effect, mortality and disadvantage of sulfonylureas?
- glipizide, glyburide
- stimulate insulin secretion
- increase weight gain
- hypoglycemia, weight gain
- decrease in microvascular events, possible increase in CVD events
MOA, weight effect, mortality and disadvantage of biguanides?
- decrease hepatic glucose production, increase insulin-mediated uptake of glucose in muscles
- neutral weight gain
- GI effect, vitamin b12 deficiency, lactic acidosis
- Contraindicated with liver, kidney or cardiac failure
- decrease in CVD events
MOA, weight effect, mortality and disadvantage of alpha -glucosidase inhibitors?
- acarbose, miglitol
- inhibit polysaccharide absorption
- neutral weight gain
- GI effect
- possible decrease in CVD events in prediabetes
MOA, weight effect, mortality and disadvantage of thiazolidinediones?
- rosiglitazone, pioglitazone
- increase peripheral uptake of glucose
- increase weight gain
- fluid retention, heart failure, edema, possible increase risk of bladder cancer with pioglitazone
- possible decrease in CVD events with pioglitazone
MOA, weight effect, mortality and disadvantage of meglitinides?
- repaglinide
- stimulate insulin release
- increase weight gain
- hypoglycemia, weight gain, frequent dosing
MOA, weight effect, mortality and disadvantage of amylin mimetic?
slows gastric emptying, suppresses glucagon secretion, increases satiety
decrease effect on weight
nausea, vomiting, worsens gastroparesis, injectable, frequent dosing
no effect on mortality
MOA, weight effect, mortality and disadvantage of GLP-1 receptor agonist?
- exenatide, liraglutide, “glutide”
- glucose-dependent increase in insulin secretion. glucose-dependent glucagon secretion slows gastric emptying, increases satiety
- decrease weight
- GI effects, hypoglycemia with sulfonyureas, possible pancreatitis, injectable, possible medullary thyroid tumors
- decrease in CVD events and mortality with DM2 with liraglutide
MOA, weight effect, mortality and disadvantage of DPP4 inhibitors?
- sitagliptin, saxagliptin, linagliptin
- glucose-dependent increase in insulin secretion, glucose-dependent suppression of glucagon secretion
- neutral weight
- hypoglycemia with sulfonylureas, increased risk of infections, possible pancreatitis, dermatologic reactions
- increased heart failure hospitalizations
which pharmacologic agents used for DM2 decrease weight?
GLP-1 receptor agonists, amylin mimetic, SGLT2 inhibitors
MOA, weight effect, mortality and disadvantage of SGLT2 inhibitors?
- canaglifozin, empagliflozin
- increase kidney excretion of glucose
- decrease weight
- hypoglycemia with insulin secretagogues, hypersensitivity reactions, increased candida infections and UTI, euglycemic DKA, hyperkalemia, fractures, amputations
- bladder cancer with dapagliflozin
- CVD and mortality
MOA, weight effect, mortality and disadvantage of bile acid sequestrants?
- colesevelam
- MOA not understood, possible decrease hepatic glucose production, possible increase in incretin levels
- neutral weight
- constipation, dyspepsia, increased TGL
- no effect long term
MOA, weight effect, mortality and disadvantage of dopamine 2 agonists?
- bromocriptine quick release
- increases insulin sensitivity, alters metabolism via the hypothalamus
- neutral weight gain
- nausea, orthostasis, fatigue
- possible decrease in CVD events
when is monotherapy used for DM2?
A1c less than 8
when should you initiate dual therapy for DM2?
A1c 7.5-9% or higher or after 3 months of metformin therapy not achieving the target
how often should you monitor glycemic control?
- q3 months with adjustments until target achieved.
- q6 months if at goal
what/when do you need to screen for DM1?
- retinopathy - start 5 years after diagnosis, then annually
- nephropathy - start 5 years after diagnosis, then annually
- Neuropathy - start 5 years after diagnosis, then annually
- CVD - hypertension at diagnosis, screen every visit
- CVD - dyslipidemia - at diagnosis and prior to initiating statin, screen annually
when should insulin be instituted early instead of starting oral drugs for DM?
- DM1 always insulin
- consistently high random plasma glucose
- A1c>10-12 without symptoms
- A1c>9 with symptoms
- signs of ketosis on physical exam
- hyperglycemia symptoms or history of DKA
what can you do to lower LDL cholesterol?
intensity statin, add ezetimibe, PCSK9, colesevelam, or niacin
what can you do to lower Non-HDL-C, TG?
intensity statin, and/or add R-grade omega 3 FA, fibrate and/or niacin
if you have a diabeticwith ASCVD, CKD3 or HFrEF, what should you do?
start long acting GLP-1 or SLGLT2
how do you diagnose hypoglycemia?
- whipple triad of:
- signs and symptoms with hypoglycemia
- associate low glucose level<55
- relief of symptoms with glucose
what are the 2 categories of hypoglycemia and it’s breakdown?
- reactive (postprandial) - requires Whipple triad, never order OGTT, post-GI surgical patients
- non-reactive (fasting)
what is the ddx of non-reactive hypoglycemia?
- factitious: insulin or sulfonylureas
- autoimmune
- insulinoma
- hormone deficiencies like adrenal insufficiency
what 4 tests are used in the work up of confirmed, nonreactive hypoglycemia?
- serum insulin
- serum proinsulin
- c-peptide
- urinary/plasma sulfonylurea test
define fasting non-reactive hypoglycemia and most common causes?
- fasting/factitious type - patient unable to maintain glucose levels with fasting
- MCC - alcohol abuse, drugs, sepsis, and renal failure
what suggests a factitious insulin injection?
low C-peptide for insulin level
what suggests oral hypoglycemic injection for cause of hypoglycemia?
- C-peptide that parallels insulin level
- high urinary/plasma sulfonyurea level
what suggests an insulinoma for the cause of hypoglycemia?
- c-peptide that parallels insulin level (1:1)
- no urinary/plasma sulfonyurea
- proinsulin level greater than 20%
- insulin level usually >3-6 whiel hypoglycemia
what suggests an autoimmune cause of hypoglycemia?
- c-peptide that parallels insulin level
- no urinary/plasma sulfonyurea
- proinsulin level normal (around 10%)
- autoantibody to insulin present
Cushing syndrome work up?
How do you treat adrenal crisis?
summary of labs in interpretation of Adrenal insufficiency?
alogirithim in suspected primary aldosteronism?
