Cushing’s Syndrome
A disease of excess cortisol, it’s caused by one of four conditions:
1) Iatrogenic (most common, taper off to fix), 2) Pituitary tumor (Cushing’s disease), 3) Adrenal Tumor, or 4) Ectopic ACTH. The patient will present with a “Cushingoid appearance”: central obesity, moon facies, extremity wasting, a buffalo hump, glucose intolerance or diabetes, and hypertension. When faced with this condition, get a 24-hr free cortisol level and confirm with 1mg Low Dose Dexamethasone Suppression test. If cortisol is ↑ it’s Cushing’s. Follow that with an ACTH level to distinguish adrenal (↓ ACTH) from extra-adrenal (↑ ACTH). If adrenal, spot it with a CT/MRI of the Adrenals. If extra-adrenal, perform a high dose dexamethasone suppression test to determine pituitary (suppresses) vs ectopic (Ø suppression). Confirm pituitary Cushings with an MRI followed by transsphenoidal resection. If ectopic, find it with CT/MRI of 1) Chest (Lung Ca), 2) Abd (Pancreatic ca), then 3) Pelvis (adrenals). Remember “Low-Dose ACTHen High-Dose.” between: primary (a tumor or adenoma called Conn’s Syndrome) where aldosterone production is independent of Renin, secondary (renovascular disease, edematous states of CHF, Cirrhosis, Nephrotic Syndrome) where the production of aldosterone is dependent on renin and is an appropriate response to ↓ renovascular flow, and mimickers (CAG, Licorice, or exogenous mineral corticosteroids). When suspected, perform 8am levels for Aldosterone, Renin, and Aldo:Renin Ratio. Ensure any hypertension medication is discontinued (ACE, CCB, Diuretics confound the test). If elevated (>20 Aldo and >20 Aldo:Renin), it’s likely primary. Confirm with the salt suppression test (where aldo will not decrease after a 200g Na load). The tumor is found by CT or MRI. If early AM levels are Ø elevated a different disease is likely provoking the aldosterone increase.
Pheochromocytoma
An overproduction of catecholamines produces either a sustained refractory HTN or Paroxysmal Five P’s which are 1) Pressure (HTN), 2) Pain (Headache or Chest Pain), 3) Pallor (vasoconstriction), 4) Palpitations (tachycardia, tremor), and 5) Perspiration. This follows the rule of 10 percents (excellent pimping question, useless for practice). Screen for this disease with 24 hr urinary metanephrines or Urinary VMA (metanephrines is better, VMA is cheaper). If , do an MRI/CT of the pelvis. They should be easy to spot. If not, a MIBG Scintigraphy can be done.
The treatment is resection but with caution; touching one can cause release of catecholamines. Pretreat first with α-blockade to prevent unopposed α-action with β-blockade, then β-Blockade, then surgery.
Clinical Symptoms of Cushing’s
Ø Adrenal Tumor
24 Hr Free Urine Cortisol and
Low Dose Overnight DST
MRI/CT Abd
Ectopic ACTH Cushing’s Disease MRI/CT Abd
Refractory HTN HTN+Hypokalemia
Aldo, Renin, Aldo:Renin
Palpitations Pressure Pallor Pain Perspiration
Pheochromocytoma
Endocrine [ADRENAL GLANDS]
Adrenal Incidentalomas
These are asymptomatic adrenal masses found on CT scan for something else - an “incidental finding.” It’s important to rule out functioning adenomas (pheo, aldo, cortisol, androgen) from nonfunctioning adenomas. All above findings must be done to rule out Cushing’s (DST), Pheo (24-hr urine metanephrines) and Aldo (plasma renin and Aldo). A direct needle biopsy should NOT be done until pheo is ruled out. It’s ok to watch and wait if
<4cm, but intervene with treatment if >4cm or there’s an increase in size over time.
Adrenal Insufficiency
The loss of adrenal function may be from a variety of etiologies, and may be sudden/acute with multiple presentations. The most common cause in the US is autoimmune adrenalitis; it’s TB worldwide. In the setting of sepsis there may be bilateral adrenal destruction from hemorrhage (Waterhouse-Friderichsen). Weird deposition disease can also compromise the adrenals (amyloid, sarcoid, and hemochromatosis). In primary failure (loss of cortisol, maintenance of ACTH) the symptoms will be hypotension, fatigue, N/V of cortisol loss, as well as the hyperpigmentation and hyperkalemia. Hyperpigmentation is a result of ACTH production trying to increase cortisol while hyperkalemia is from deficient aldosterone. In secondary failure, no ACTH is produced so hyperpigmentation is absent. Because aldosterone production is intact there’s also no hyperkalemia. It’s key to make sure it’s not a primary deficiency so perform a cosyntropin test (exogenous ACTH administration). Establish a baseline cortisol in the morning (<3ug = Dz, >18ug = ruled out).
Give the ACTH then reassess in 60 minutes to determine if there’s any change in cortisol. (3, 3, 3 = Ø ACTH problem = 10 deficiency) vs (3, 3, 20 = ACTH problem, 2o deficiency). Treat this by giving the steroids they don’t have. Prednisone for all types and fludrocortisone for primary only (it’s a synthetic aldo that has its function retained through the RAAS in secondary).
r/o… With
Cushing’s Dexamethasone Suppression test
Pheo 24-Hr Urine
Conn’s Aldo/Renin
Hypotension + Hyperkalemia + N/V
Adrenal Insufficiency
↑ Cortisol after 60 minutes Ø ∆ Cortisol
Dz Path/Etiology Presentation Diagnostic Tx
Cushing’s Iatrogenic
Low Dose Dexa Suppression ACTH levels
High Dose Dexa Suppression CT/MRI Abd/Pelvis/Thorax
Pheo Adrenal Tumor Paroxysmal Pain Pressure Palpitations Pallor
Cortisol Level @ 3am Cosyntropin Test CT/MRI
1o = Prednisone (cortisol) and Fludrocortisone 2o = Prednisone Only Pituitary Failure Hyperpigmentation
Medulla à Catecholamines
Endocrine [ANTERIOR PITUITARY]
Anatomy
The pituitary is divided into two structures: 1) the adenohypophysis (anterior pituitary), which receives endocrine signals from the hypothalamus 2) the neurohypophysis (posterior pituitary), which has axon terminals from neurons of the hypothalamus in it. The pituitary’s a small endocrine gland that regulates endocrine and metabolic function throughout the body. There can be problems with overproduction or underproduction of just one or all hormones. Because of its location within the optic chiasm, tumors of the pituitary can present with bitemporal hemianopsia. We’ll discuss the typical hyper and hypo secretory disease here.
1) Prolactinoma
A benign tumor that autonomously secretes Prolactin will cause a prolactinemia. Prolactinemia presents differently in men than women. They’re caught early in women as microadenomas, because women tend to notice galactorrhea and amenorrhea.
There’s been no time for the tumor to grow; it’s small and presents without field cuts. In men, who don’t lactate or have periods, there’s nothing to tip them off that something’s wrong (decreased libido may be the only symptom). Thus, the tumor grows. As it becomes a macroadenoma it digs into the optic chiasm to produce a bitemporal hemianopia. In the case of field cuts it’s easy to be pretty sure there’s a tumor. But in the case of a microadenoma other causes of prolactinemia must be ruled out.
For example, dopamine antagonists (antipsychotics) disinhibit Prolactin while ↑↑TRH (from hypothyroidism) stimulates its production. So, before getting an MRI test, get Prolactin levels and a TSH after looking over their med list. Treat by using dopamine agonists (cabergoline > bromocriptine). Consider surgery only after medical therapy fails; unlike most tumors Prolactinomas are very sensitive to medical therapy. Follow prolactinomas with prolactin levels q3months and an MRI annually until stable.
2) Acromegaly
A benign tumor that autonomously secretes Growth Hormone will cause things that can grow to grow. In a child, before the closure of the growth plates, that means the long bones - resulting in gigantism. But in an adult it means the hands, feet, face, and visceral organs. It also induces gluconeogenesis and causes the patient to present with glucose intolerance or even frank diabetes. The thing that kills these patients is the cardiomegaly and subsequent diastolic heart failure. The diagnosis is made biochemically. However, GH is pulsatile, and so it can’t be used to make the diagnosis. Instead, because GH exacts its effects through the liver via ILGF-1 (somatomedin); the diagnosis begins there. A failure to suppress GH levels in a glucose tolerance test (next page) is a finding and should prompt the confirmatory MRI. The only treatment is surgery. However, radiation or medical therapy with octreotide (somatostatin) can be used for residual tissue to ↓GH production which will ↓ILGF effects.
3 Levels of Feed Back and Endocrine Regulation of the Ant Pituitary
(1) Hypothalamus GnRH TRH CRH GHRH
(3) Target Organ Ovaries Thyroid Adrenals Liver Metabolic
Posterior Pituitary Oxytocin ADH
↑TRH
↑TSH
↓T3/T4
TRH @ High Doses stimulates PROLACTIN Dopamine
Big Hands, Face, Feet, Cardiomegaly, DM
Measure Somatomedin C
Endocrine [ANTERIOR PITUITARY]
3) Cushing’s Disease
Autonomous secretion of ACTH causes ↑cortisol. This is covered in the adrenal disorders.
4) Central Hyperthyroidism
An incredibly rare secretion of TSH causes ↑T4/T3. This is covered in thyroid disorders.
5) Hypopituitarism
The lack of one or all pituitary hormones can cause some problems for the body. There are a variety of ways pituitary function can be lost. There are acute losses that usually present as really sick (coma, hypotension, death) and chronic losses that result in losing lesser hormones first. Let’s start with chronic then go over some specific syndromes that need to be known about acute diseases. Because the less important hormones are lost first (FSH and GH before TSH), screening can be done with an insulin stimulation test - the reverse of the glucose suppression test. If hypoglycemia fails to stimulate GH then it’s hypopituitarism. Confirm with an MRI and replace deficient hormones. If possible, reverse the underlying cause if there is one.
Acute loss of function is much worse. Specific syndromes to be aware of are Sheehan’s and Apoplexy. Sheehan’s is a post-partum hypopituitarism after prolonged labor, usually with some blood loss. The pituitary becomes ischemic and dies. This can typically be detected by the inability to lactate as the first sign.
Apoplexy is a medical emergency; a pre-existing pituitary tumor outgrows its blood supply and bleeds into the pituitary. The patient rapidly decompensates with stupor, nuchal rigidity, headache, nausea and vomiting, etc.
6) Empty Sella Syndrome
This is an incidental finding in a patient who has no endocrine abnormalities but is found to have an “absent pituitary” on an MRI they had for some other reason. If it ain’t broke, don’t fix it. They have a pituitary - it’s just not in the sella.
Infection
Infarction Tumor
Surgery
Radiation
ACUTE CHRONIC
↓TSH = Lethargy, Coma, Death 1st To go
↓ACTH = Hypotension, Coma, Death
↓FSH/LH = Not Felt
Acromegaly Hepatomegaly, Cardiomegaly
More on Acromegaly
Meninges
Meninges fill Sella Turcica
Patient Presentation Pathology Dx Tx
Prolactinoma F: Amenorrhea, Galactorrhea, Ø Vision ∆s, Microadenoma
M: Vision ∆s, Macroadenoma Best: Surgery when pregnancy, field cuts, medication failure Acromegaly Children: Gigantism
Adults: Big hands, Big Feet, Big
Acute: Coma, Lethargy, Hypotension Chronic: Less important go first Post-partum after a long labor Previous Tumor Bleeds, Stupor Nuchal Rigidity, Nausea/Vomiting
Start: Replace Missing Hormones Best: Treat underlying disease if possible Ø ∆ Cortisol (late disease)
Hypopituitarism
Endocrine [DIABETIC EMERGENCIES]
Hypoglycemia in a Diabetic
Hypoglycemia in a diabetic can come from a number of causes.
The usual suspects are too little food, too much exercise, and too much medication. Hypoglycemia is defined as a bG < 70 or symptoms of hypoglycemia (palpitations, perspiration, presyncope); it’s corrected with ingestion of sugar. Severe hypoglycemia may cause coma, anoxic brain injury, and death.
The most important thing to do is get the sugar up. Do it with an oral glucose load if the patient is awake, or with IV D50 if the patient is in a coma. After the event has resolved, assess life-style and medications to determine exactly what happened and try to prevent it in the future.
Hypoglycemic events are potentially fatal and should be treated with significantly more acuity than a high reading.
Hypoglycemia in a Non-Diabetic
Hypoglycemia, a bG < 60 AND symptoms, in a non-diabetic is usually factitious disorder. Two potential disease states (that are quite rare) are insulinoma and autoimmune hypoglycemia. To discover if the patient is doing it to themselves, obtain a C-peptide, Pro-Insulin, bG, and Secretagogue screen.
Endogenous insulin comes from Pro-insulin, cleaving the peptide portion to result in insulin. Thus, if there’s NO rise in C-peptide, the insulin must be exogenous (self-injecting). Your job is done if the C-peptide is normal.
Endogenous insulin secretion may be induced by secretagogues (like sulfonylureas) or produced by insulinomas. The only way to tell the two apart is to obtain a secretagogue screen. If positive, they’re ingesting secretagogues - tell them to stop.
Only evaluate for insulinoma if the C-peptide is elevated AND the secretagogue screen is negative. Perform a 72-hour fast, retest for all the same things above, and if positive perform the CT scan or MRI of the abdomen to find + resect the tumor.
If all else fails, consider the option of looking at insulin antibodies.
Endocrine [DIABETIC EMERGENCIES]
Diabetic Ketoacidosis
DKA is a life-threatening emergency of Type I diabetics. There is plenty of sugar in the blood, but without insulin none of it can get into the cells. It’s as if the patient is starving. The brain activates ketones from fatty acids, causing both ketosis and acidosis. Simultaneously, the high levels of sugar in the blood spill into the urine. With the Tmax of the renal tubules at only about 180, excess glucose is spilled into the urine. Glucose is a potent osmotic diuretic; the patient becomes dehydrated.
The patient will present obtunded or in a coma. They will be dry.
Diagnose the condition by finding elevation blood glucose (Diabetic) ketones in the urine and blood (Keto) and acidosis on ABG / anion gap on BMP (Acidosis).
The treatment is threefold: Replete Potassium before giving Insulin, IV Insulin, and Fluid. Monitor therapy with hourly blood glucoses and BMPs every 4 hours. If the gap hasn’t closed but the glucose is approaching normal (this value differs per protocol) switch to D5 ½ NS. As the anion gap resolves (“the gap closes”) bridge to subQ insulin long acting and let them eat.
While insulin noncompliance is the most common cause of DKA, also look for NSTEMI, GI bleeds, and infections as precipitating causes.
Hyperosmolar Hyperglycemic Nonketotic Coma
HHNKC or HHS is the life-threatening emergency of Type II diabetics. No ketones are made because there’s sufficient insulin to feed the brain. No acidosis occurs because fatty acids aren’t accessed. However, the patient will still present with coma because of profound dehydration. The blood glucoses are often much more elevated in HHNKC than in DKA + the diuresis has gone on longer. This patient needs fluids and IV insulin.
Mechanism of dehydration in hyperglycemia. Excess glucose is lost in urine and draws with it water, leading to potent diuresis.
Treatment of DKA. Replete K, give insulin, then give fluids.
HHS/HHNKC is the same thing, except no need to follow anion gap.
Characteristic DKA HHNKC / HHS
Path: Type I, Insulin Dependent Diabetes Mellitus (IDDM)
Type II, Non-Insulin Dependent Diabetes Mellitus (NIDDM)
Pt: + Diabetic Coma
+ Ketones + Acidosis
+ Diabetic Coma - Ketones - Acidosis
Dx: bG 300-500
U/A: + Ketones ABG: + Acidosis BMP: + Gap
bG 800-1000 U/A: - Ketones ABG: - Acidosis BMP: - Gap
Tx: Replete K
IV Fluids – Bolus a lot IV insulin
Follow the GAP
Replete K
IV Fluids – Bolus a lot IV Insulin
Follow the symptomatic improvement
Endocrine [DIABETES INSULIN MGMT]
Insulins
Learning insulins for exams is a nightmare. Everything makes sense if trade names are used. I’m going to let YOU learn how to recall generics, because it’s easier using what we use in real life and I want you remembering the medicine first. It’s imperative to learn the difference between their peak onset and how long they last. All insulins require SubQ injections. Some hints to help get started. 1) L drugs (Lantus and Levemir) are Long acting and all equivocal (except for how good the meal is at the drug rep dinner). 2) Log math is more advanced than drawing a Line, so Log drugs (Humalog Novolog) are used in more complex ways (qAc) versus the 3) Lin drugs (HumuLin NovoLin), which as we’ll see are ancient, not great, and useful for those who don’t want to think. Finally, 4) NPH is the rapid part of the log combos, while 5) regular insulin is a longer acting (medium) insulin.
Insulin Regimen
The goal of insulin regimens is to control the blood glucose as though it were a normal pancreas. That means post prandial glucose spikes are met by insulin spikes post-prandially. There is also a certain level of insulin always floating around in the body – it’s called basal insulin. So to simulate a normal pancreas the basal-bolus is best. Insulin demand can be approximated by 0.5 Units/kilogram the total amount per day. In the basal bolus method, ½ is in the night time as Long Acting Insulin (the basal). The other ½ is divided qAC of short acting insulin (the bolus). It’s important to remember that a blood sugar is affected by the insulin that precedes it. If the AM Dose is high, increase the nighttime dose. If the bG taken near lunch is high, increase the breakfast dose.
A lot of people try the Idiot Insulin method. It’s called (I call it) idiot insulin because the same amount of medium acting insulin is given regardless of the blood sugar. If patients don’t want to check bG or are afraid of needles, they can use this method. It has poor basal coverage and poor post prandial coverage, but it’s only biD dosing.
The worst method is sliding scale insulin where no basal insulin is given. Rather, a certain amount of short-acting insulin is given with each accucheck. Bad hospitalists will do this. Since current bG is a product of the last insulin it will create hyperglycemic peaks and hypoglycemic troughs as the nurse tries to chase down the bG on your orders. If following another regimen and sugars are still high, adjustment of daily doses is appropriate.
However, if the patient eats a cake or has ridiculous bG one time, using the sliding scale is a great supplement - but only on top of an existing regimen.
Basal insulin qPM HumaLog
NovoLog
Rapid acting Insulin Combo
Prandial Insulin qAC HumuLin
NovoLin
Medium acting Insulin Combo (old school, easy)
Idiot Insulin biD
NPH Rapid Acting Prandial qAC
Regular Rapid Acting Generally useless
IDIOT INSULIN
2/3 AM Humulin 70/30
0.5Units/kg Novolin 50/50
1/3 PM
1/2 Bolus Lantus/Levemir 0.5Units/kg
1/2 Prandial Novolog/Humalog
Effect Findings
Somogyi Effect Too MUCH insulin at night à High AM bG Dawn Phenomena Too LITTLE insulin at night à High AM bG Check early AM bG to tell the difference
Complications What we do
CAD or HF ACE-i
Nephropathy Microalbumin Screen, ACE-i Peripheral
Neuropathy
Foot care, education, educations
Eyes Fundoscopic Exams, Laser
Erectile
Dysfunction Nighttime Tumescence, Viagra Control the Blood Sugars is paramount
BASAL BOLUS
CHASING THE SUGAR (DON’T EVER DO THIS)
SS
Breakfast Lunch Dinner Sleep
Wake Log Log Log Levemir
Endocrine [MEN SYNDROMES]
This is for those going for the gold. I include it because it was my first patient in residency. It was also likely my last encounter with it.
MEN1 Syndrome
Also known as Wermer’s Syndrome, this is an autosomal dominant mutation of MEN1 gene that causes hyperplasia or adenomas of the “3 Ps:” Pituitary Adenomas, Parathyroid Adenomas, and Pancreatic Adenomas. There’s a strong association with Gastric Ulcers (Zollinger-Ellison syndrome from the pancreatic adenomas), Hypoglycemia (Insulinoma), and Hypercalcemia (PTH).
MEN2A and MEN2B
These are essentially the same disease and aren’t clearly separated. Both are caused by a mutation in the RET proto-oncogene. They cause endocrine tumors everywhere except the 3ps. Look for Pheochromocytomas and thyroid adenomas. The parathyroid gland can also be involved, but isn’t classic. Really, the only difference between 2A and 2B is the presence of neuronal tumors found in MEN2B.
MEN1 = Pituitary + Pancreas + Parathyroid
MEN2A = Pheochromocytomas + Thyroid + Parathyroid MEN2B = Pheochromocytomas + Thyroid + Neuronal Real life vs test
This is rare (~1 in 50,000) – you’re not going to see it. If there’s a combination of:
- recurrent endocrine neoplasias + - age <40 +
- family history +
- multiple organ systems affected
You’d suspect something was up and do a mutational analysis of the MEN1/2 genes.
Endocrine [OUTPATIENT DIABETES]
Diagnosing Diabetes
Screening is indicated when there are risk factors such as an elevated BMI, hypertension, or advanced age. Different screening tools exist, each with their own advantages.
The random glucose is convenient – it can be obtained at any time without preparation and it’s a one-time test. The diagnosis is made if the random glucose is > 200 and there are symptoms of
The random glucose is convenient – it can be obtained at any time without preparation and it’s a one-time test. The diagnosis is made if the random glucose is > 200 and there are symptoms of