* Pituitary gland is on the sella turcica surrounded by the sphenoid bone and around that area is the optic chiasm. So pituitary disease commonly affects visual field, specifically bitemporal hemianopsia.
* Pituitary is divided into posterior and adenohypophysis, secreting hormones (ACTH, TSH, etc) and is affected directly by other hormones in the hypothalamus. Usually adenohypophysis secretes hormones that affect organs in the periphery. Stages of control are hypothalamus, pituitary, and end organs. Posterior pituitary secrets oxytocin and ADH, which are produced by the hypothalamus and stored in the pituitary.
* 32yo woman comes to your office because she has noticed a milk-like discharge from her breast for the past four weeks. Examination reveals galactorrhea but is otherwise normal (no visual field cuts or amenorrhea).
* With galactorrhea, think prolactinoma because these are the most common active pituitary tumors. They secrete autonomous prolactin. Prolactin is under continuous inhibition from dopamine. When dopamine is inhibited or if autonomous adenoma will you get prolactinemia.
* In women, the prolactinoma is usually a microadenoma. Thus there is minimal pressure phenomenon. They usually presents with amenorrhea and galactorrhea +/- hemianopsia.
* In men, the prolactinoma is usually a macroadenoma. They rarely present with gynecomastia or galactorrhea. They usually present with visual field cuts, headaches, and pressure phenomenon.
* With galactorrhea presentation, do not jump to adenoma as the cause. Look for other causes like dopamine inhibitors like haloperidol (depletes dopamine) and primary hypothyroidism, which has low T3 and low T4. The low T3 and T4 go back as positive feedback to pituitary to increase TSH and also goes into hypothalamus to increase thyroid releasing hormone (TRH). In a normal individual hormone, TRH activates TSH release and that activates T3/T4 release from thyroid. With primary hypothyroidism, TSH is up and TRH is up. TRH at high doses seems to be an activator of prolactin. Check for TSH; TRH is not tested for because it is expensive and has to be sent out. * 32yo woman comes in with galactorrhea. She is on no dopamine depleting medications and has a normal TSH and T4. What is the next test to order? Answer is prolactin level.
* If prolactin level is elevated, do an MRI of the pituitary to look for the lesion.
* Treatment of prolactinomas is bromocriptine, which is a dopamine activator and thus a prolactin inhibitor. Decreasing production of prolactin from a prolactinoma would shrink the size of the tumor.
* Treatment of prolactinomas that are macroadenomas (usually men) may need surgery or radiotherapy.
* In rare scenarios, prolactinomas occur in older women. In this case, you are not worried about pregnancy so you can watch the patient and not treat if there is no pressure phenomenon.
* Acromegaly with pituitary adenoma is caused by a macroadenoma 75% of the time. Acromegaly is due to hypersecretion of growth hormone. Growth hormone mainly works through the liver by secreting insulin-like growth factor (ILGF, somatomedins), which has an effect on tissue and bone causing it to grow.
* Acromegaly symptoms are enlarged head, larger feet, shoe size, ring size, tongue grows, jaw grows, and organs grow such as the heart which leads to congestive heart failure and is the most common cause of death.
* Before considering a MRI of the pituitary (80-90% of cases) in acromegaly, you have to document that the patient has autonomous hypersecretion of growth factor, done by a glucose tolerance test.
* Glucose causes the release of insulin and counter-regulatory hormones like growth hormone, glucagon, and cortisol. Insulin puts glucose into cells and lowers blood glucose. Counter-regulatory hormones keeps glucose levels high in the blood. If glucose is high, normal response is increased insulin and decreased counter-regulatory
hormones. Screening test for acromegaly is to give the patient glucose then measure growth hormone after an hour, normal response is decrease in growth hormone. If after glucose load, growth hormone is elevated, this is an inappropriate response and we say the patient likely has acromegaly due to autonomous hormone release. * 80% of acromegaly patients have elevated glucose and about 30% of them have diabetes mellitus.
* We could also measure ILGF levels, which would always be elevated in acromegaly patients. Then do the MRI looking for the tumor in the pituitary.
* Treatment for acromegaly is octreotide (somatostatin). Somatostatin is a statin of somatic activity. ILGF are somatomedins, or mediators of somatic activity. Next treatment option is bromocriptine, which shrinks the size of the tumor in acromegaly for unknown reasons. Surgery and radiotherapy are also options.
Pituitary Disease: Hypopituitarism
* Hypopituitarism is loss of pituitary hormones over time. The first hormones to be lost are the ones you need the least, and those are FSH, LH, and growth hormone. You can live without these. Then TSH is lost, which is a bit more important. Lastly you lose the most important, ACTH which affects the adrenals.
* Screening test for hypopituitarism is the insulin-tolerance test. Give patient 5U of insulin to cause hypoglycemia. Appropriate response is no insulin release and elevated counter-regulatory hormones. So you expect high glucagon, high GH, high cortisol. You measure growth hormone an hour later and expect it to be elevated. You do not just measure GH because it changes throughout the day so you have to provoke it. If GH is not high an hour after 5U insulin given, probably hypopituitarism. You can check the cortisol level at the same time to see if ACTH is missing too. You can also check the levels of FSH and LH in the blood.
* Pituitary apoplexy is a medical emergency. Patients usually have a pre-existing pituitary adenoma that was not treated well or not treated at all. The adenoma increases in size and the patient bleeds into the adenoma then virtually blows out their pituitary. History is patient with pituitary adenoma comes in with stupor, nuchal rigidity, vomiting, and headaches.
* Treatment of pituitary apoplexy is medical stabilization, high-dose corticosteroids, evaluate electrolytes, administer appropriate hormones, neurosurgical consult for transsphenoidal decompression of the tumor.
* Sheehan syndrome usually occurs after a prolonged and labored pregnancy. The first sign of Sheehan syndrome is the inability to lactate. This can occur even 5 years after pregnancy. If it looks like Sheehan syndrome, do the insulin tolerance test to make sure it is not hypopituitarism.
* Treatment of Sheehan syndrome is to replace hormones they have lost.
* In children, any space occupying lesion can cause hypopituitarism. The most common in children is a craniopharyngioma. In adults, it would be stroke syndromes, cancers, granulomas.
* Patients with empty sella syndrome usually have normal endocrine function. In empty sella syndrome, the patient is missing the diaphragmatic surfaces holding the pituitary in. The meninges come into the sella and push out the pituitary. So the pituitary is pushed off to the side and squished between the meninges, thus cannot be easily visualized on CT or MRI. These patients had no endocrine issue but got a CT or MRI for another procedure and were found to have an empty sella. You cannot have empty sella syndrome with normal endocrine function. Pituitary Disease: Posterior Pituitary
* Diabetes insipidus (DI) occurs when patients are missing the major water-retaining hormone in their body, antidiuretic hormone (ADH). This is needed to concentrate your urine, else you lose free water.
* DI patients complain of polyuria and polydipsia. It may occur because the patient is missing ADH, called central diabetes insipidus (CDI). CDI can occur with any space occupying lesion or anything affecting the central nervous system, namely stroke syndromes, tumors in the brain, granulomas in the brain, and trauma to the head.
receptors in the kidney do not function. The causes of NDI are lithium and demeclocycline. These drugs can make the ADH receptors in the kidney unresponsive to ADH.
* Insipid means devoid of characteristic, so diabetes insipidus has dilute urine.
* Test for DI is the water deprivation test, where plasma osmolality is plotted against urine osmolality. In a normal individual will get dehydrated and Posm will increase. At the same time, the patient does not make urine to conserve free water. Normal is increased Posm and increased Uosm (urine concentrates). A patient with DI cannot do this, so as they are getting more dehydrated they will keep putting out dilute urine. Posm will increase, serum Na+ is increasing, but they are putting out dilute urine (Uosm low/not changing). At this point, you cannot differentiate CDI from NDI, so you give the patient vasopressin (ADH). If the patient has no ADH (CDI), you will start to see a normalization of Uosm (Uosm increasing and concentrating). If you give ADH and there is no change in Uosm, this can only be NDI since the kidney receptors are not responding to ADH.
* Treatment for CDI is to give vasopressin (ADH) or give intranasal desmopressin. Desmopressin is like ADH but only different by one amino acid, however you do not have the pressor effects of ADH.
* Treatment for NDI is hydrochlorothiazide or amiloride. The diuretics get rid of sodium and help retain water. This sounds like a paradox because the patient is getting rid of lots of urine, but the aim is to retain water. The
mechanism for thiazide diuretics is to decrease distal tubular sodium reabsorption, which increases urinary excretion, which decreases extracellular volume, which increases proximal sodium and water reabsorption, which decreases distal delivery of sodium and water, and finally decreases urine output.
* Patients presenting with polyuria and polydipsia either have diabetes mellitus (check serum and urine glucose) then think about DI, but also think about psychogenic polydipsia.
* Psychogenic polydipsia is characterized by large intakes of water and large outputs of urine. These patients do not wake up in the middle of the night to go to the bathroom. This disease runs in families. Water deprivation test will show almost normal response. When these patients drink lots of water the wash out the medulla of the kidney and lose concentrating capabilities.
* Patients with DI usually have access to water, so they can take in 20L and put out 20L. It is when they lose access to water that they get very dehydrated. Common scenario is a patient on lithium for many years who goes into the hospital for surgery (or another scenario where water access is lost) and now they become very dehydrated showing with severe hypernatremia.
* Syndrome of inappropriate ADH (SIADH) secretion is when patients produce small amounts of concentrated urine. These patients hold on to too much free water, which dilutes the sodium and causes hyponatremia. * SIADH can occur with CNS processes like tumors, strokes, granulomas, infections, trauma.
* SIADH can occur with lung processes like abscess, COPD, tuberculosis. * SIADH can occur with medications like vinblastine and vincristine.
* Treatment of SIADH is to treat the primary disease, then SIADH usually resolves. Sometimes the sodium is so low we have to treat the SIADH. Treatment of choice is water restriction. Treatment could also include drugs that cause NDI like lithium and demeclocycline, demeclocycline is probably preferred due to less side effects and less drug-drug interactions.
* In severe hyponatremia, hypertonic saline can be used. Do not replace too quickly due to risk of central pontine myelinolysis. Correcting hypernatremia too quickly with free water can result in cerebral edema and seizures. Thyroid Function Testing
* Thyroid gland produces T4 as the main secretory product.
* Do not assume enlargement or nodules of the thyroid mean hyperthyroidism. This is why we need to objectively assess the thyroid by looking at thyroid hormones, T4, T3, and TSH (indirect measurement).
* The best test for screening for thyroid disease is thyroid stimulating hormone (TSH) as it is the most sensitive and specific test. The current TSH testing can diagnose hypothyroidism or hyperthyroidism with a 95% confidence interval, so they are very good tests.
* If the TSH is normal, in general that patient is euthyroid. Forget about the T4 and forget about the T3.
* Thyroid levels of control are hypothalamic function (TRH), pituitary (TSH), and T4/T3 from thyroid. The thyroid produces mostly T4, T4 in the periphery gets converted to T3.
* T3 is a more potent hormone with a better effect. Because T3 is more potent, it has a stronger feedback. To suppress TRH and TSH, you would give T3 hormone.
* When your thyroid puts out T3 + T4, nearly all of it is bound to albumin. This is called thyroid binding globulin and it is an inactive form, so does nothing to TSH or TRH for feedback nor does it have metabolic effects. The free T4 is less than 0.1% of the total, it is metabolically active, and has the feedback effect to TSH and TRH. To see how the thyroid is really working, you want free T3 and free T4, not the total because you only care about free T4. * Free T4 use to be a difficult test, so people measured total T4 then got RT3U (resin T3 uptake) to indirectly
measure free T4 index. Resin T3 uptake does not measure T3, it is an indirect measure of T4. Again, this test is not done anymore so look for a free T4 test.
* Since 99.9% of thyroid hormones are bound to albumin, any changes in albumin and protein levels in the body will fluctuate the total T3 and total T4 levels. Example would be pregnant patient or patient taking estrogen, they have increased proteins so total T4 will increase. Is this patient hyperthyroid? No. Free T4 in this patient would be normal and TSH would be normal. So be careful when you see a total T4 or total T3 instead of free T4 or free T3. Example patient with nephrotic syndrome or cirrhosis, total protein level is down. Total T3/T4 would be down in this patient but it is not hypothyroid. Free T4 and TSH would be normal in this patient.
* With fluctuations in protein the body will keep the free T3 and free T4 stable.
* Radioactive iodine uptake scan (RAI-uptake) is a way to directly measure function o the thyroid. Radioactive iodine is given to the patient, wait 24h, then scan the thyroid, repeat in 48h to see what the uptake is. Normal is 10- 40% uptake just as a note. Anything under this would be hypothyroidism, anything over this is hyperthyroidism. * Primary hyperthyroidism: TSH low, free T4 elevated, free T3 elevated, RAI-uptake scan high. Example is Graves disease, toxic nodular goiter.
* Thyroiditis: TSH low, free T4 elevated, free T3 elevated, RAI-uptake scan is low. Example is subacute thyroiditis. Thyroid hormone is being spilled into the periphery due to destroyed thyroid cells but uptake is low because thyroid is injured. This patient should not be treated with antithyroid medication, treatment is to wait.
* Secondary hypothyroidism: TSH low, free T4 low, free T4 low, RAI-uptake scan is low. Example is
hypopituitarism. Likely to have abnormal growth hormone, LH, and FSH because usually not just one pituitary hormone missing.
* Pregnancy or protein-increasing medication: TSH normal, free T4 normal, free T3 normal, RAI-uptake scan normal, elevated total T4.
* Exogenous thyroid medication use (e.g. weight loss attempt): TSH low, free T4 elevated, free T3 elevated, RAI- uptake scan low or normal. Thyroid hormones use to be in weight reduction medication a few decades ago even in this country.
* Anti-microsomal antibodies sometimes associated with Hashimoto disease. * Thyroid globulin immunoglobulin sometimes associated with Graves disease.
* A patient is intubated in the ICU and the patient’s FT4 was high or low. Someone thought this patient might have a thyroid problem, but TSH came back normal. Since this is an ICU patient, they likely have a lot of other comorbid conditions. This patient has sick euthyroid syndrome. There is no need for endocrine management here.
Hyperthyroidism
* Graves disease is the most common cause of hyperthyroidism. The cause is an immune process, antibodies that affect the TSH thyroid receptors, antibodies act like TSH to rev-up the thyroid. The thyroid enlargement is diffuse and is the only time in thyroid disease where you get proptosis and exophthalmos.
* Other Graves signs include dermopathy, palpitations, tachycardia, intolerance to heat, weight loss, diarrhea, menstrual irregularities, tremor, bruit over thyroid, sometimes swelling of the feet (pretibial myxedema).
* Graves laboratory findings would be low TSH, increased FT4, and elevated RAI-uptake if you felt you needed it. * Management in the acute phase is to relieve symptoms and reduce peripheral thyroid hormone. Anti-thyroid medications are propylthiouracil (PTU) and methimazole to decrease thyroid hormone level. Symptomatic relief includes beta-blocker therapy (propranolol, atenolol) until patient is out of acute phase meaning they feel better and become euthyroid.
* Management after acute phase is definitive treatment with radioactive iodine to kill the thyroid. Within months or years the patient will become hypothyroid, so you have to follow this patient every six months to check thyroid hormones. When they become hypothyroid, then give thyroid medication (synthroid or any other T4 form). * Complication of PTU and methimazole is agranulocytosis. If patient is on this medication and calls you saying they feel horrible and are running a high fever. Tell them to stop the medication and have their white cells checked. It is reversible agranulocytosis as long as you catch it.
* If agranulocytosis occurs with PTU then you cannot give the patient methimazole, they will get agranulocytosis with that as well.
* Proptosis and exophthalmos commonly gets worse when you treat Graves disease. Ophthalmopathy is treated separately as patient may not be able to close their eyes and may get eye ulcers. So they may need surgery, or orbit radiation, or steroids.
* In pregnant patient with Graves disease the only anti-thyroid medication we can use is PTU. We can also use propranolol. Both of these cross the placenta and have side effects. Propranolol can cause small for dates. So we can only use these at low doses. Give them a little bit of PTU and propranolol to cool down the thyroid, then take the patient to surgery in the second trimester. Radioactive iodine has not been shown to cause cancer, but you definitely
do not want to give it to a pregnant patient.
* Toxic nodular goiter is more common in adults and older patients. These patients usually had a non-toxic goiter prior. Toxic goiter means the thyroid goiter produces thyroid hormone. Non-toxic goiter means nothing is being produced from the goiter.
* Toxic nodular goiter exam will not show a diffuse enlargement. You will find nodules, maybe one, maybe many. * Presentation occurs mostly in elderly patients and they have mainly cardiac manifestation such as atrial
fibrillation, tachycardia, congestive heart failure.
* Both hyperthyroidism and hypothyroidism cause proximal muscle weakness. Thyroid Storm
* Thyroid storm definition is a hyperthyroid patient with delirium, fever, hypotension, CHF. This is high output cardiac failure, treated with propranolol.
* Thyroid storm usually in patients with Graves disease and precipitated by a condition such as infection or surgery. * Treatment is propranolol even if they have hypotension, PTU, and iodide. Iodide is the cornerstone of thyroid storm treatment. Thyroid will either output T3/T4 or grab iodide but not generally both. It would rather grab onto iodide, so giving the patient iodide will down-regulate the production of T3/T4.
* Iodide buys you some time. If you do not manage the thyroid storm patient, a couple days later they will have