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Pathology Chapter 24: The Endocrine System (pages 1107-1130) The thyroid gland has 2 bulky lateral lobes connected by a thin isthmus, usually below and anterior the larynx - - - - The thyroid is divided by thin fibrous septae into lobules made of many follicles, which are filled with thyroglobulin, which stains PAS positive o The follicles are lined by epithelium In response to things from the hypothalamus, thyrotrophs in the anterior pituitary release thyroid-stimulating hormone (TSH, aka thyrotropin) TSH then binds to its receptor on the thyroid follicle epithelium o This causes a conformational change and activation of the receptor, allowing it to associate with a G protein o Activation of the G protein eventually results in an increase in intracellular cAMP, which stimulates thyroid growth, and hormone making and release When the thyroid stops listening to TSH and hyperfunctions, it’s called thyroid autonomy Thyroid follicular epithelial cells convert thyroglobulin into mainly thyroxin (T4), and lesser amounts of triiodothyronine (T3) T4 and T3 are released into systemic circulation, where they reversibly bind to plasma proteins, like thyroxine-binding globulin and transthyretin, for transport to peripheral tissues o The binding proteins help to maintain serum unbound (“free”) T3 and T4 concentrations within narrow limits so that is just enough to meet the tissues’ needs In the periphery, most of the free T4 is deiodinated to T3 T3 then binds to thyroid hormone nuclear receptors in target cells with more affinity than T4 would, and has more activity than T4 When thyroid hormone interacts with its nuclear thyroid hormone receptor (TR), it forms a complex that then goes to thyroid hormone response elements (TREs) in target genes Thyroid hormone does things to increase the basal metabolic rate - This includes triggering carb and lipid break down, and stimulating protein making in cells One of the most critical roles of thyroid hormone is in brain development in the fetus and newborn Goitrogens are agents that can inhibit thyroid hormone making - When goitrogens inhibit thyroid hormone making, it triggers TSH to be released and increase, which leads to hyperplastic enlargement of the thyroid gland, called goiter Propylthiouracil – drug that inhibits oxidation of iodide, causing a block in the making of thyroid hormones - Propylthiouracil also inhibits peripheral deiodination of circulating T4 to T3, fixing symptoms of thyroid hormone excess Giving people with a hyperfunctioning thyroid iodide, also blocks the release of thyroid hormones - In large doses, iodide inhibits proteolysis of thyroglobulin (so the hormones aren’t cleaved off it) o So the thyroid hormone is made and put into colloid, but not released inot the blood Thyroid gland follicles also have parafollicular (C) cells, which make and release calcitonin - Calcitonin promotes the absorption of calcium by the bones, and inhibits resorption of bone by osteoclasts Thyrotoxicosis is a hypermetabolic state caused by elevated levels of free thyroxine and T3 - - - - - - - Since thyrotoxicosis is usually caused by overfunctioning of the thyroid, it’s called hyperthyroidism Sometimes though, the thyroid isn’t overfunctioning, and the problem could be excessive release of premade thyroid hormone (thyroiditis) or by an extrathyroidal source o A lot of people use the terms hyperthyroidism and thyrotoxicosis interchangeably The three most common cause of thyrotoxicosis are from hyperfunctioning of the thyroid: o Diffuse hyperplasia of the thyroid- like in Grave’s disease o Hyperfunctional goiter o Hyperfunctional cancer of the thyroid The symptoms from hyperthyroidism are from the hypermetabolic state it causes, and overactivity of the symps Excessive thyroid hormone increases the basal metabolic rate, making the skin soft, warm, and flushed, due to increased blood flow and peripheral vasodilation to lose the heat o This causes heat intolerance to be common o The increased metabolic rate causes sweating to increase o The increased metabolic rate can also cause weight loss despite an increased appetite Heart changes are among the earliest and most consistent feature of hyperthyroidism o Includes increased cardiac output, due to increased contractility and oxygen requirements, tachycardia, palpitations, and enlarged heart o Arrhythmias and heart failure are more common in older people o Some people can develop reversible left ventricular dysfunction and “low output” heart failure, called thyrotoxic or hyperthyroid cardiomyopathy o Hyperthyroidism can make pre-existing heart problems worse Neuromuscular problems from hyperthyroidism are signs of an overactive symp system, including tremor, hyperactivity, emotional and anxiety issues, insomnia, and thyroid myopathy (muscle weakness and decreased muscle mass) Eye changes in thyroid conditions can be a wide, staring gaze and lid lag, due to symps overstimulating the levator palpebrae – page 1109 o True thyroid opthalmopathy causing proptosis is only seen in Grave’s disease In the GI, hyperthyroidism causes hypermotility, malabsorption, and diarrhea - - - - - In the skeletal system, thyroid hormone stimulates bone resorption, which can cause osteoporosis and easy fractures during chronic hyperthyroidism Thyroid storm- medical emergency of severe abrupt hyperthyroidism o Thyroid storm happens most often in people with underlying Grave’s disease o Probably caused by an acute increase in cathecholamine levels, like during an infection, surgery, or stopping antithyroid medicines, or any form of stress o They usually present with a fever, and can progress to tachycardia and death by cardiac arrhythmia Apathetic hyperthyroidism- thyrotoxicosis in old people, where effects of aging blunt the features of the hyperthyroidism o Often not noticed until they’re losing weight or get blood work for heart problems The measurement of serum TSH concentration is the most useful screening test for hyperthyroidism o Hyperthyroidism decreases TSH release right away, even before symptoms show up o Once a low TSH is seen, free thyroxine is measured, and the diagnosis of hyperthyroidism is confirmed if it is increased If you inject them with TRH and see a rise in TSH after, it excludes secondary (pituitary) hyperthyroidism Once you’ve diagnosed them with hyperthyroidism, you can use radioactive iodine to see what part of the thyroid is the problem, which can help you determine the cause o Graves- increased uptake of the iodine o Toxic adenoma- only increased uptake at one part o Thyroiditis- decreased uptake Quick drug summary: o β-blockers- stop sympathetic symptoms o Thionamide-blocks new hormone making o Iodine-blocks release of the thyroid hormone Hypothyroidism is usually a primary (intrinsic at the thyroid) condition, that can lead to goiter (enlarged thyroid, from compensatory rise in TSH) - Hypothyroidism is caused by anything that decreases the making of thyroid hormone Hypothyroidism is somewhat common (up to 4 of people), and risk increases with age o Hypothyroidism is way more common in women Primary hypothyroidism can be congenital, acquired, or autoimmune Congenital hypothyroidism is usually caused by endemic iodine deficiency in the diet o Can also be an inborn error in thyroid hormone making (called dyshormonogenetic goiter) at: Iodide transport into the thyrocytes Iodide organification - when iodide binds to the tyrosines of thyroglobulin (the storage protein) Coupling to form active thyroid hormones o - - - Mutations to thyroid peroxidase are the most common cause of dyshormonogenetic goiter o Pendred syndrome- mutation to the gene for pendrin, causing hypothyroidism and sensorineural defects Pendrin is an anion transporter on the apical surface of the thyrocyte o Thyroid hormone resistance syndrome – the thyroid hormone receptor can’t bind thyroid hormone Both thyroid hormones and TSH will be high in this case Acquired hypothyroidism can be caused by surgery or radiation-induced destruction of the thyroid o Often a result of getting rid of too much thyroid when treating hyperthyroidism Autoimmune hypothyroidism is the most common cause of hypothyroidism in parts of the world that have plenty of iodine o Most autoimmune hypothyroidism cases are Hashimoto thyroiditis Autoantibodies like anti-microsomal, anti-thyroid peroxidase, and antithyroglobulin are found Usually causes goiter Secondary hypothyroidism is caused by a deficiency of TSH, or sometimes TRH o Pituitary problem Classical manifestations of hypothyroidism include cretinism and myxedema o Cretinism- hypothyroidism in infancy or childhood Causes impaired skeletal system and CNS development, showing mental retardation, shortness, coarse facial features, a protruding tongue, and umbilical hernia The amount of retardation depends on when the kid is exposed to less thyroid hormone Normally, mom thyroid hormones cross the placenta and are needed for fetal brain development Mom hypothyroidism during the period of brain development is the worst o Myxedema- hypothyroidism in older children and adults Shows slowing physical and mental activity Shows fatigue, mental sluggishness (which both can resemble depression), cold intolerance, weight gain Symps are decreased, so you get constipation and decreased sweating Often their skin is cool and pale because of decreased blood flow Decreased cardiac output happens, and can decrease exercise capacity and cause shortness of breath Hypothyroidism also causes increase in total cholesterol and decrease in HDL They also have accumulation of ECM stuff, like glycosaminoglycans and hyaluronic acid in the skin and viscera - This causes edema, broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice Measuring TSH is the most sensitive screening test for hypothyroidism o It will be increased in primary hypothyroidism o TSH won’t be increased in secondary hypothyroidism, like a pituitary problem o Thyroxine will always be decreased with any kind of hypothyroidism Thyroiditis- inflammation of the thyroid gland - Inflamed thyroids can cause neck pain and tenderness at the thyroid o Infections can cause fever and other systemic signs too Hashimoto thyroiditis o Hashimoto thyroiditis is the most common autoimmune thyroiditis, and the most common cause of hypothyroidism in parts of the world that get enough iodine o Hashimoto thyroiditis is characterized by gradual thyroid failure due to autoimmune destruction of the thyroid o It’s most common from ages 45-65 o The autoimmunity destroys the thyroid o More common in women, and in middle-aged people o Commonly caused by mutations to CTLA4 and PTPN22 (both inhibit T cells) o Most cases of Hashimoto thyroiditis will involve circulating antibodies against thyroglobulin and thyroid peroxidase o The autoimmunity causes apoptosis of thyrocytes, and their replacement with inflammatory cells and fibrosis o Ways autoimmunity can kill the thyroid cells: CD8+ caused death Cytokine caused death – excessive T cell activation leads to making of cytokines from TH1, like interferon-γ, which causes macrophage to kill the thyroid follicles Binding of anti-thyroid antibodies – includes anti-thyroglobulin and anti-thyroid peroxidase o Hashimoto shows goiter (enlarged thyroid) and lymphocytic inflammatory infiltrate Also shows atrophic thyroid follicles, lined with Hurthle cells (epithelial cells with an eosinophilic, granular cytoplasm) Hurthle cells are characteristic of Hashimoto thyroiditis, and they are a metaplastic response by the epithelium to ongoing injury Morphology also shows fibrosis only within the capsule of the gland, unlike Reidel thyroiditis Classic Hashimoto thyroiditis shows increased interstitial connective tissue o The classic presentation of Hashimoto thyroiditis would be a middle-aged woman coming in with painless goiter and some degree of hypothyroidism The enlargement of the thyroid is symmetric o - - Some cases can involve hasitoxicosis, where before the hypothyroidism begins, antibodies destroy enough thyroid follicles to cause release of the colloid and all the stored thyroid hormones, causing a temporary hyperthyroidism o People with hashimoto thyroiditis are at risk for developing other autoimmune diseases Subacute granulomatous thyroiditis (aka De Quervain thyroiditis) o De Quervain (granulomatous) thyroiditis is the most common cause of thyroid pain Usually De Quervain is just a temporary thyroid inflammation and hyperthyroidism that will go away in 6-8 weeks o Another one more common in middle-age and women o De Quervain thyroiditis is thought to be triggered by a virus, usually an upper respiratory infection o Occurs more often in the summer o The thyroid may be unilaterally or bilaterally enlarged o Instead of looking rubbery and brown like normal thyroid, De Qeurvain thyroiditis will look yellow-white and firm o Inflammation occurs, including multinucleate giant cells that give it the name granulomatous o They have high thyroid hormones, but unlike in Grave’s disease, radioactive uptake of iodine is decreased (thyroiditis) Subacute lymphocytic thyroiditis (aka painless thyroiditis) o Usually brings them in for goiter and mild hyperthyroidism o Again, more common in middle age, and women o Postpartum thyroiditis is an example of a lymphocytic painless thyroiditis, that happens in 5% of women o Some of these patients can transition from hyperthyroid to hypothyroid o Also includes Riedel thyroiditis, a rare one that causes fibrosis of the neck o Only shows a lymphocytic infiltrate, other than that the thyroid looks normal Grave’s disease – the most common cause of endogenous hyperthyroidism - - Characterized by 3 things: o Hyperthyroidism o Ophthalmopathy that causes exophthalmos (protruding eye) o Dermopathy called pretibial myxedema Most often occurs between 20-40 years of age Women have Grave’s disease way more than men do Grave’s disease and Hashimoto make up the two extremes of thyroid autoimmune disorders o Grave’s – hyperthyroid, Hashimoto-hypothyroid Like Hashimoto, Grave’s has also been linked to gene problems with CTLA4 and PTPN22 Grave’s disease is characterized by an autoimmunity to the TSH receptor Grave’s results in many antibodies, including: o - - - Thyroid-stimulating antibody- an IgG that binds to the TSH receptor and mimics TSH, causing continuous stimulation of the thyroid follicle to make thyroid hormone Almost all cases of Grave’s have thyroid-stimulating Ig, and they’re specific for Grave’s disease, unlike the other 2 Ig’s seen o Thyroid-growth stimulating Ig- also targets the TSH receptor and causes proliferation of the follicle epithelium o TSH-binding inhibitor Ig- bind and inhibit TSH, and can also mimic TSH So it can both stimulate and inhibit thyroid hormone making The ophthalmopathy in Grave’s shows increased volume of the extraocular eye muscles and connective tissues, caused by: o T cells infiltrating the retro-orbital space o Swelling of eye muscles o Accumulation of ECM stuff, like HA and chondroitin sulfate o Fatty infiltration o All of these displace the eye forward and interfere with the function of the eye muscles Morphology of Grave’s: o Grave’s has a goiter from hypertrophy & hyperplasia of thyroid follicular epithelial cells The thyroid will be symmetrically enlarged o Colloid in the follicles is pale – everything’s getting pushed out of it o There’s a lymphocyte infiltrate of mainly T cells o Treating with iodine causes involution of the epithelium and accumulation of colloid, due to blocked thyroglobulin secretion o Treating with propylthiouracil makes the hyperplasia and hypertrophy worse by stimulating TSH secretion o The heart can hypertrophy The enlargement of the thyroid in Grave’s can be accompanied by an increased flow of blood through the thyroid, causing an audible bruit Grave’s causes symp overactivity that causes a characteristic wide, staring gaze, and lid lag Graves causes exophthalmos-protrusion of the eyeball Graves can cause pretibial myxedema (dermopathy), which will look scaly and thick They’re at risk for other autoimmune diseases Tests for Graves show increased free thyroid hormone, and decreased TSH o Radioactive iodine uptake will be increased Diffuse and multinodular goiters show impaired making of thyroid hormone, most often caused by a dietary deficiency - - Causes a compensatory rise in TSH, causing hypertrophy and hyperplasia of the thyroid follicular cells, causing a goiter o So anything that stimulates the follicles (TSH, things that act like it like Grave’s) will cause goiter Usually, this is enough to return the person to a euthyroid (normal) state of thyroid hormone o If it doesn’t work, you get hypothyroidism with a goiter Diffuse nontoxic (simple) goiter - goiter without nodules - - - More common in females Can be called colloid goiter because the enlarged follicles are often filled with colloid Endemic goiters happen in places where food supplies are low in iodine o Less iodine means less thyroid hormone making and more TSH, causing goiter o Some foods can interfere with thyroid hormone making and are called goitrogens Ex: cabbage, cauliflower, cassava Goiter can also be caused by hereditary enzyme defects that interfere with thyroid hormone making Two morphologic phases to a diffuse nontoxic goiter: o Hyperplastic phase- symmetric enlargement of the thyroid o Colloid involution- when the colloid fills the follicles Usually, the TSH increase makes them euthyroid (their thyroid hormone levels are compensated) o So any problems they have are from mass effects from the enlarged thyroid – page 1117 o So thyroid hormones are normal, but TSH would be high Multinodular goiter - - All chronic simple goiters will convert to a multinodular goiter at some point Multinodular goiters cause extreme enlargements, and are often confused with cancer It’s thought that multinodular goiter can happen because of variations in the response of follicular cells to external stimuli o If some follicular cells have some sort of growth advantage, they can give rise to clones of proliferating cells to form a nodule o Nodules can grow without an external stimulus o Mutations to the TSH signaling pathway that cause continuing activation of making TSH can cause these nodules The development of the nodule produces stress that can rupture follicles and vessels leading to hemorrhage, scarring, and calcification Multinodular goiters are multilobulated asymmetrically enlarged thryoids Unlike cancers, multinodular goiter does not have a capsule between the hyperplastic nodules and thyroid parenchyma Symptoms of a multinodular goiter are caused by such a big mass o It can compress airways and vessels in the neck or upper thorax Most of them are euthryoid, or have subclinical hyperthyroidism (seen only as low TSH) Plummer syndrome – the minority of cases where the nodule in a chronic goiter becomes autonomous, causing hyperthyroidism o There won’t be any eye problems, like there are in Graves o Most of these nodules won’t become cancerous, but it’s possible Single solitary nodules on an otherwise normal thyroid are more common in women, and happen more as you get older Most solitary nodules (growths) on the thyroid turn out to not be cancer, or to just be a benign neoplasm - 1% of solitary thyroid nodules are malignant The few cases that are cancerous have a good survival rate Solitary nodules are more likely to be cancerous than multiple nodules Nodules in younger people are more likely to be cancerous Nodules in males are more likely to be cancerous Nodules that take up radioactive iodine (hot nodules) are much more likely to be benign Radiation to the head and neck increases the risk for thyroid cancer You check a nodule for cancer by fine-needle aspirating it Thyroid adenoma – page 1119 - - - - - Thyroid adenomas are usually solitary masses derived from the follicular epithelium o So they’re often called follicular adenomas Most adenomas are nonfunctional, but a minority can make thyroid hormones to cause hyperthyroidism o Those that do make thyroid hormone are called toxic adenomas, and don’t listen to TSH Half of thyroid adenomas have gain-of-function mutations to the TSH receptor, which allows the follicular cells to secrete thyroid hormone without any TSH stimulation o This includes mutations to the α-subunit of the G protein, coded by the GNAS gene o These mutations are rare in follicular carcinomas, which is why most of these won’t progress to carcinoma The thyroid adenoma will be well separated from adjacent thyroid tissue by a well-defined capsule o This is important in telling the difference between adenoma, and multinodular goiters or carcinomas, and a capsule is the hallmark of a follicular adenoma It’s common to see hemorrhage, fibrosis, and calcification in thyroid adenomas, just like in multinodular goiters Sometimes, the neoplastic cells develop brightly eosinophilic granular cytoplasm, called oxyphil or Hurthle cell change – page 1119 bottom right pic o These ones act exactly like the adenomas that don’t develop this Malignancy is more common in cold nodules than hot nodules (those that make thyroid hormone) - o Those that make thyroid hormone will take up radioactive iodine You can only diagnose a follicular adenoma with histology because the diagnosis is the integrity of the capsule Usually, a follicular adenoma presents as a unilateral painless mass o Larger ones can cause mass effect symptoms, like problems swallowing Follicular adenomas have a great prognosis and don’t recur or metastasize Most follicular adenomas won’t progress to carcinomas, but they are able to o A minority of follicular adenomas has mutations to RAS, PIK3CA, or have a PAX8-PPARG fusion gene, which are all mutations you also see in follicular carcinomas Thyroid carcinomas - Thyroid carcinomas are uncommon, and more common in women if it’s an adult Most thyroid carcinomas, except medullary carcinomas, are derived from the thyroid follicular epithelium, and most are well differentiated The four major thyroid carcinomas are: papillary, follicular, anaplastic, and medullary o Papillary thyroid carcinomas are by far the most common The two common pathways where the follicular cancers (all except medullary) comes from are the MAP kinase pathway, and the PI3/AKT pathway o In normal cells, theses pathways are temporarily (transiently) activated by the binding of a growth factor ligand to a receptor tyrosine kinase, causing autophosphorylation of the receptor, causing signal transduction into the cell o In carcinomas, a mutation leads to constant activation even when there’s no ligand o Papillary carcinoma- usually activates the MAP kinase pathway Can do so by rearranging RET or NTRK1, which both encode receptor tyrosine kinases, or by a mutation in BRAF Normally, the tyrosine kinase coded for by RET is not expressed in a thyroid follicle cell Papillary cancers move the RET gene so that the tyrosine kinase will be expressed in the thyroid follicle cells The RET gene is moved so that it fuses with the gene of something is expressed normally There’s many genes it can fuse with, but in general it’s just called a RET/papillary thyroid carcinoma (PTC) gene The now expressed tyrosine kinase then activates the MAP kinase pathway o Follicular carcinomas- often have an activating mutations to the PI3K/AKT pathway This includes activating mutations to RAS and PIK3CA, and inhibiting mutations to PTEN tumor suppressor Follicular carcinomas also show fusion of the PAX8 gene with a peroxisome proliferator gene (PPARG) o - - Anaplastic (undifferentiated) carcinomas – very aggressive and lethal tumors that can arise denovo, or from de-diferrentiation of the other forms They express more mutations and more often express them than the others o Medullary carcinomas- usually involve RET mutations The major environmental risk factor for thyroid cancer is ionizing radiation o Iodine deficiency is also linked to increasing the risk for follicular cancers Papillary carcinoma- by far the most common thyroid cancer o Can happen at any age, but are most common between 25-50 o Most thyroid cancers from radiation are papillary carcinomas o The hallmarks of a papillary carcinoma are – page 1121 Branching papillae – have a fibrovascular stalk Nucleus with dispersed chromatin, giving a clear appearance called the “ground glass” or “orphan annie eye” nuclei May also see intranuclear inclusions or grooves The diagnosis of papillary carcinoma is made base on these features in the nucleus Psammoma bodies- calcified structures, almost never seen in follicular and medullary carcinoma Signs of the tumor invading the lymphatics o The follicular variant of papillary carcinoma- has the characteristic nucleus of a papillary carcinoma, but looks follicular Most common variant of papillary carcinoma Has a mutation in BRAF and sometimes RAS, and less RET/PTC fusions It’s encapsulated and metastases less often than other papillary carcinomas o Tall cell variant – has tall columnar cells with very eosinophilic cytoplasm lining the papillary structures These ones invade the blood more and leave the thyroid more, and almost always have BRAF mutations o Diffuse sclerosing variant – includes fibrosis along with the papillary growth pattern o Most papillary carcinomas present as asymptomatic thyroid nodules that can be moved around freely o Papillary carcinomas are cold masses o Papillary carcinomas have a great prognosis Follicular carcinoma – page 1123 o More common in women, and present at an older age than papillary carcinomas o Follicular carcinomas are more common in places with dietary iodine deficiency o Most follicular carcinomas are made of uniform cells forming small follicles containing colloid, like normal thyroid o Their nucleus doesn’t have the features that papillary carcinoma does, and there’s no psammoma bodies o Spread to the lymphatics is not common in follicular carcinoma, so they don’t go to lymph nodes o - - Follicular carcinomas commonly involve vascular spread with metastases throughout the body, unlike follicular adenomas o The more invasive the follicular carcinoma is, the worse the prognosis o Most follicular carcinomas are cold nodules o Most are treated with thyroidectomy Anaplastic (undifferentiated) carcinoma – undifferentiated tumors of the thyroid follicular epithelium o They are extremely aggressive and almost always lethal o Occur in older people o The tumor will have large giant cells and spindle cells o Anaplastic carcinomas usually present as a rapidly enlarging neck mass, that has spread beyond the thyroid capsule into other parts of the neck o Death usually results from the rapid compromise of vital structures in the neck Medullary carcinoma- tumors of the parafollicular (C) cells of the thyroid o Medullary carcinomas secrete calcitionin o Cases can be sporadic, or familial Sporadic will show up as a single nodule, while familial can have multiple nodules, and be part of multiple endocrine neoplasia syndromes (MEN)-p 1125 MEN happens from RET mutations o Medullary carcinomas can also secrete VIP (causing diarrhea) or ACTH (causing Cushign syndrome) o MEN’s often also include tumors in the adrenals and the parathyroids Thyroglossal duct cysts are remnants from the development of the thyroid - They can become infected and even cancerous There are 4 parathyroid glands, made mostly of chief cells - - Chief cells have granules holding parathyroid hormone (PTH) Often chief cells have a “water-clear” appearance from lakes of glycogen The parathyroids also have larger oxyphil cells, which show eosinophilic cytoplasm and tons of mitochondria, but few granules In infancy, the parathyroids are made almost entirely of sheets of chief cells, but then the stromal fat in the parathyroid increases as you age, peaking at a 1/3 the parathyroids at age 25 Parathyroid gland activity is controlled by the level of free (ionized) calcium in the blood o Decreased free calcium stimulates making and release of PTH Jobs of PTH – to increase the level of free calcium o PTH increases reabsorption of calcium in the kidney tubules o PTH increases conversion of vitamin D to its active form in the kidneys o PTH increases excretion of phosphates in the urine o PTH increases calcium absorption in the GI Once free calcium in the blood is increased by PTH, the calcium inhibits any more PTH release - So excessive PTH can cause hypercalcemia Hypercalcemia is one of the most common complications of malignant tumors o So if hypercalcemia is symptomatic, it’s more often from cancer, while if it’s asymptomatic, it’s more often primary hyperparathyroidism o Cancers that cause hypercalcemia are usually more advanced, and so have a worse prognosis o Hypercalcemia from malignancy is caused by increased bone resorption that releases the calcium, by either a tumor that invaded the bone, or one that didn’t Many tumors secrete PTH-related protein, which promotes expression of receptor activator of nuclear factor kB ligand (RANKL) on osteoblasts RANKL binds to RANK on osteoclast precursors to cause differentiation into osteoclasts To inhibit RANKL to RANK binding, osteoblasts can release osteoprotegerin (OPGN), which acts as a decoy receptor of RANKL PTH-related protein inhibits osteoprotegerin secretion, promoting osteoclasts and bone resorption Hyperparathyroidism can be primary, or secondary usually from kidney problems Primary hyperparathyroidism is one of the most common endocrine problems, & causes hypercalcemia - - - - Most of the time (90%), primary hyperparathyroidism is from a single spontaneous adenoma o Less often, it’s from primary hyperplasia (10%), or carcinoma (less than a %) Primary hyperparathyroidism usually happens in adults, and more often in women after middle age Multiple endocrine neoplasia-1 (MEN-1) – inactivating mutation to the MEN1 tumor suppressor gene that can cause parathyroid adenomas and hyperplasia Multiple endocrine neoplasia-2 (MEN-2) – activating mutation to the tyrosine kinase receptor RET, that can cause primary hyperparathyroidism Familial hypocalciuric hypercalcemia – mutation to the parathyroid calcium-sensing receptor gene (CASR) makes the parathyroids over function because the receptor isn’t as sensitive to extracellular calcium Common mutations seen in parathyroid adenomas are to cyclin D1 and MEN-1 o Cyclin D1 gene is often relocated to be next to the PTH gene, causing overexpression of cyclin D1 protein, forcing cells to proliferate o 1/3 of parathyroid tumors that aren’t part of MEN-1 still show MEN-1 mutations Unlike in primary hyperplasia of the parathyroids, a parathyroid adenoma will have shrunken glands outside the adenoma, due to feedback inhibition from high blood calcium Parathyroid adenomas are usually made mostly of chief cells When the parathyroids do hyperplasia, usually it’s the chief cells undergoing hyperplasia o Hyperplasia usually shows all 4 parathryoids being hyperplastic, although maybe not each as big as the other Carcinoma of the parathyroids will show just one of the parathyroids being enlarged o - - - The only way to tell the difference between parathyroid carcinoma and parathyroid adenoma, is if it metastasizes or invades local tissue Hyperparathyroidism will also cause skeletal and kidney changes: o The bones will have increased #’s of osteoclasts, which resorb the bone to increase blood calcium Osteoblasts are increased to try and compensate o Often the bone has widely spaced trabeculae like that seen in osteoporosis More severe cases have the cortex thinned, and the marrow has more fibrous tissue, accompanied by hemorrhage and cysts, called osteitis fibrosa cystica o Hyperparathyroidism can cause clusters of osteoclasts, giant cells, and hemorrhagic debris, called brown tumor of hyperparathyroidism o PTH-induced hypercalcemia favors formation of urinary tract stones (nephrolithiasis), and calcification of the renal interstitium and tubules (nephrocalcinosis) Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia The way you tell the difference between hypercalcemia from primary hyperparathyroidism, or cancer elsewhere: o In primary hyperparathryodiism, serum PTH is increased despite high blood calcium o In tumors, PTH levels are low from the increased blood calcium Symptomatic primary hyperparathyroidism shows “painful bones, renal stones, abdominal groans, and psychic moans:” o Bone – the hyperparathryroidism causes bone pain from fractures weakened by osteoporosis or osteitis fibrosa cystica o Kidney stones (nephrolithiasis) can show pain and obstructive uropathy, and chronic renal insufficiency can cause polyuria and secondary polydipsia o GI – constipation, nausea, peptic ulcers, pancreatitis, and gallstones o CNS problems – depression, lethargy, and seizures o Heart valve calcifications Secondary hyperparathyroidism is caused by anything that causes chronic low calcium, which forces the parathryoids to have to work - - The most common cause of secondary hyperparathyroidism is by far kidney failure Chronic renal insufficiency decreases phosphate excretion, which increases blood phosphate, which can decrease blood calcium and stimulate PTH release Also, loss of functioning parts of the kidney decreases the amount of 1α-hydroxylase, so less vitamin D is made active, and so less calcium is absorbed from the GI o Vitamin D also normally suppresses the parathryoids and PTH release The parathyroid glands in secondary hyperparathyroidism are hyperplastic Symptoms of secondary hyperparathyroidism are mainly those of kidney failure, with less bone or other changes usually seen from high PTH Vitamin D supplements and phosphate binders can help treat secondary hyperparathyroidism Hypoparathyroidism is way less common than hyperparathyroidism - - - Acquired hypoparathyroidism is usually from surgery, like a thyroidectomy that accidentally removed the parathyroids, or when you mistake them for lymph nodes Autoimmune hypoparathyroidism happens in chronic mucocutaneous candidiasis and primary adrenal insuffiency, together called autoimmune polyendocrine syndrome type 1 (APS1) o APS1 is caused by mutation to the autoimmune regulator (AIRE) gene, and usually starts in childhood when they first get candidiasis Then years later the hypoparathyroidism and adrenal insufficiency show up Autosomal-dominant hypoparathyroidism – gain of function mutation to the CASR gene, causing it to be too sensitive to calcium and suppress PTH The hallmark of hypocalcemia is tetany, characterized by neuromuscular irritability, from decreased serum free calcium o Symptoms include numbness, paresthesias (tingling), and carpopedal spasm, lifethreatening laryngospasm, and generalized seizures o Classically, hypocalcemic tetany shows Chvostek sign and Trousseau sign Chvostek is elicited by tapping the course of their facial nerve, which causes contractions of the muscles of the eye, mouth, or nose Trousseau sign – carpal spasms caused by blocking circulation to the forearm and hand with a blood pressure cuff for several minutes Other symptoms of hypocalcemia include: o Mental status changes – like emotional instability, anxiety and depression, confusion, hallucinations, and psychosis o Parkinsonian-like movements o Increased intracranial pressure – causes papilledema o Calcification of the lens of the eye – causing cataracts o Prolonged QT intervals o Tooth changes early in life – dental hypoplasia, failure of eruption, defective enamel and root formation, and abraded carious teeth Pseudohypoparathyroidism – end organs don’t listen to PTH, causing increased PTH, causing hypocalcemia, hyperphosphatemia