IUHS Student-2-Student USMLE Step 1 Recall
Endocrinology
Thyroid
Thyroid Hormones
the unbound
T3 and T4 enter cells and interact with nuclear receptors, which change gene expression and ultimately up-regulate carbohydrate and lipid catabolism and stimulate protein synthesis in a wide range of cells...Parafollicular C cells
in the interfollicular stroma, the thyroid gland also contains a populatin of
parafollicular cells, or C cells, which synthesize
and
secrete the hormone calcitonin...
this hormone
promotes the absorption of calcium by the skeletal system and inhibits the resorption of bone by osteoclasts...
Hyperthyroidism
thyrotoxicosis is a hypermetabolic state caused by elevated levels of free T3 and T4
...it is often referred to as hyperthyroidism b/c it is caused most commonly by hyperfunction of the thyroid gland...long usage often equates these terms...by either name,
the syndrome is manifested by nervousness, palpitations, rapid pulse, fatigability, muscular weakness, weight loss with good appetite, diarrhea, heat intolerance, warm skin, excessive perspiration, emotional lability, menstrual changes, a fine tremor of the hand (particularly outstretched), eye changes, and variable enlargement of the thyroid gland...diffuse hyperplasia of the thyroid associated with graves disease (accounts for 85% of cases)
...the terms primary and secondary hyperthyroidism are sometmies used to designated hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such as a TSH secreting pituitary tumor...
less common cause of secondary hyperthyroidism include secretion of excesive amounts of thyroid hormone by ectopic thyroid arising in ovarian teratomas (struma ovarii)...hypermetabolic state related to overactivity of the sympathetic nervous system....excessive levels of thyroid hormone result in an
increase in the basal metabolic rate...Diagnosis - free T4 levels are usually increased...TSH levels are extremely sensitive to free T4 levels and are thus decreased to two levels in patients with primary hyperthyroidism (hyperthyroidism owing to intrinsic thyroid disease)...measurements of radioactive iodine uptake provides an additional direct indication of the level of activity within the thyroid gland...I-131 iodide uptake is increased..
Primary Hypothyroidism
presents as
increased cold intolerance, loss of energy, and hair loss...high TSH and low free T3
...accounts for vast majority of cases of hypothyroidism...the
most common cause of hypothyroidism is iodine-sufficient areas of the world is chronic autoimmune thyroiditis, or hashimoto thyroiditis...Secondary Hypothyroidism
secondary hypothyroidism is that caused by TSH deficiency
, and tertiary (central) hypothyroidism is caused by TRH deficiency...Cretinism
cretinism refers to hypothyroidism developing in infancy or early childhood...the term cretin was derived from the french chretien, meaning christian or christ-like, and was applied to these unfortunates b/c they were considered to be so mentally retarded as to be incapable of sinning...
in the past, this disorder occurred fairly commonly in areas of the world where dietrary iodine deficiency is endemic, such as the himalayas, inland china, and africa and other mountainous areas...it has become much less frequent in recent years, owing to the widespread supplemenation of foods with iodine...on rare occasions, cretinism may also result from inborn errors in metabolism (enzyme deficiencies) that interfere with the biosynthesis of normal levels of thyroid hormone (sporadic cretinism)...
clinical features of cretinism include impaired development of the skeletal system and CNS, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia...
Myxedema
the term myxedema is applied to
hypothyroidism developing in the older child or adult...the clincial manifestations vary with the age of onset of the deficiency...the older child shows signs and symptoms intermediate between those of the cretin and those of the adult with hypothyroidism...in the adult, the condition appears insidiously and may take years to reach the level of clincial suspicion...clinical features of myxedema are characterized by a slowing of physical and mental activity
...the initial symptoms include generalized fatigue; apathy, and mental sluggishness, which may mimic depression in the early stages of the disease...speech and intellectual functions become slowed...patients with myxedema are listless, cold intolerant, and frequently overweight..reduced cardiac output probably contributes to shortness of breath and dcreased exercise capacity, two frequent complaints in patients with hypothyroidism
...Hashimoto Thyroiditis
most common cause of hypothyroidism in areas of the world where
iodine levels are sufficient...characterized by gradual thyroid failure b/c of
autoimmune destruction of the thyroid gland...some cases of Hashimoto thyroiditis are associated with
HLA-DR5 and a minority are linked to HLA-DR3...the frequency of other autoimmune disorders, such as systemic lupus erythematous and rheumatoid arthritis, is increased in patients with Hashimoto disease, as it is in individuals with Graves disease...
histologically, there is infiltration of the thyroid stroma by an
intense lymphoplasmacytic infiltrate, with the formation of lymphoid follicles and transforms the thyroid follicular cells into acidophilc cells...
thyroid lymphomas
are often found in Hashimoto's Thyroiditis...hypothyroidism may eventually occur...Lymphoid follicles are often present histologically...There is a genetic deficiency in antigen-specific suppressor T lymphocytes...anti-TSH receptor antibodies
block the action of TSH, thus accounting for the hypothyroidism...anti-microsomal antibodies...Hurthle cells are associated with Hashimoto's thyroidits...great chance of getting malignant lymphoma
....
Subacute (Granulomatous) Thyroiditis
subacute thyroiditis, which is also referred to as
granulomatous thyroiditis or DeQuervain thyroiditis, occurs much less frequently than does hashimoto disease...the disorder is most common between the ages of 30-50 and, similar to other forms of thyroiditis, affects women considerably more often than men (3 to 5:1)...
tender asymetrical goiters with pain radiating to the ear
...subacute thyroditis is
believed to be caused by a viral infection or a postviral inflammatory process...the majority of patients have a history of an upper respiratory infection just before the onset of thyroiditis...the disease has a seasonal incidence with occurrences peaking in the summer, and clusters of cases have been reported in association with
coxsackievirus, mumps, measles, adenovirus, and other viral illnesses...there is fairly strong association with
HL
A-B35
in some ethnic groups...
the gland may be
unilaterally or bilaterally enlarged and firm, with an intact capsule...it may be slightly adherent to surrounding structures...on cut section, the involved areas are firm and yellow white and stand out from the more rubbery, normal brown thyroid substane...histologically the changes are patchy and depend on the stage of the disease...early in the active inflammatory phase,
scattered follicles may be entirely disrupted and replaced by neutrophils forming microabscesses...later the more characteristic features appear in the form of aggregation of lympohocytes, histiocytes, and plasma cells about collapsed and damaged thyroid folllicles...multinucleate giant cells
enclose naked pools or fragments of colloid, hence the designation granulomatous thyroiditis..the presentation of subacute thyroiditis may be sudden or gradual...it is characterized by
pain in the neck, which may radiate to the upper neck, jaw, throat, or ears, particularly when swallowing...fever, fatigue, malaise, anorexia, and myalgia accompany a variable enlargement of the thyroid
...the resultant thyroid inflammation and hyperthyroidism are transient, usually diminishing in 2-6 weeks, even if the patient is not treated...it may be follwed by a period of transient, usually asymptomatic hypothyroidism lasting form 2-8 weeks, but recovery is virtually always complete... Diffuse Nontoxic (simple) Goiterdiffuse nontoxic (simple) goiter specifies a form of goiter that diffusely
involves the entire gland without producing nodularity...b/c the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition...this disorder occurs in both an endemic and a sporadic distribution...
endemic goiter occurs in geographical areas where the soil, water, and food supply contain only low levels of iodine
...the term endemic is used when goiters are present in more than 10% of the population in a given region..such conditions are particularly common in mountainous areas of the world, including the Alps, andes, and himalayas...the lack of iodine leads to decreased synthesis of thyroid hormone and a compensatory increase in TSH, leading to follicular cell hypertrophy and hyperplasia and goitrous enlargement...with increasing dietary iodine supplementation, the frequency and severity of endemic goiter have declined significantly...variations in the prevalence of endemic goiter in regions with similar levels of
iodine deficiency point to the existence of other causative influences, particularly dietary substances, referred to as goitrogens...the
follicles are lined by crowded columnar cells, which may pile up and form projections similar to those seen in graves disease...the accumulation is not uniform throughout the gland, and some follicles are hugely distended, whereas others remain small...rare patients are hyperthyroid, and the TSH level is almost invariably elevated, as it may be to a lesser extent in marginally euthyroid individuals
...the goitrous enlargement may be plainly evident or nonvisible, even with the head raised...Iodine induced hyperthyroidism is called the Jod-Basedow phenomenon and can occur in patients with endemic goiter who move to areas where iodine is plentiful...Multinodular Goiter
with time,
recurrent episodes of hyperplasia and involution combine to produce a more irre
gular
enlargement of the thyroid, termed multinodular goiter...
virtually all long standing simple goiters convert into multinodular goiters...they may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter)...
multinodular goiter produce the most extreme thyroid enlargements
and are more frequently mistaken for neoplastic involvement than any other form of thyroid disease...b/c they derive from simple goiter, they occur in both sporadic and endemic forms, having the same female-to-male distribution and presumably the same origins but affecting older individuals b/c they are late complications...
radioiodine scan and 24h uptake show a patchy pattern but normal amount of radioiodine uptake
...Graves Disease
graves disease is the
most common cause of endogenous hyperthyroidism...it is characterized by the triad of clinical findings:
(1)
hyperthyroidism owing to hyperfunctional, diffuse enlargement of the thyroid...(2)
infiltrative ophthalmopathy with resultant exophthalmos...(3) localized, infiltrative dermopathy sometimes called
pretibial myxedema, which is present in a minority of patients...graves disease has a
peak incidence between the ages of 20-40, with women being affected up to seven times more commonly than men...this is a very common disorder that is said to be present in 1.5-2.0% of women in the U.S....genetic factors are important in the causation of graves disease...an increased incidence of graves disease occurs among family members of affected patients, and the concordance rate in monozygoitc twins is as high as 60%...
the occurence of this disorder is strongly associated with the presence of major histocompatibility haplotypes
HLA-B8- and DR3, although how these associations increase disease susceptibility is not clear...
thyroid scan and 24h uptake show uniformity of uptake and an increased percentage uptake
...Autoantibodies to the TSH receptor or thyroid stimulating immunoglobulin (TSI)
: almost 50 years ago, serum from patients with graves disease was found to contain a long acting thyroid stimulator (LATS), so named because it stimulated thyroid function slower than TSH...LATS proved to be an IgG immunoglobulin that binds to the TSH receptor and stimulates adenylate cyclase activity, with resultant increased relase of thyroid hormones...almost all patients with graves disease have detectable autoantibodies to the TSH receptor...as noted previously, the antibody is relatively specific for graves disease, in contrast to thyroglobulin and thyroid peroxidase antibodies...Thyroid growth stimulating immunoglobulins
: also directed against the TSH receptor, thyroid growth stimulating immunoglobulins have been implicated in the proliferation of thyroid follicular epithelium...TSH-binding inhibitor immuoglobulins
: these anti-TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroid epithelial cells...in so doing, some forms of TSH-binding inhibitor immunoglobulins mimic the action of TSH, resulting in the stimulation of thyroid epithelial cell activity, whereas other forms may actually inhibit thyroid cellin graves ophthalmopathy, the
volume of both the retro-orbital connective tissue and the extraocular muscles is increased, owing to inflammation and the accumulation of extracellular matrix components, including proteoglycans and hyaluronic acid...these changes
displace the eyeball forward and can interfere with the function of the extraocular muscles...the
thyroid gland is usually symmetrically enlarged b/c of the presence of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells...increases in weight to over 80gm are not uncommon...the gland is usualy smooth and soft, and its capsule is intact...on cut section, the parenchyma has a soft, meaty appearance resembling normal muscle...tissue shows follicles with papillary infoldings lined by tall columnar cells
...histologically the
dominant feature is too many cells...the follicular epithelial cells in untreated cases are tall and more crowded than usual...this crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid...the clincial finding in graves disease include changes referable to thyrotoxicosis as well as those associated uniquely with graves disease -
diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy...the degree of thyrotoxicosis varies from case to case and may sometimes be less conspicuous than other manifestations of the disease...diffuse enlargement of the thyroid is present in all cases
of graves disease...the thyroid enlargement may be accompanied by inceased flow of blood through the hyperactive gland, often producing an audible bruit...the
ophthalmopathy in the disorder is caused by a combination of the sympathetic overactivity that accompanies thyrotoxicosis and the deposition of matrix components behind the eyeball...these produce a characteristic wide, staring gaze and lig lag, and the eyes protrude abnormally...the extraocular muscle are often weak...the proptosis may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting corneal injury...the
infiltrative dermopathy, or pretibial myxedema, is most comon in the skin overlying the shins, where it presents as scaly thickening and induration of the skin...however, it is present only in a minority of patients...the skin lesions may be slightly pigmented papules or nodules and often have an orange peel texture...laboratory finding in graves disease include
elevated free T4 and T3 levels and depressed TSH levels...b/c of ongoing stimulation of the thyroid follicles by thyroid sitmulating immunoglobulins, radioactive iodine uptake is increased, and radioiodine scans show a diffuse uptake of iodine...treatment of graves disease consists of decreasing the symptoms of hyperthyroidism that are induced by increased beta-adrenergic tone
(tachycardia, palpitations, tremulousness, anxiety), and measures aimed at decreasing thyroid hormone synthesis, such as the administration of thionamides (prophylthiouracil), radioiodine ablation, and surgical removal...increased free thyroxine
... Papillary Carcinoma of the Thyroid
papillary carcinomas are the
most common form of thyroid cancer 80%...they occur at any age but occur most often in the twenties to forties and account for the vast majority of thyroid carcinomas associated with previous exposure to ionizing radiation...a high incidence of papillary carcinoams has been found in patients with gardner syndrome (famililar adenomatous polyposois coli) and cowden disease (familial goiter and skin hamartomas)...
aspiration of a nodule will display "small hard balls" of neoplastic follicular cells
...Clear nuclei, lymph node metastases
...papillary carcinomas can reveal
branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells...in most neoplasms, the epithelium covering the papillae comprised well differentiated, uniform, orderly, cuboidal cells, but at the other extreme are those with fairly anaplastic epithelium showing considerable variation in
cell and nuclear morphology...when present, the papillae of papillary carcinoma
differ from those seen in areas of hyperplasia...in contrast to hyperplastic
papillary lesions, the neoplastic papillae have
dense fibrovascular cores...
the
nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts and optically clear or empty appearance, giving rise to the designation "ground glass" or "orphan annie" nuclei...as currently used, the diagnosis of papillary carcinoma is based on nuclear features rather than a papillary architecture...eosinophilic intranuclear inclusions or grooves representing invaginations of cytoplasm are present...
concentrically calcified structures termed
psammoma bodies are often present within the lesion, usually within the cores of papillae...these structures are almost never found in folllicular and medullary carcinomas and so, when present, are diagnostic of a papillary carcinoma....the carcinoma, which is
usually a single nodule, moves freely during swallowing and is not distinguished from a benign nodule...
hoarseness, dysphagia, cough, or dyspnea suggest advanced disease...
a variety of diagnostic tests have been employted to separate benign from malignant thyroid nodules, including radionuclide scanning and fine-needle aspiration cytology the best test for distinguishing between benign and malignant nodules...
the prognosis of a patient with thyroid cancer is related to the type of tumor..the overall
10-year survival rates are 98% for papillary and 92% for follicular carcinomas...5-20% of patients have local or regional occurrences, and 10-15% have distant metastases
...in general, the prognosis is less favorable among elderly patients, patients with invasion of extrathyroidal tissues, and patients with distant metastases...radiotherapy with iodine 131 is effective for metastases
... Follicular Adenoma of the Thyroid
follicular carcinomas are the
second most common form of thyroid cancer 15%, accounting for about 10-20% of all thyroid cancers...as a general rule, they
tend to present in women at an older age than do papillary carcinomas, with a peak incidence in the forties and fifties...the
incidence of follicular carcinoma is increased in areas of dietary iodine deficiency, suggesting that, in some cases, nodular goiter may predispose to the development of the neoplasm...there is no compelling evidence that follicular carcinomas arise from preexisting adenomas...
"cold nodule"...
blood vessel and capsular invasion by malignant thyroid follicles
...follicular carcinomas are composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid...in other cases, follicular differentiation may be less apparent...occasional tumors are dominated by cells with abundant granular, eosinophilic cytoplasm (hurthle cells)...
follicular carcinomas present as slowly enlarging painless nodules...most frequently, they are "cold nodules" on scintigrams, although in rare cases, the better differentiated lesion may be hyperfunctional, take up radioactive iodine, and appear warm on scintiscan...
follicular carcinomas have little propensity for invading lymphatics, and therfore regional lymph nodes are rarely involved, but vascular invasion is common, with spread to bone, lungs, liver, and elsewhere...
Medullary Carcinoma of the Thyroid
inherited as
autosomal dominant...masses are
solid and firm, with a tan cut surface. An immunoperoxidase stain for calcitonin is positive in the nests of dark blue cells of these massesmedullary carcinomas of the thyroid are
neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid...the cells of medullary carcinomas, similar to normal C cells, secrete calcitonin, the measurement of which plays an important role in the diagnois and post operative follow up of
patients...
in some instances, the tumor cells elaborate other polypeptide hormones, such as carcinoembryonic antigen (CEA), somatostatin, serotonin, and vasoactive intestinal peptide (VIP)...the tumor arises sporadically in about 80% of cases...
the remainder occur in the setting of
MEN syndrome IIA or IIB or as familial tumors without an associated MEN syndrome...germ line mutations in the
RET protooncogene play an important role in the development of medullary carcinomas associated with the MEN IIA syndrome...histologic examination can reveal
organoid nests of tumor cells separated by broad bands of stroma...small polygonal cells infiltrating stroma having congo-red positive material...medullary carcinomas are
composed of polygonal to spindle shaped cells, which may form nests, trabeculae, and even follicles...
stains
positive with congo red stain...5 year survival rate of about 50%
...familial medullary carcinomas not associated with MEN II, in contrast, are often fairly indolent lesions...
most often also associated with
pheochromocytomas...associated with ectopic production of ACTH
...RET protooncogene is associated with MEN IIA-B syndromes
...Anaplastic Carcinoma of the Thryoid
anaplastic carcinomas of the thyroid are undifferentiated tumors of the thyroid follicular epithelium...in striking constrast to the differentiated thyroid carcinomas,
anaplastic carcinomas are aggressive tumors, with a mortality approaching 100%...these neoplasms are composed of highly anaplastic cells, which may take one of three histologic patterns: (1) large, pleomorphic giant cells; (2) spindle cells with a sarcomatous appearance; and (3) small
anaplastic cells resembling those seen in small cell carcinomas arising in other sites...anaplastic carcinomas present as a rapidly enlarging bulky neck mass...in most cases, the disease has already
spread beyond the thyroid capsule in to adjacent neck structures or metastasized to the lungs at the time of presentation...compression and invasion symptoms, such as dyspnea, dysphagia, hoarsness, and cough, are common....
there is
no effective therapy for anaplastic thyroid carcinoma, and the disease is uniformly fatal...