Pathoma Endocrine Pathology Flashcards
What are the two most common types of pituitary adenomas? How does this relate to most common presentation?
- Prolactinomas
- Gonadal (non-functional)
Most common presentation is reproductive dysfunction
Prolactin -> GnRH inhibition
Gonadal -> nonfunctional tumor impinges and causes hypopituitarism
What are some causes of hyperprolactinemia which are not prolactinoma?
- Estrogens - i.e. pregnancy or birth control pills -> number one cause of lactotroph hyperplasia
- Primary hypothyroidism - Increased TRH levels stimulate PRL
- D2 antagonist antipsychotics, cocaine use
How can pituitary stalk disease be related to prolactin levels?
Compressing lesions (i.e. macroadenoma, sarcoidosis) of the hypothalamus and pituitary stalk may occur and cause decreased dopamine levels -> less tonic inhibition of lactotrophs
-> note that compression can also cause Diabetes Insipidus
What are the symptoms of acromegaly?
Think acral (distal extremities) + megaly (large)
Prognathism - enlarged chin Acral growth - large hands / feet Visceromegaly - increased organ size Hypermetabolism -> diabetes, HTN Hyperhidrosis - increased sweating Arthritic complaints -> joint swelling
What are the common causes of death in acromegaly / what important conditions are they at greater risk for?
Congestive heart failure -> most common cause of death
Patients also have increased relative risk of colon and breast cancer
-> IGF-1 has a permissive effect in tumorigenesis
How is diagnosis of acromegaly made?
- Increased serum IGF-1 levels -> represents the integration of growth hormone levels
- Glucose suppression test -> if IGF-1 is inconclusive, glucose can be given. A positive test is failure to suppress GH levels by administration of glucose.
- > since GH normally increased glucose levels / causes insulin resistance
Give three medical treatments for the treatment of acromegaly (resection of the pituitary GH adenoma should be obvious as first-line).
- Octreotide (GHIH/somatostatin analog)
- Pegvisomant (GH receptor antagonist)
- Cabergoline (dopamine agonists have some efficacy in treatment of this condition, mechanism unknown, possibly due to somatotrophs / lactotrophs having the same precursor)
What screening test is commonly used for Cushing’s syndrome? How does it work?
Overnight dexamethasone suppression test
-> 1 mg of dexamethasone is taken at 10pm. Plasma cortisol is drawn next morning at 8am. If cortisol is suppressed to <5 micrograms/dL, Cushing’s syndrome is very unlikely
What are other screening tests other than the dexamethasone suppression test which can be used for Cushing’s syndrome?
- 24 hour urine cortisol - will be elevated
- Midnight salivary cortisol level -> cortisol should be lowest at this time. If increased there is likely an issue (cortisol is lowest at 8am and highest at midnight).
If 2 screening tests are normal, Cushing’s syndrome is unlikely.
Give two drugs which are used in the treatment of Cushing’s syndrome.
- Ketoconazole - inhibits 17,20 desmolase, the first step of steroid synthesis. Think of the tin man opening the witch’s area with the key where she is using her book to make make male/female hormones and moon facies
- Mifepristone - potent antiprogesterone + potent glucocorticoid receptor antagonist -> remember the medpharm coursepack, it’s real homie.
What are some causes of hypopituitarism?
- Congenital
- CNS irradiation
- Mass effect
- Empty sella syndrome
- Ischemia (pituitary apoplexy)
Occurs when >75% of pituitary tissue is lost
What hormones are most likely to be affected by CNS irradiation?
More peripherally located cell types in the gland -> GH / PRL, rather than centrally located ACTH / TSH (more essential for life)
What is pituitary apoplexy and what patients are most susceptible?
Sudden hemorrhage into the pituitary gland. Usually occurs in patients with the presence of an existing pituitary adenoma requiring extra oxygenation -> hemorrhagic infarction.
What are the symptoms of pituitary apoplexy?
- Sudden onset severe headache
- Visual disturbance -> bitemporal hemianopia
- Diplopia due to CN3 palsy
- Features of hypopituitarism -> i.e. emergent cortisol insufficiency leading to hypotension
It is a medical emergency.
What is Sheehan syndrome and what causes it? What type of infarct is it?
ISCHEMIC (not hemorrhagic) infarct of pituitary following postpartum bleeding -> hypotension leads to infarction of pituitary gland which was increased in size during pregnancy (to secrete more prolactin)
What are the presenting symptoms of Sheehan syndrome?
Failure to lactate -> loss of prolactin secretion
Absent menstruation / loss of pubic hair -> failure of LH / FSH secretion
Cold intolerance -> loss of TSH
What are the possible causes of central DI?
Pituitary tumor (mass affect disrupting posterior pituitary or hypothalamus), autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic
Is a tumor more likely to secrete ACTH + FSH/LH or GH + PRL and why?
More likely to be GH + PRL
-> lactotrophs and somatotrophs have a closer common cell lineage
What is lymphocytic hypophysitis and what causes it?
Autoimmune inflammation of adenohypophysis caused by infiltration of lymphocytes, leading to destruction of anterior pituitary with fibrosis.
Usually occurs in women during late pregnancy or shoftly after delivery
What is empty sella syndrome / how does it occur?
Syndrome where pituitary appears missing +/- loss in pituitary function due to compression by herniation of the subarachnoid space with CSF into the sella (area of bone).
-> Pituitary is normally not surrounded by CSF because the diaphragma sellae is a piece of dura which forms a covering and disallows CSF from leaking in
What is primary vs secondary empty sella syndrome and who does it occur in? How does it present?
Primary - protrusion of a diverticulum of arachnoid membrane into sella. Occurs in middle-aged women, often with obesity and hypertension (same demographic as pseudotumor cerebri) -> presents as headache.
Secondary - pituitary fails to take up entire space of sella which allows CSF to seep in, follows surgical resection, apoplexy, or radiation treatment of sellar tumor
What is one cause of SIADH related to the lungs which is NOT small cell lung cancer?
COPD is associated with SIADH by an unknown mechanism
Also, obviously Legionnaire’s disease can cause it.
How does hyperthyroidism increase BMR and also increase SANS?
BMR - by increasing synthesis of Na+/K+ ATPase to allow cells to depolarize more often / work faster
SANS - upregulate B1 receptor (remember that cortisol is responsible for the alpha1 receptor upregulation)
How does hypothyroidism cause secondary lipoproteinemia? Why is this clinically relevant?
- Low BMR slows LPL activity
- LDL levels increased due to lack of T4 stimulation of SREBP2
Relevant because hyperlipidemia responds very well to T4 replacement therapy -> should be screening for hypothyroidism especially in young females with dyslipidemia
-> hyperthyroidism actually causes HYPOcholesteremia
How does T3/T4 affect blood glucose levels?
Hyperthyroidism - hyperglycemia (increased stress)
What is the pathogenesis of Hashimoto’s thyroiditis? What antibodies are present and are they the cause of disease?
Sensitization of autoreactive CD4+ cells to thyroid antigens, causing activation of immune system.
CD8 T cells -> perforin/granzymes / Fas pathways.
Cytokine-mediated -> macrophage activation via IFNy
Antibody-dependent cell-mediated cytotoxicity via NK cells -> probable minor role of antibodies, more of a marker.
- Antithyroglobulin antibodies
- Anti-thyroperoxidase antibodies (antimicrosomal)
How does the thyroid appear microscopically in Hashimoto’s? What cells are characteristically seen?
Replacement of thyroid parenchyma with a diffuse mononuclear inflammatory infiltrate causing follicular atrophy
- > looks like a lymph node
- > can progress to marginal B cell lymphoma (t(11;18))
Hurthle cell change - characteristic of this disease -> eosinophilic metaplasia of follicular cells, as they have no colloid to hold onto anymore.
What is the pathogenesis of Subacute Granulomatous Thyroiditis and what is it also called?
Also called De Quervain thyroiditis
Pathogenesis: Viral infection -> antigen-induced, CD8 T-cell mediated injury to thyroid follicular cells -> It is a type of infectious thyroiditis, but we put it in its own class because of its unique histology
What is Subacute Lymphocytic Thyroiditis and who tends to get it? What is the pathogenesis?
Also called Painless thyroditis (vs de Quervain), it is an auto-immune mediated lymphocytic infiltrate, so it is more common in women. (Note: all thyroid conditions are more common in women)
However, it is especially common in POSTPARTUM women
-> this is analogous to lymphocytic hypophysitis seen in the pituitary during pregnancy
What does the thyroid look like in subacute lymphocytic thyroiditis and is it painful? What’s the clinical progression?
Thyroid looks mildly enlarged with a lymphocytic infiltrate, however it is subacute and vs de Quervain’s it is NONPAINFUL (autoimmune, non-infectious mediated)
Similar thyroid hormone level presentation as de Quervains: mild early thyrotoxicosis -> hypothyroid -> euthyroid resolution
What can you confuse Riedel thyroiditis with and why? How does it present?
Simulates an invasive neoplasm such as anaplastic carcinoma since it invades surrounding structures with fibrosis (i.e. retroperitoneum). Riedel “fibrosing” thyroiditis -> an autoimmune condition.
Presents as a “hard as wood” / rock hard PAINLESS goiter, some may be hypothyroid. But patients are generally too young to have anaplastic carcinoma and there are no malignant cells on biopsy.
What is the true definition of a goiter?
A goiter is a process by which impaired thyroid hormone synthesis leads to increased TSH secretion and thus thyroid follicular hyperplasia. It does not refer to Hashimoto’s or graves’ which is a “goitrous enlargement” where the thyroid is enlarging due to a pathologic process (i.e. inflammatory infiltrate, or nonstop stimulation of thyroid release)
What is the general underlying mechanism of goiter which causes diffuse -> multinodular?
There is some reason for impaired thyroid hormone synthesis, which leads to increased TSH secretion.
Persistent TSH stimulation causes variable response of thyroid follicular epithelial cells (initially diffuse, becomes nodular). This leads to uneven hyperplasia + areas of involution = nodules. Rupture of follicles / blood vessels causes hemorrhage / fibrosis of the gland, with dystrophic calcification. Surrounding areas are variably active -> multinodular
What are the etiologies of goiter?
- Iodine deficiency - most common in developing world
- Hereditary enzyme defects in thyroid synthesis -> more TSH is needed to stimulate gland -> goiter
- Ingestion of goitrogens -> i.e. brussel sprouts, cabbage, cauliflower
- Idiopathic need for increased TSH to maintain euthyroid.
What is hot nodule vs a cold nodule? Which one is more likely malignant?
Based on the amount of radioactive iodine uptake. Hot = lots of uptake.
Hot nodules as in a goiter or Graves disease (more diffuse) are usually benign.
“Cold” nodules, or low uptake, are usually benign as well, but warrant biopsy (malignant nodules are generally cold). These ones can be malignant.
What is the hormonal thyroid state of most people with goiter?
Goiter -> clinically euthyroid, but have a goiter to maintain that euthyroid state.
Those with “toxic” multinodular goiter will have autonomous nodules and may present with hyperthyroidism
-> toxic = produce T3/T4 independent of TSH
What is a benign neoplasm of the thyroid called, and what does it look like histologically? How can it be differentiated from a carcinoma?
Thyroid adenoma, usually a follicular adenoma with proliferation of thyroid follicles. -> in rare instances they can produce hormone and still be benign, but are generally cold.
These have a well-circumscribed capsule. Differentiated from a follicular carcinoma via lack of invasion through capsule or vasculature.
What two types of thyroid carcinoma are associated with RET mutations. Which one is associated with an MEN, and what cell is it derived from?
- Papillary carcinoma - associatied with RET fusion protein
- Medullary carcinoma of thyroid (Parafollicular / C cell derivation) - associated with RET mutation, in MEN2A and MEN2B syndromes.
What are the three types of thyroid carcinoma derived from follicular cells, which one is most common, and what mutations are associated with them?
- Papillary carcinoma - most common, associated with RET mutation
- Follicular carcinoma - associated with RAS mutations. Similar to follicular adenoma.
- Anaplastic carcinoma - no mutation in particular
What is the primary risk factor for papillary carcinoma of the thyroid and who tends to get it?
Risk factor: Exposure to ionizing radiation in childhood (i.e. lymphoma, acne treatment, nuclear radiation)
Tends to be seen in younger females
What is the histologic appearance of papillary carcinoma and how is the diagnosis definitively made?
Typically a papillary growth structure, with psammoma bodies (since a papillary carcinoma).
Diagnosis definitively made based on nuclear features of the cancer, even in the absence of papillary growth pattern:
“Orphan Annie Eyes” - Empty-appearing nuclei with chromatin on the edge, and intranuclear grooves with a ground-glass appearance of the nucleus.
Papi and Moma adopted Little Orphan Annie
What is the risk factor for follicular carcinoma of the thyroid and how must diagnosis be made?
Increased prevalence in areas of endemic iodine DEFICIENCY.
Diagnosis is made via biopsy with detection of invasion through the capsule or into the vasculature! Need to biopsy the entire sample to tell
-> this is the reason why fine needle aspiration for a follicular adenoma is insufficient to rule out cancer.
What is the pattern of spread of follicular carcinoma of the thyroid carcinoma and its prognosis?
Despite being a carcinoma, this is one of the few carcinomas which spreads hematogenously to lungs / bone. Remember this because it infiltrates VASCULAR structures (seen in lab). Other examples of carcinomas which do this are RCC, HCC, and choriocarcinoma.
Prognosis is actually pretty good, depending on tumor stage.
Other than salt and pepper chromatin, what else can be seen histologically on examination of a medullary thyroid carcinoma?
Amyloidosis -> due to accumulated AE amyloid derived from calcitonin.
Remember that it can occur bilaterally in MEN2 syndromes, and the tumor marker is calcitonin
Give two causes of dyshormonogenetic goiter and what syndrome they can cause in a person?
Cause congenital hypothyroidism - Cretinism, due to inability to properly produce thyroid hormone. This is just one cause of the condition.
- Genetic defect in thyroperoxidase - most common
- Pendred syndrome - mutation in Cl-/I- anion exchanger
What are two common places for myxedema to occur in hypothyroidism? Why does this occur?
Larynx - giving them a deepening of the voice
Tongue - macroglossia
Occurs due to deposition of GAGs
Where does papillary thyroid carcinoma spread to and what is the prognosis?
Generally spreads to cervical lymph nodes regionally, the prognosis is very good even despite this.
