Endocrine Flashcards
(222 cards)
1
Q
MEN1 typically has tumours where?
A
95% parathyroid, 70% pituitary, pancreas 50% and adrenal 40% (but normally non-functional adenoma).
3x Ps and adrenal
2
Q
MEN2a has what features? And what about MEN2b?
A
Pheochromocytoma, medullary thyroid carcinoma, parathyroid (70%). MEN2b is the same as MEN2a PLUS Marfinoid features and visceral gangliomas.
3
Q
Which hormones are classically carried by carrier proteins?
A
Thyroxine (t4), triiodothyronin (T3), the steroid hormones (aldosterone, cortisol, oestrodiol, progesterone, and testosterone, growth hormone and insulin like growth factors 1 and 2.
4
Q
Where are ADH/AVP and oxytocin synthesised?
A
The supraoptic nuclei and the paraventricular nucleus of the hypothalamus.
4
Q
Where are ADH/AVP and oxytocin synthesised?
A
The supraoptic nuclei and the paraventricular nucleus of the hypothalamus.
5
Q
What are the zones of the adrenal cortex? What’s the acronym to remember is order?
A
From superficial to deep glomerulosa, fasciculata, reticularis. Acronym GFR.
6
Q
What are the final hormones output each of the zones of tghe adrenal cortex?
A
The way or remembering is salt, sugar, sex. Glomerulosa produces aldosterone, fasciuclaris produces cortisone, and reticularis produces the sex hormones.
7
Q
What are the hormones produced by the anterior pituatary gland?
A
FLAT PEG. FSH, LH, ACTH, TSH, Prolactin, endorphins, GH.
The FLAT hormones are those that act on other endocrine tissue, which produce another hormone to act on other tissue, and are named the tropic hormone. The PEG hormones are direct acting on non-endocrine tissues.
8
Q
In what order are pituatary hormones typically lost in the presence of pituatary adenoma?
A
Go look for the adenoma please. GH, LH, FSH, TSH, ATCH, Prolactin.
9
Q
What is the most common type of hormone produced by a pituatary adenoma?
A
Prolactinomas make up at least 30% of all pituatary adenomas
10
Q
Which part of the pituatary gland receives an arterial blood supply?
A
The posterior pituatary (neurohypophysis) recieves arterial supply from the superior hypohyseal artery (direct branch from the carotid artery) and the inferior hypohyseal artery (branch off the meningiohypophyseal branch which comes off the internal cariotid artery). The anterior pituitary however only receives blood from the pituitary portal system.
11
Q
What is the name of the cells in the anterior pituatary that produce growth hormone?
A
Somatotrophs.
12
Q
What is the name of the cells in the anterior pituitary that produce TSH?
A
Thyrotrophs
13
Q
What is the name of the cells in the anterior pituitary that produce FSH and LH?
A
Gonadotrophs
14
Q
What is the name of the cells in the anterior pituitary that produce prolactin?
A
Lactotrophs
15
Q
What is the neuotransmitter that inhibits the activity of lacotrophs and suppresses the production of prolactin?!
A
Dopamine. This is the issue with taking dopamine receptor antagonists - they end up causing hyperprolactinaemia which can cause inadvertant lactaion.
16
Q
Waht is the effect of growth hormone release?
A
It stimulates the production of IGF-1 by multiple somatic tissues - especially the liver.
17
Q
What is the effect of TSH?
A
It acts on thyroid follicular cells to make thyroid hormone.
18
Q
What is the effect of ACTH?
A
It acts at the fasciculata and reicularis cells of the adrenal cortex to produce corticosteroids
19
Q
What is the effect of FSH?
A
It acts at ovarian follicular cells to make oestrogens and progestns. It also acts at sertoli cells in testicles to initiate spermatogenesis
20
Q
What is the target of LH in men?
A
Leydig cells to make testosterone
21
Q
What is the target of prolacitn?
A
Mammary glands to initiate and maintain milk production
22
Q
What is the only anterior pituitary gland hormone that has not been shown to have a negative feedback loop?
A
Prolactin. It’s production is suppressed by dopamine, however there is no clear mechanism by which increased prolactin leads to increased dopamine.
23
Q
What is the purpose of the ‘small diameter’ neurons in the hypothalamus?
A
They produce the ‘releasing hormones’ that travel via the pituitary portal system to act on the ‘troph’ cells of the anterior pituitary.
24
What is the purpose of the 'large diameter' neurons of the hypothalamus?
These neurons, with bodies in the supraoptic nuclei and the paraventircular nuclei, have axons that project into the neurohyphophysis and release oxytocin and ADH for them to be released.
25
What is neurophysin?
Neurophsyin is co-secreted with ADH from the neurohypophysis as part of its processing. Failure for the neurophysin to properly cleave from the ADH can cause issues with both elements secreting properly. This can lead to partial or complete diabetes insipidus.
26
What causes pseudohypoparathyroidism?
Theses patietns have a defect in their PTH G protein coupled receptor - this leads a PTH that doesn't do anything. These patients end up with high PTH levels, low serum calcium and high serum phosphate.
27
What is made by the adrenal medulla?
Adrenaline (mostly) and noradrenaline. Both are derived from the maino acid tyrosine and are considered 'amine' hormones.
28
What is the the hormone that is in excess in carcinoid syndrome that causes the symptoms?
Serotonin
29
Outside the CNS, where is serotonin typically produced?
It's produced in the neuroendocinre cells that are found in GI and respiratory tracts.
30
What are the symptoms of carcinoid syndrome?
Spontaneous and intense flushing ina typical pattern involving the head and necke, associatedd with diarrhoea, bronch9ospasm, and occasionally righded valvular disease. Typically the tumours responsible are in the intestines or are in the bronchial trees.
31
What type receptors are the adrenoreceptors?
They are all G protein-coupled receptors.
32
What is the precursor molecule for all steroid hormones?
Cholesterol (mostly from LDL) -> pregnenolone (happens in the adrenal glands, testes or ovaries)
33
What are the only two organs in the body with tissue capable of forming hormones out of cholesterol?
1) the adrenal glands and 2) the gonads
34
How are steroid hormones transported around the body?
They are hydrophobic, so they usually bind to binding protein to move around the body.
35
Which of T3 and T4 has higher affinity for intracellular thyroid hormone receptors?
T3
36
Where does T3 come from?
It's manufactured in two places. 1) along with thyroglobulin and T4 in the follicular cells of thyroid. T3 and T4 are secreted in there free forms, wresteled from thyroglobulin during secretion. 2) in peripheral tissues, particularly the liver, T4 is cconverted into T3 and secreted into the plasma
37
How is GH secreted?
It is stored in vesicles, as with all amine peptide hormones (cf with steroid hormones), and then released in a highly variable, pulsatile, minute - minute, manner. This makes it difficult to measure. Instead, IGF-1 should be measured.
38
When is GH usually secreted?
~70% of growth hormone is thought to be secreted during slow wave sleep.
39
What are the steroid hormones?
Cortisol, aldosterone, oestridiol, progesterone and testosterone.
40
What pituitary hormone increases in response to Ghrelin?
Produced by the stomach and also by the arcuate nucleus of the hypothalamus - ghrelin leads to increased secretion of growth hormone. Ghrelin also stimulates appetite.
41
What impacted does hypothalamic somatostatin have on growth hormone production?
Somatostatin is produced in the hypothalamus and transported by the portal venous system where it inhibits the production of growth hormone from the somatotrophs (thus 'somato' 'statin'). Note that somatostaint is also produced by pancreatic islet cells (delta cells) and D cells in the GI tract - although the types outside the CNS have slightly different structure.
42
How does insulin-like growth factor negatively feedback to reduce the production of growth hormone?
3 ways. It stimulates the production of hypothalamic somatostatin, which inhibits the anterior pituitary somatotrophs from making GH. IGF-1 also directly acts on the anteior pituitary directly, downregulating GH production. IGF-1 also acts on the hypothalamus, down regulating the production of GHRH (growth hormone releaseing hormone)
43
What type of receptor does growth hormone bind to?
Tyrosine kinase associated receptor - within the JAK2 family
44
What is the impact of growth hormone on blood sugar regulation? What does this mean for patients with acromegaly?
Growth hormone (not IGF-1/2), which has wildly fluctating and pulsatile release mainly at night, is said to act like an anti-insulin - increases lipolysis, increases gluconeogenesis, decreases muscle uptake of glucose. As such patients with acromegaly often end up with glocuse intolerance or frank diabetes.
45
What are the actions of IGF-1?
Unlike GH which acts like an 'anti-insulin' IGF-1 acts very much like insulin. It increases the uptage of glucose by muscle and fat, encourages lipogenesis, stimulates amino acid uptage, stimulates protein synthesis. Noteably however, IGF-1 has a lower effect on circulating blood sugar than insulin, and continues to promote growth whilst having a small impact on circulating blood sugar.
46
What are the actions of IGF-2?
Very similar to IGF-1, which is very similar to insulin (e.g. glycolysis, lipogenesis, glycogenolysis, protein synthesis etc. The main difference between IGF1/2 is that IGF 2 is not as dependent on GH for its production.
47
Apart from growth hormone, and the hormones it stimulates production of (IGF1/2), what other hormones are important for growth?
T3/4, insulin, glucocorticoids, and sex hormones
48
What cancer is associated with abuse of androgenic anabolic steroids?
Hepatocellular carcinoma
49
Where is the satiety centre located?
Ventromeial nucleus of the hypothalamus
50
Where is the hunger centre located?
Lateral hypothalamus. If this area is ablated, animals completely lose the will to eat.
51
What is leptin?
It's a hormone produced by adipocytes that influences the hypothalamic satiety and hunger centres to reduce appeptite.
52
What is the action of POMC and neuropeptide Y?
These are produced in the arcutate nucleau of the hypothalamus in respons to stimulation from insulin and leptin. They act on hunger and satiety centres to reduce appetite and increase sympathetic activity to consume more energy.
53
Where is synthesised, but not circulating, thyroid hormone stored?
It's stored in proteinacious material as an extracellular pool, but surrounded by and stuck to the thyroid, called thyroid colloid. The protein that makes up the thyroid colloid for the most part is thyroglobulin.
54
What is the hormone made by the thyroid gland that is not T3/T4? What is the name of the cell that makes it?
Calcitonin, but by the C cells.
55
How is idodide (iodine anion) taken into follicular thyroid cells?
By the NIS! (the sodium/iodide cotransporter)
56
How does thryoid hormone make its way out of the thyroid colloid pools?
When demand for thyroid hormone is detected (TSH receptor activity) the follicular cells take up iodinated thyroglobulin, hydrolyze it, and realese T4 and T3 intoth the blood for binding to thyroid binding globulin and other proteins.
57
What percentage of free thyroid hormone released from the thyroid is T4?
~90%. The remaining 10% is T3.
58
What percentage of T3 comes frome the thyroid and what comes from peripheral conversion from T4?
25% is from the thyroid, the remainder comes from T4->T3 conversion.
59
What are the most common clinical scenarios that lead to elevations in thyroid binding globulin?
Pregnancy, oral oestrogen therapy, hepatitis, chronic heroin use.
60
What can lead to reduced thyroid binding globulnin concentrations?
Nephrotic syndrome, chronic steroid use, liver failure.
61
If thyroid binding globulin levels change, do free T4/T3 levels also change?
No. The protein bound thyroid acts a buffer to enable a near constant level of free T4 and T3 to have their actions on peripheral tissues.
62
What tissues can deidonate T4 -> T3?
Type 1 deiodinases work in the liver, kidneys and thyroid (peripheral) and type 2 deiodinases work in the pituitary and central nervous system (slighly different enzymes between periphreal and central conversion).
63
Sick euthyroid syndrome is the result of what?
Stress causes reduction in Type 1 deiodinases causing a reduction in circulating T3. However, the type 2 deiodinases that work in the pituitary gland are not impacted by this, and so the TSH producing thyrotrophs continue to receive the same T3 concentration and the same amount of TSH is produced. This leads to sick euthyroid patients having low T3 with normal T4 and low/normal TSH.
64
What hormones do hypothalamic neurons
and thyrotrophs of the anterior pituatary respond to limit the creation of TSH?
T3 - converted from T4 in the thyrotrophs and arcuate nucleus cells of the hypothalamus by type 2 deiodinase. This sends a negative feedback signal. In the the hypothalamus this leads to reduced producdtion of thyroid releasing hormone. In the pituitary this leads to reduced TSH production.
65
Which hormone is, as a percentage, more likely bound to Thyroid bidning globulin in plasma? (T4 or T3)
T4. T3 is more likely to be free. This contributes to somewhat to why it is more biologically significant - it has a 25x higher free to bound ratio. Furhter, once intracellulur, a proprotion of T4 is convereted to T3, which means that the cytoplasmic concentration of each ends up being about the same. Then, the nuclear receptors for thyroid hormone are 10x more likely to bind to t3 than t4. This means that at the end of theday, T3 is primarily responsible for the biological impacts of thyroid hormone.
66
By what mechanism does hyperthyroidism lead to tremor, sweathing, increased temporature and tachycardia?
Likely increased expression of beta adrenergic receptors
67
What is the target of abs in patients with Graves' disease?
The TSH receptor on the follicular cells of the thyroid. They activate the TSH receptor and sitmulate the unregulate production of T4/T3
68
What protein is typically targetted by autoantibodies in patients with hypothyroidism secondary to hashimotos's thryoiditis?
Anti-follicular cells, anti-microsomes, and inhibitory (rather than activating) binding to the TSH receptor. However, the most useful are the anti thyroglobulin and anti-TPO (thyroperoxidase) abs. Note that these abs are quite common in the well population - they can be found in low levels at least in up to 20
68
What protein is typically targetted by autoantibodies in patients with hypothyroidism secondary to hashimotos's thryoiditis?
Anti-follicular cells, anti-microsomes, and inhibitory (rather than activating) binding to the TSH receptor. However, the most useful are the anti thyroglobulin and anti-TPO (thyroperoxidase) abs. Note that these abs are quite common in the well population - they can be found in low levels at least in up to 20% of the population, despite clnically significant hypothyroidism only impacting 1-2% of the population.
69
What is thought to initiate damage in hashimotos hypothyroidism - B-cells or T cells?
T-cells. This is because the abs found in hashimotos hypothyroidism are polyclonal and rise after damage begins in the thyroid. Although autoantiboides in this condition are likely a secondary phenomena, they are typically IgG1/3, and so they are able to fix complement and likely contribute to damage later in the disease.
70
When does the fetal thyroid gland start producing thyroid hormone?
2nd trimester. In 1st trimester, it is critical that the mother is providing the right amount of thyroid hormone. It is controlversial how much T3/T4 traverses the placenta. Some argue that the placenta produces T3 from T4.
71
What things trigger the secretion of aldosterone from the glomerulosa?
Angiotensin II, ACH, plasma potassium.
72
What dynamic test is performed to establish a diagnosis of acromegaly if there is ambiguity about the diagnosis?
Oral glucose tolerance test. In patients without an unregulated source of GH, GH levels will reduce reliably 2hrs after the administration of 75mg of oral glucose. If the GH level does not reduce, it is likely the patient has acromegaly.
73
What are the common physical features associated with a diagnosis of acromegaly?
Coarsening of facial features (frontal bossing, large nose, jaw enlargement, separation of teeth and macroglossia), skin thickening and hypertrophy, carpal tunnel syndrome, arthropathy (due to cartilage overgrowth), OSA, sexual dysfunction.
74
Why does pituitary stalk compression lead to increased secretion of prolactin?
Because dopamine, that is produced in the hypothalamus, is delivered to the lactotrophs of the anterior pituitary via the stalk and causes prolactin inhibition. Stalk compression reduces the amount of dopamine making it to the anterior pituitary, and prolactin secreion is free to increase.
75
Other than changes to physicial appearence, what other coniditions are likley to result from acromegaly?
Hypertension and arrythmias are thought to occur more frequently as a result of hypertrophic cardiomyopathy. Goitre and prostate enlargement are not uncommon. Increased appetite, polyuria and polydipisa are seen due to glucose intolerence.
75
Other than changes to physicial appearence, what other coniditions are likley to result from acromegaly?
Hypertension and arrythmias are thought to occur more frequently as a result of hypertrophic cardiomyopathy. Goitre and prostate enlargement are not uncommon. Increased appetite, polyuria and polydipisa are seen due to glucose intolerence. Headaches secondary to the pitutary mass are common.
76
Acromegaly is sometimes the presenting problem associated with one of the MEN (multiple endocrine neoplasia) syndromes. Which one?
MEN1. Pituitary adenomas are present in 10-40% of patients with this condition. MEN1 is due to germline mutations in the MEN-1 gene, which encodes for a protein called menin. The other tumours seen in this condition are parathyroid adenomas leading to hyperparathyroidism, and pancreatic neuroendocrine tumours.
77
What is the definition of acromegaly remission?
Normal IGF-1 levels, and nadir GH after oral glucose testing.
78
What cancers are associated with acromegaly?
Colon and thyroid. Colonoscopy is recommended for all patietns with acromegaly, and thyroid US should be performed if there is a nodular thyroid gland.
79
What is the definition of a microadenoma?
<10mm in diameter
80
What is the first line treatment for acromegaly secondary to a growth hormone producing pituitary adenoma?
Transphenoidal debulking surgery. 70-90% remission is achieved with microadenomas, and 30-60% for macroadenomas.
81
On histopathology of a growth hormone producing adenoma, what do you expect to see if it was growing agressively?
Sparsely granulated adenomas are more aggressive than densely granulated ones.
82
If sugery fails to induce remission for a patient with a growth hormone producing adneoma, what is the next line of therapy?
Somatostain analogues. Recall that somatostatin is a negative regulatory of growth hormone production. First generation options - octreotide and lanreotide - are available and work by binding to SST-2/5 receptors. However, more effective second generation psireotide (high SST-5 affinity) is more effective.
83
What are the adverse effects of somatostatin analogue therapy used for acromegaly?
Octrotide and lanreotide cause gall stones or biliary sludge in up to 25% of patients. They, as well as the second generation pasireotide, also cause hyperglycaemia and can cause frank diabetes.
84
After surgery and somatostatin analogues, what other oral treatment options are available for acromegaly?
Dopamine agonists - particualalry cabergaline - can reduce the concentration of GH and IGF-1 in about 1/3 of patietns. However cabergoline carries a lot of potential side effects. Of great concern - valvular heart disease, and fibrotic disease of the pericardium, lungs, pleura or retroperiotoneal. Other general concerning adverse effects common to dopamine agonists: nausea, vomiting, abdominal pain, constipation, headaches, dizziness, orthostatic hypotension, wekaness, fatigue, nasal congetsion, peripheral oedema, digital vasospasm, dyskinesias, impulse control disorders, drowsiness.
85
What is pegvisomant?
It's a recombinant growth hormone analogue that competes with GH for receptor binding used to treat acromegaly. It's highly effective at normalising IGF-1 levels, but is very expensive. It doesn't shrink pituitary somatotroph adenomas though, as it doesn't target GH production.
86
When is radiotherapy indicated in acromegaly?
For aggressive pituatary adenomas uncured by surgery and resistant to medical treatment.
87
What is the treatment for an adrenal crisis?
Administration of 100mg of hydrocoritsone IV once state, followed y 100mg QID for 1 day, then 50mg QID for 1 day, then consideration of oral replacement.
88
Why don't you need to give fludrocortisone when initially treating adrenal insufficiency?
Because 50-100mg of hyrdocortisone has enough mineralcorticoid activity to perform the tasks of absent cortisol and aldosterone.
89
In most cases Addison's disease (adrenal insufficiency) is autoimmune in aetiology. What are the antibodies directed against most commonly in autoimmune Addison's disease?
Directed against an enzyme called 21-hydroxylase. These abs are speicific for primary adrenal insufficiency.
90
What is the most common non-autoimmune cause of adrenal insufficiency in developing countries?
Tuberculosis infection of the adrenal glands.
91
In devloped coutries, what are the most common non-autoimmune causes of adrenal insufficiency?
Infections impacting the adrenal glands, infiltrative disease (e.g. haemochromatosis, amyloidosis, histiocytic disorders, sarcoidosis), metastatic malignancy to the adrenal glands, infarction of the adrenal glands due to coaglupathic haemorrhages (e.g. antiphospholipid syndrome, HITS, sepsis).
92
How much of the adrenal cortex needs to be destroyed before there will be clinically apparent Addison's disease?
About 90%
93
What is the usual presenting symptoms of adrenal insuffciency?
1. Fatigue and lethargy are the most common symptoms. Patients complain of worsening weakness as the day goes on.
2. Anorexia and weight loss
3. Dizziness
4. nausea, vomiting, vague abdominal pain
5. salt craving
94
What are the usual exam findings for a patient with adrenal insufficiency?
1. Evidence of weight loss
2. Generlised mucosal and cutaneous hyperpigmentation - more pronounced over scars, palms, knuckles and scars. Secondary to high amounts of ACTH which stimulates melanocortin receptors.
3. Postural hypotension due to mineralocorticoid deficiency
4. Loss of aillary and pubic hair in premenopausal women
95
Which of the adrenal gland produced hormones is least dependent on ACTH?
Aldosterone. DHEA/DHEA-S and Cortisol will both be markedly reduced in secondary adrenal insufficiency (ACTH deficiency), but aldosterone will be relatively preserved. In primary adrenal insufficiency, all zones of the adrenal cortex (including the aldosterone producing glomerulosa zone) are impacted.
96
What is required to diagnose primary adrenal insufficiency?
Low baseline cortisol, low baseline DHEA/DHEA-S, low aldosterone, high baseline ACTH, abnormal (low) synthetic ACTH cortisol response, high renin (due to the low aldosterone, there is an increase in the production of renin -> angiotension I -> angiotensin II -> in an attempt to produce more aldosterone).
97
When should baseline ACTH be collected?
In the morning at the same time as morning cortisol
98
In primary adrenal insufficiency, which is the first hormone to be lost due to cortical desctrcution?
Serum dehydroepiandrosyterone (DHEA) and DHEA - sulfate (DHEA-S).
99
How should adrenal hormone replacement be managed during minor and major stressors in primary adrenal insufficiency?
During minor stresses (minor surgery, febrile illness etc), patients are advised to double their oral maintence glucocorticoid (no change to mineralocorticoid). For major stressors, usually at least double parenteral equivalent glucocorticoid is required. There is a greater need for glucocorticoid during pregnancy, but this is usually managed with a 6 weekly review of blood tests and symptoms and dose adjusted gradually.
100
What defines and adrenal incidentaloma?
Adrenal mass greater than 1cm in diameter found serendipitously.
101
What sized incidental adrenal tumours should trigger functional testing?
Any size.
102
What functional testing should be performed for incidental adrenal tumours?
Dexamethasone suppression test 1mg + midnight salivary cortisol (to look for cortisol producing tumour), aldosterone/renin plasma levels (to look for aldosterone producing tumour), 24hr urinary metanephrines (to look for pheochromocytoma).
103
What size of adrenal mass is concerning for primary adrenal malignancy?
Greater than 4cm.
104
Are adrenal carcinomas hormonally active?
Often yes.
105
If patients have a positive dexamethasone suppression test with 1mg of dexamethasone, what should be done next to confirm the diagnosis of cushing syndrome?
24hr urine cortisol, morning coritsol, serum corticotropin (ACTH - adrenocorticotrophic hormone aka corticotropin).
106
In patients with a reduced renin/aldosterone ratio, and who you are suspicious may have primary hyperaldosteronism, what should be the next test?
Plasma aldosterone concentration on an unrestricted salt diet, 24hrlyt urinary aldosterone excretion, and saline suppression test (saline, in a normal patient, will suppress the excretion of aldosterone)
107
What are the types of thyroid disease that can be caused by amiodarone?
Amiodarone induced hypothyroidism, amiodarone induced thyrotoxicosis type 1 and amiodarone induced thyrotoxicosis type 2.
108
What is amiodarone induced thyrotoxicosis type 1?
AIT type 1 is the result the very large iodine load that comes with taking amiodarone daily (much greater than recommend daily amount) in a patient who has underlying Grave's disease or underlying multinodular goitre with hormone productive nodules. The excess iodine provides more substrate for the production of thyroid hormone and leads to thyrotoxicosis.
109
What is amiodarone induced thyrotoxicosis type 2?
AIT 2 is the direct result of driect toxic effects of amiodarone on thyroid cells causing thyroiditis in a previously normal thyroid gland. In comparison to AIT, thyroid imaging is uninteresting - normal vascularity, decreased uptake sesamibi thyroid scintigraphy. You do not expect to see TSH receptor abs in AIT 2, but you do in AIT 1.
110
How do you treat amidarone induced thyrotoxicosis type 1?
Treat as for Grave disease - carbimazole or polythiouracil.
111
How do you treate amiodarone induced thyrotoxicosis type 2?
High dose oral steroids.
112
How do you treat amiodarone induce hypothyroidism?
Continue amiodarone if it's still needed. Provide levothyroxine (t4) replacement.
113
How does polythiouracil work for the treatment of Grave disease?
Thyroid peroxidase inhibitor. Thyroid peroxidase usually works by converting iodide to an iodine molecule and incorporates it inthe amino acid tyrosine. Monoiodotyrosine and diiodotyrosine are the subcomponents of T3 (i.e. triiodothyronin) and T4 (thyroxine).
114
When is polythiouracil (PTU) used over carbimazole?
1st trimester of pregnancy. However, it is known to cause hepatotoxicity, so by second trimester of pregnany, it is preferred that patients used carbimazole. Carbimazole can't be used in the first trimester as it has been associated with foetal abnormal devlopement if used early in pregnancy.
115
What other random adverse affects have been associated with PTU?
Apart from causing hepatic toxicity during pregnancy and at other times, it can cause hypothyroidism (to be expected), but has also been associated with small vessel ANCA-associated vasculitis occuring within weeks of starting the drug. Agranulocytosis occurs in about 0.5% of patients so mus be monitored for (5 per 1000 pts). Important derm issues: erythema nodosum, alopecia, SJS, TEN
116
How does carbimazole work?
It's a prodrug which is converted to methimazole in vitro. Methimazole also inhibits thyroid peroxidase preventing the iodination of tyrosine to form the substrates of T3 and T4.`
117
What is autoimmune polyendocrine syndrome type 1?
There are 2 types. Type 1 is due to mutations in the AIRE gene, leading to a loss of central T cell tolerance. This leads to helper and cytotoxic T cells that are not tolerant to self tissue. Subsequently autoantiodies from autoreactive B-cells targeting vulnerable tissues (often endocrine tissues) are promoted by autoreactive Th cells. The result is autoantibodies to IL-17 (leading to an absence of fungus fighting Th17 cells) with associated 1) chronic candidiasis and autoimmunity targetting:
2) parathyroid glands (primary hypoparathyroidism)
3) adrenal glands (primary hypoadrenalism)
118
What is autoimmune polyendocrine syndreom type 2?
HLA variant dependent disease characterised by autoreactive T cells eventuating in type 1 diabetes, followed by other autoimmune diseases includin hypothyroidism, autoimmune gastritis, pernicious anaemia, vitiligo, primary ovarian insufficiency, and alopecia.
119
What gene is mutated in the disease Immune dysfunctoin, polyendocrinopathy, enteropathy, X-linked (IPEX)?
FOXP3 or something up or downstream from it. FOXP3 is the critical gene for the Treg system.
120
What are the three types of adipocytes?
White, brown and thrermogenic beige.
121
What do white adipocytes do?
Most common. Store tirglycerides and cholesterol. Secrete leptin, adiponecting and other adipokines.
122
What do brown adipocytes do?
Small amounts of lipid containing, but large amounts of a mitochrondia membrane protein called uncoupling protein 1, and mitochonria that contain iron. The uncoupling protein, in response to sympathetic stimulation, causes the mitochondria electron transport chain to break (uncouple) leading to heat generation instead of ATP production. Brown fat is primarily located in the supraclavicular, paravertebral and mediastinal regions. Stimulated by unmyelinated sympathetic nerves.
123
Calcitonin (made in the thyroid C cells), does what?
It is secreted in response to rising calcium levels. It inhibits osteoclast action and reduces serum calcium levels, but its effects are transitory. It has the opposite effect of PTH.
124
Where are thermogenic beige adipocytes found?
Scattered throughout white adipose tissue. They contain uncoupling protein 1 and lipids. Importantly, they demonstrate that there can be browning of white adipocytes.
125
What are each of the three Cushing disease screening tests doing?
Midnight salivary cortisol is testing for loss of nighttime cortisol inhibition, 24hr urinary cortisol is looking for overall cortisol production excess, and dexamethasone suppression test is looking for loss negatvie feedback response to increased circulating cortisol. It is recommended that at least 2 of the 3 tests is done to make the diagnosis.
126
How do you determine if secondary cushings syndrome is being caused by an ectopic ACTH secreting tumour or a pituitary adenoma?
With imaging (MRI head, CT chest). If this fails, can do an 8mg dexamethasone suppression test, which should subdue a pituitary adenoma, but will have no impact on ectopic ACTH. Alternatively, you can do petrosal sinus sampling to directly test ACTH levels leaving the pituitary.
127
What is the role of intensive glycaemic control for diabetic nephropathy?
In type 1 diabetes, intensive glycaemic control has been shown to reduce diabetic neprhopahty progression, and the benefit persists even if poor glycaemic control follows the period of good control. In DN caused by type 2 diabetes however, the benefits of tight glycaemic control are limited to reducing the relative risk of developing microalbuminuria - mortality risk was not improved.
128
Are ACEi and ARBs equivalently good for diabetic patients with diabetic nephropathy?
Both are equally renoprotective, however ACEi have been shown to have superior cardiac beenefits in the diabetic cohort. Additionally, the renoprotective effects of ACEi and ARBs is dose related, so the highest tolerated dose should be prescribed. Note that a 10% GFR reduction with ACEi and ARB use is expected and medication should be continued despite this.
129
When treating DKA, do you still give the patients long acting insulin?
Not until the patient is eating and drinking properly. Initial treatment is insulin infusion IV with glucose if required.
130
When should you administer IV bicarb to patients with acidosis (e.g. DKA)?
Only if the pH has dropped below 7.
131
What are the most common causes of erectile dysfunction?
Vascularar/ateriogenic dysfunction (40%), dibetes (30%), Medications (15%), Pervic surgery/radiation/trauma (6%)
132
How do phosphoiesterase-5 inhibitors work to treat erectile dysfunction?
Cavernosal vascular smooth muscle relaxes allowing for blood to fill the penis. Venous outflow obstruction occurs to trap blood in the erect penis. Smooth muscle relaxation is mediated by nitric oxide release which causes increased intracellular cylcic GMP. This cyclic GMO sequestors intracellular calcium to the sarcoplasmic reticulum and reduces muscle contraction. Phosphodiesterase 5 converts cGMP to 5'-guanosine monophosphate, allowing calcium levels in the cell to normalise. Inhibiting PDE5 therefore prolongs cGMP existence and prolongs smooth muscle relaxation.
133
What diseases should be assessed for if someone presents with erectile dysfunction?
Cardiovascular disease (exercise stress tests), obstructive sleep apnoea, diabetes, medications that cause ED, urogenital abnormalities, connective tissue disease
134
What medications can cause erectile dysfunction?
SSRIs, thiazide diuretics, weak associateion with beta blockers alpha blockers, androgen deprivation therapy (for prostate cancer), spironolactone, keoconazole
135
What is Peyronie's disease?
Fibrous plaque forms in the subcutaneous tissue of the penis causing it to bend out of shape and be painful during erections.
136
What treatments have demonstrated effectiveness in the treatment of Peryronie's disease?
Injectable clostridium histolyticum colleganse followed by penile modelling/traction. Injectable verapamil.
137
What are the cells called in the adrenal medulla that are capable of synthesising adrenaline?
Chromaffin cells
138
What is the name of the enzyme that is unique to chromaffin cells and nerve terminals of the CNS that allows them to convert tyrosine to catecholaemines?
Tyrsoine hydroxylase. This enzyme increases its activity in response to sympathetic activation - producing more catecholamines.
139
What type of molecule is dopamine? What amino acid is it based on? What has it got to do with cheese?
It's a catecholamine. The catecholamines are all based on tyrosine. They rely on monoamineoxidases (MAO) to be degraded. People who take monamine oxidase inhibitors, either for parkinson's disease to prolong the existence of dopamine, or for depression, end up with elevated amounts of noradrenaline/adrenaline circulating. If people taking these drugs consume a large amount of tyrosine, they end up driving the production of large quantities of catacholaemines and can end up with a hypertensive crisis. Aged cheese has a lot of tyrosine in it.
140
What the four cell types of the pancreas?
Alpha, beta, delta, and F cells.
141
What do each of the cell types of pancreas secrete?
Alpha cells secrete glucagon. Beta cells secrete insulin, C-peptide and amylin. Delta cells secrete somatostatin. F cells secree pancreatic polypeptide.
142
Which glucose channel is used by beta islet cells to detect the serum plasma glucose level, and by hepatocytes to traffic glucose?
GLUT1 and GLUT 2. Importantly, neither of these are insulin dependent. Contrast with GLUT 4 which is on skeletal muscle, heart and other tissues.
143
How do the sulfonylureas (e.g. gliclazide) work?
Bind to sulfonylurea receptors on beta-islet cells and cause the release of insulin.
144
Other than glucose, what else can stimulate/inhibit the release of insulin from beta cells?
Beta-adrenergic activation increases insulin secretion, alpha adrenergic stimulation inhibits it. During exercise, there is extensive alpha-adrenergic activation preventing insulin secretion and preventing hypoglycaemia whilst exercising. Incretins are the next group - these are substances produced in response to eating that stimulate the production of insulin. They include GLP-1, cholecystokinin and gastric inhibitory polypeptide.
145
What glucose transporters are on CNS tissue?
GLUT3 - they are insulin indepent.
146
In familial hypocalciuric hypercalcaemia, what gene is mutated, and what is its inheritance pattern?
It's the CaSR gene. It's an autsomal dominant condition.
147
What's the pathophysiology of FHH (familial hypcalciuruic hypercalcaemia)?
Heterozygous CaSR gene mutation affecting the calcium receptors in the parathyroid gland and in the distal convoluted tubule of the kidney. The effect of this mutation is that normal plasma calcium set-point is shifted up by 10-30%. Even with elevated calcium levels, these patients aren't excreting calcium in their urine, and their PTH level remains normal instead of low. It may even be high if the patient has vit D deficiency and has 'relatively low' calcium for them (say, 5% above the normal range). This isn't to say they don't regulate their clacium levels, but PTH inhibition and urinary calcium excretion just starts at a higher concentration of plasma calcium.
148
What cell produces parathyroid hormone?
Chief cells.
149
What inhibits the production of PTH by chief cells?
Calcium and vitamin D
150
What are primary functions of PTH?
Increase conversion of 25-OH-vitamin D to 1, 25 - (OH)2- vitamin D, which increases the intestinal absorption of calcium. PTH also increasees the kidney tubule resoprtion of calcium, and reduces the resorption of phosphate. Lastly, it stimulates osteoclasts to strip calcium from bones when chronically elevated. If released intermittently, PTH actually increases bone deposition.
151
Sildenafil is succesful treatment for erectile dysfunction in what percentage of patients?
Around 65%. Side note, it doesn't increase cardiovascular risk, which was a concern for a period.
152
Which chemotherapy can cause premature ovarian failure?
All alkylating agents are a concern in this regard. The one most talked about it is cyclophosphamide.
153
Androgren replacement in men with androgen deficiency has only been reliably shown to improve what?
Libido and erectile function
154
What is hungry bone syndrome?
The big drop in serum iCa seen after parathyroidectomy.
155
What is done to reduce the chance of hungry bone syndrome prior to parathyroidectomy?
Calcitriol pre-operatively.
156
How is severe hypocalcaemia managed?
IV calcium, oral calcium and vitamin D are all used. Something not to do is give phosphate, even if it is low, as this will cause further reduction in calcium levels by binding to it in the serum.
157
Which metabolite is particularly important for macrophage and dendritic cell activation?
Citric acid apparently. The Kreb's cycle, though inherently important for every cell, was isolated in a paper as being espeically important for macrophages and dendritic cells.
158
MEN2A and 2B (AKA MEN3) involve mutations in which gene?
Germline RET gen mutations
159
MEN4 is related to a mutation in what?
Cyclin-dependent kinase inhibitor1B.
160
What tumors are found in patients with MEN4?
Parathyroid and anterior pituitary tumours are most common. They are often associated with adrenal tumours, renal tumours or tumours of the reproductive organs.
161
What does the RET gene encode?
A tyrosine kinase for members of the glial cell line-derived neurotrophic facotr family of extracellular signalling moleculres. Loss of function mutations in this gene are associated with Hirschprungs' disease, and gain of function mutations with MEN2A and 2B.
162
How are RET gene mutations inherited
163
How is MEN2 inherited?
Autosomal dominant.
164
What cancers is the Von Hippel Lindau gene mutation associated with?
Phaeochromocytoma, retinal angioma, and haemangioblastoma.
165
What cell type is impacted by MODY (maturity onset diabetes of the young) mutations typically?
Beta-islet cells
166
What features would suggest that young onset diebetes might be caused by MODY gene mutation instead of T1DM?
An absence of autoantibodies to pancreatic islet cells or insulin. Evidnece of endogenous insulin production. Measurable C-peptide in the presence of hyperglycaemia. Low insulin requirement for treatment. Lack of ketoacidosis when insulin is ommited from treatment (usually, but when unwell it can occur)
167
What features differentiate MODY from type 2 diabetes?
Onset before 45 years old. Lack of obesity. Normal lipid studies. Mild stable hyperglycaemia that does not progress or respond much to pharmacologic therapy OR extreme sensitivity to sulfonylureas.
168
What are the most common types of MODY?
MODY2 and MODY3 (each account for 30-60% of all MODY). Then MODY1 and MODY5 account for ~10%. The remaining up to 20% is accounted for by 10 other genes.
169
What gene is mutated in MODY1?
HNF4A. Beta cell defect leading to insulin secretion deficit. Sensitive to sulfonylurea.
170
What gene is mutated in MODY2 (most common subtype along with MODY 3)? What is the pathogenesis of the disease? What is the treatment?
GCK - glucose sensing defect. Often subtle stable fasting hyperglycaemia. Doesn't usually require treatment.
171
What gene is mutated in MODY3? What is the pathogenesis of the disease? What is the treatment?
HNF1A - beta islet cell dysfunction leading to progressive failure to secrete insulin. Renal gylcosouria with positive OGTT. Respond avidly to sulfonylureas or GLP-1 agonists. Insulin may still be required in some cases.
172
What gene is mutated in MODY5? What's the pathogenesis of the disease? What are the treatment options?
HNF1B. Beta-islet cell defect leading to poor insulin secretion. Develop pancreatic hypoplasia. Often associated with renal anomalies and urogenital tract anomalites. Can be treated with sulfonylureas, but often require insulin.
173
How is MODY normally inherited?
Autosomal dominant.
174
What is going on with osteoclastic and osteoblastic activity in Paget's disease?
Increased osteclastic and osteoblastic activity leading to disorganised and mechanically weak bone.
175
What dene mutation is most commonly associated with Paget's disease?
SQSTM1 - present in ~50% of patients
176
How do patients with Paget's disease of bone normally present?
Bone pain at site of Pagetic lesions. Neurological symptoms due to bone overgrowth such is hearing loss, facial pain, hydrocephalus, spinal stenosis, are sometiems seen. High output cardiac failure is sometimes seen. The most common presentation however is an isolated elevated ALP or lesion seen on XR.
177
How is Paget disease of bone treated?
If necessary, it can be treated with bisphosphonates to reduce osteoclastic activity. Zoldronate has the most evidence.
178
What are the most commonly impacted bones in Paget disease?
Pelvis, spine, femur, tibia and skull.
179
Is the prevalence of peripheral neuropathy higher in t1 or t2dm?
Peripheral neuropathy is almost twice as common in patients with T2DM than T1DM.
180
Tight glycaemic control in type 1 diabetes is able to delay the onset of preipheral neuropathy. Does this also apply to T2DM?
No - for whatever reason it seems to have no impact on the onset or progression of peripheral neuroapthy in T2DM.
181
What mechanisms are thought to be important in the pathogenesis of diabetes related gastroparesis?
1) Autonomic neuropathy - vagel neuropathy leads to impaired antral contruction, and disturbed pyloric coordination, and reduced gastric secretions. 2) Enteric neuropathy - the myenteric plexus between longitudinal and circular muscle layers of the gut are damaged and become dysfunctional with hyperglycaemia 3) Loss of the Intertitial Cells of Cajal - this is most common abnormality in diabetic and idiopathic gastroparesis. These gut pacemaker cells generate slow wave electrical activity that control mooth muscle contractility in the stomach.
4) Blood glucose fluctuations, caused by pyloric dysfunction, further worsen gastroparesis.
182
Which diabetes mellitus treatment is a risk factor for developing gastroparesis?
GLP-1 agonists. They are contraindicated in patients who already have gastroparesis.
183
What are the diagnostic criteria for PCOS?
Diagnosis is made if the patient has other causes excluded, and meets two of the following:
1) clinical and/or biochemical signs of hyperandrogenism. 2) oligo or anovulation 3) polysystic ovaries on abdominal US.
Subtypes (A-D) are defined on the bases of which of the above 3 is not present.
184
What is the definition of phenotype A of PCOS?
Have all 3 diagnostic criteria: hyperandrogenism, oligmenorrhoea, and US features of PCOS. Asscoicated with methabolic disease.
185
What is the definition of phenotype B PCOS?
Hyperandrogenism, oligomenorhoea, but no PCO on US. Still associated with increased risk of metabolic syndrome.
186
What is the definition of phenotype C PCOS?
Hyperandrogenism and US features of PCO, but no oligamenorrhoea. Still carries increased risk of metabolic syndrome.
187
What is the definition of phenotype D PCOS?
Oligomenorrhoea, US features or PCO, but no hyperandrogenism. Does not carry an increased risk of metabolic syndreom like PCOS A-C.
188
What cancer are patiets with PCOS more likely to get?
Endometriral cancer. Importantly, there has been no increased risk of breast or ovarian cancer associated with PCOS.
189
What imaging modalities should be used to see a phaeochromocytoma if it is suspected clinically and biochemically?
CT abdomen/pelvis can identify masses within the adrenal glands, but is unable to distinguis subtypes. MRI adrenal glands is able to distinguish phaechromocytomas from other adrenal masses on T2-weighted images where they appear hyperintens (other adrenal tumours appear hypointense). If there is strong suspicion of a tumour but MRI/CT cannot spacially resolve one, a metaiodobenzylguanidine (MIBG) scan can be done - MIBG is taken up into adrenergic tissue and will show up before MRI or CT can resolve it.
190
Conditions that increase the lifespan of RBCS, or decrease their turnover, falsely elevate HbA1c. So to do conditions that increase protein glycation. Name some conditions that do this.
Asplenia, anaemia secondary to iron/b12/folate deficiency, or conditions that increase portein glycation on RBCs (iron deficiency does this).
191
Conditions that decrease the lifespan of red blood cells, or increase their turnover, cause falsley low HbA1c. So to do conditions that reduce RBC glycation. What situations might do this?
Blood loss, haemolytic anaemia, CKD, pregnancy, EPO therapy, chronic liver disease (secondary to splenomegaly), and decreased glycation secondary to vitamin C and E supplementation, alcohol, antivirals (e.g. ribavirin) and some antibiotics (e.g. trimethoprim).
192
What pituitary hormone increases with adenoma size regardless of whether or not the tumour is hormone productive?
Prolactin - becuase dopamine suppression reduces with pituitary stalk compression, leading to elevated prolactin levels. Remember that dopaminergic therapy can only be used to treat true prolactinomas, which will produce very high levels of prolatcin (not the slight increases seen due to stalk compression).
193
What are the clinical features of a prolactinoma in a man?
Hypogonadism, reduced libido, erectile dysfunction, gynaecomastia, infertility.
194
What medications can elevated prolactin levels?
Anti-dopaminergic medications. Especially anti-pscyhotics, but also metoclopramide and domperidone.
195
What is cabergoline? What is its alternative for the treatment of prolactinoma?
A long acting dopamine agonist - taken twice per week. The alternative treament is bromocriptine.
196
What is now considered standard of care treatement for patients with T1DM?
Real time continuous glucose monitoring.
197
When might you treat subclinical hypothyroidism?
In younger individuals with a TSH >7.0 who have a possibility of becoming pregnant, noting the importance of thyroid hormones in the first semester of pregnancy. There is a general recommendation for treating anyone with a TSH >10.0, or if there is a goiter, or if thyroid peroxidase ab is positive.
198
After commencing thyroxine replacement therapy for hypothyroidism, when should thyroid function tests be repeated?
6 weeks after commencing treatment. Once normalised, 12 monthly is adequate.
199
What are the other components of the TSC and PI3k growth signalling pathways? Note that these are all sometimes mutated in cancer and considered oncogenes.
TSC -> PI3K -> AKT -> MTOR
200
What downstream growth signal follows the RAS/BRAF molecules? Note that these are each sometimes mutated in cancer and considered oncogenes.
RAS -> BRAF -> MEK -> ERK
201
What is the treatment for papillary thryoid cancer?
Totatl thyroidectomy is the mainstay of treatment. Radioactive iodine ablation and long-term TSH suppression using thyroxine is an important adjuvant therapy.
202
What tumour marker is used for papillary thyroid carcinoma?
Serum thyroglobulin is used to monitor for tumour recurrence. It should be undetectable. Doing a stimulation test using recombinant TSH is used if there is uncertainty about the eradication of disease - a spike in thyroid hormone production is consistent with disease recurrence.
203
Which mutations are most likley associted with thyroid cancer?
BRAF and RAS mutations - most commonly associated with thyroid follicular and papillary cancers.
204
If an FNA is done on a concerning thyroid nodule and is non-diagnostic, what should be done next?
Repeat for more cells in 3 months.
205
What if the FNA done on a thyroid nodule is not diagnostic but shows atypia?
Analyse the specimen for BRAF and RAS mutations.
206
Which medications should be avoided in gender affirming treatment?
Progestins. They increased risk of thrombosis, weight gain and coronary artery disease. GnRH analogues are used as puberty blockers in adolescents only.
207
What are the symptoms of B1 (thiamin) deficiency?
Acute deficiency (sudden drop, caused by things like alcohol intake) causes Wernicke's encephalopathy with ocular abnormalities, mental state changes and ataxia. Acute or chonric B1 deficiency can cuase Wet, Shoshin or Dry beri beri.
208
What is wet beriberi?
Caused by acute or chronic B1 deficiency, it is a syndrome of high cardiac output heart failure with oedema and orthopnoea.
209
What is Shoshin beriberi?
Low-ouput cardiac failure with lactic acidosis and peripheral cyanosis secondary to B1 deficiency (acute or chonic)
210
What is dry beriberi?
Chronic B1 deficiency leading to distal peripheral neuropathy.
211
What are the symptosm of Zinc deficiency?
Delayed wound healing, impaired taste, loss of appetite, hair loss, fertility issues, increased susceptibility to infection.
212
What are the symptoms of Vit A deficiency?
Nigh blindness, Bitot's spots, poor wound healing, hyperkeratinisation of the skin, loss of taste, corneal xerosis.
213
After malabsorptive gastric bypass, which vitamin deficiencies are most likely?
Fat absorption is reduced by ~75% following these procedures, and so there is a high likelihood of fat soluable vitamin malabsorption (ADEK and zinc). However, with roux-en-Y procedures, there is also jejunem bypass. This is where B1 (water soluble) is normally absorbed, so B1 deficiency occurs in 50% of patients.
214
What ADH related disease can chronic lithium use cause?
Nephrogenic diabetes insipidus. The lithium makes the collecting duct insenstitive to ADH.
215
How do you detect the diference between central and nephrogenic diabetes insipidus?
Circulating ADH will be normal or elevated in patients with nephrogenic diabetes insipidus, and low in the nephrogenic form. Further, demospression will correct central diabetes insipidus, but will not correct the nephrogenic form.
216
What are the abolute contraindications to all GLP-1 agonists?
Type 1 diabetes and a history of pancreatitis for all GLP-1 agonists. For patients with gastroparesis or outflow obstruction, short acting GLP-1 agonists are contraindicated, and long acting ones should be used with caution due to their effect on slowing gastric emptying. GLP-1 agonists should not be used in patients with a history of mudullary thyroid cancer or MEN2A/2B. Exenatide and lixisenatide cannot be used with renal impairment, and lirglutide and dulaglutide should be used with caution. Semaglutide was associated with progression of diabetic retinopathy in the trials that examined its outcomes.
217
What are the major side effects to be aware of in GLP-1 agonist treatmnet?
GI - gastric dysmotility as well as nausea and vomiting. Pancreatitis. Gall bladder and biliary disease. Semiglutide - diabetic retinopathy. Hypoglycaemia when combined with other agents that can cause it (e.g. insulin on sulfonylureas)
218
Which patient groups should not be prescribed an SGLT2i?
Patients at high risk of foot ulcers and possible amputation - severe PVD, marked peripheral neuropathy, evidence of poor foot care, recurrent and/or severe urinary tract infections inlcuding necrotising fasciitis of the perineum (fournier's gangrene), marked hypotension.
219
What cancer risk is thought to be possibly associated with SGLT2i use?
Bladder cancer. There is currently post market surveillence under way for this.
