Endocrine Flashcards
What step in the citric acid cycle is essential to gluconeogenesis and why?
Gluconeogenesis requires the hydrolysis of GTP for the phosphorylation and decarboxylation of oxaloacetate to PEP (phosphoenopyruvate) by PEP carboxykinase.
GTP is formed during the conversion of succinyl CoA to succinate.
When is metformin contraindicated?
Major side effects are gastrointestinal upset and lactic acidosis
Metformin is contraindicated in any situation that might precipitate lactic acidosis:
- Renal failure
- Liver dysfunction
- Congestive heart failure
- Alcoholism
- Sepsis
How does prolactin affect the GnRH-LH/FSH axis?
Inhbits/decreases levels of all of them
Which congenital adrenal hyperplasia results in a virilized baby girl?
21-hydroxylase deficiency
What two reactions does 21-hydroxylase normally catalyze?
- Conversion of 17-hydroxyprogesterone –> 11-deoxycortisol
2. Conversion of progesterone –> 11-deoxycorticosterone
What can cause increased insulin, c-peptide, and pro-insulin levels?
- Sulfonylurea or meglitinide abuse
2. Insulinoma
What does an increased urinary VMA excretion and an adrenal mass raise your suspicion of?
Pheochromocytoma - VMA is a catecholamine metabolite
What is the genetic defect associated with MEN 2A and 2B?
Germ-line mutation of the RET proto-oncogene which affects neural crest cell migration
Both chromaffin cells of the adrenal medulla and parafollicular cells (C-cells) of the thyroid originate from neural crest; this is why we see tumors in both the adrenal medulla and the thyroid
What are the amino acids with 3 titratable protons?
- Arginine
- Aspartic acid
- Cysteine
- Glutamic acid
- Histidine
- Lysine
- Tyrosine
What enzyme does IP3 activate?
Protein kinase C
What can you give to prevent thyroid absorption of radioactive iodine isotopes?
Potassium iodide - competitive inhibition
Presentation: Vomiting, abdominal pain, hypotensive, tachycardic, hypoglycemic, generalized hyperpigmentation
Diagnosis?
Adrenal crisis
What is the treatment for adrenal crisis?
Corticosteroids
What is the mechanism of flutamide?
Competes with testosterone and DHT for testosterone receptors
Flutamide is a non-steroid anti-androgen used for treatment of prostate cancer in combination with GnRH agonists
What enzyme mutation can result in mild hyperglycemia?
Glucokinase - glucose sensor within pancreatic beta cells
How does septic shock lead to lactic acid formation?
Impaired tissue oxygenation decreases oxidative phosphorylation, leading to shunting of pyruvate to lactate after glycolysis
What is often the cause of pneumonia in elderly patients with dementia or hemiparesis?
Dysphagia leading to aspiration
Which tissues contain well-developed smooth endoplasmic reticulum?
All steroid-producing cells (e.g. cells in the adrenals, gonads, liver)
What is the medication of choice for gestational diabetes?
Insulin
What is biotin?
CO2 carrier on the surface of the carboxylase enzyme that is necessary for numerous conversions, including pyruvate to oxaloacetate
What volume condition does diabetes insipidus lead to?
Hyperosmotic volume contraction - loss of free water water with retention of electrolytes
In overweight individuals, what is believed to increase insulin resistance?
FFA and serum triglycerides
How do you differentiate diabetes insipidus from polydipsia?
Water deprivation test - with polydipsia, you will see a steady, reliable, and prompt increase in urine osmolality and a paltry response to vasopressin (< 10%)
With polydipsia, you will also see serum Na < 142 because of intake of so much water vs. DI where you are excreting water and retaining the electrolytes
How does estrogen affect thyroid hormone levels?
Estrogen leads to increase in TBG (thyroid binding globulin) which leads to increase in circulating total T4 and total T3. However, the level of free thyroid hormone is normal.
What is the only glucose transporter that is responsive to insulin and what tissues is it found in?
Glut 4 - found in muscle cells and adipocytes
What should be monitored in patients taking amiodarone (for side effects)?
Thyroid function tests
Is pancreatic islet amyloid deposition associated with type I or type II diabetes?
Type II
How do we treat congenital adrenal hyperplasia?
Low dose corticosteroids to suppress excess ACTH secretion
What is the characteristic histologic finding of Hashimoto’s thyroiditis?
Mononuclear, parenchymal infiltration with well-developed germinal centers
Why do antipsychotics (e.g. risperidone) cause amenorrhea?
They have antidopaminergic action which leads to hyperprolactinemia which inhibits the release of GnRH.
What are serum levels of LH, FSH, testosterone, and sperm count in Klinefelters?
Decreased testosterone, sperm count
Increased LH/FSH
In Klinefelter’s - serum inhibin levels are decreased as a result of damage to the semniferous tubules
What happens to testosterone and DHT levels when you give leuprolide?
Transient increase that gives way to decrease in both testosterone and DHT
Leuprolide is a GnRH analog
Thyroid histology: Extracellular deposits of amyloid formed by calcitonin secreted from neoplastic parafollicular cells
Diagnosis?
Medullary thyroid carcinoma
What is MEN 1?
Para-Pan-PIt: Parathyroid, Pancreas, Pituitary tumors
What is MEN 2A?
MPH: Medullary thyroid, Pheochromocytoma, Hyperplasia of the parathyroid
What is MEN 2B?
MMMP: Medullary thyroid, Marfanoid habitus, Mucosal neuromas, Pheochromocytoma
Where is ADH synthesized?
Hypothalamus - paraventricular and supraoptic nuclei
What causes a neonate to be hypoglycemic if the mother has gestational diabetes?
Diffuse hyperplasia of the islets
The baby responds to high sugars from mom by increasing its insulin production via hyperplasia of the insulin producing cells. This results in hypoglycemia once the baby is delivered.
Why does hyperaldosteronism lead to paresthesia and muscle weakness?
Excess K secretion to maintain electroneutrality from increased Na retention (increased ENaC is a result of aldosterone)
Hypokalemic states can give rise to paresthesia and muscle weakness
What is glyburide?
Sulfonylurea
What is the mechanism of action of sulfonylureas?
Insulin secretion in type II diabetics
What is neurophysin?
Carrier protein for oxytocin and vasopressin
Why might inhibin production impaired in patients with 1 testicle?
Inhibin is produced by sertoli cells which are found in the semniferous tubules of the testes
What is the mechanism of action of beta blockers in treating thyrotoxicosis?
- Decrease in the effect of sympathetic response of the target organs
- Decrease in the rate of peripheral conversion of T4 to T3
What is the mechanism of action of anastrozole?
Selective inhibitor of aromatase
What class of drugs bind PPAR-gamma and what is their mechanism of action?
Glitazones/thiazolidinediones
They increase insulin sensitivity in peripheral tissues
What is the mechanism of action of thionamides?
Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification (coupling) of iodine –> inhibition of thyroid hormone synthesis
Does methimazole or PTU decrease peripheral conversion of T4 to T3 in addition to blocking thyroid peroxidase?
just PTU
What effect does tamoxifen have on the endometrium?
Hyperplasia
What causes exophthalmos?
Increased soft tissue mass within the bony orbit which results from enlargement of the extraocular muscles and increased fibroblast proliferation and ground substance production
Which symptom of Graves disease will not be improved with a beta blocker?
Exophthalmos
What happens to C peptide after it is cleaved from proinsulin?
Packaged in secretory granules and secreted along with insulin in equimolar concentrations
What is PPAR-gamma?
Receptor that belongs to the steroid and thyroid superfamily of nuclear receptors
What are the functions of thyroid peroxidase?
- Oxidation of inorganic iodine
- Formation of mono and diiodotyrosine
- Coupling that forms T3 and T4
Where are neurophysins secreted from?
Posterior pituitary
What are 4 characteristics of SIADH?
- Low plasma sodium and osmolality
- Inappropriately concentrated urine
- Increased urinary sodium
- Clinically normal body fluid volume
What paraneoplastic syndrome should you expect with small cell lung cancer?
SIADH
What is heavily methylated DNA associated with?
Low transcription activity - heavily methylated DNA is typically found in heterochromatin which is condensed and transcriptionally inactive
What does delayed puberty and anosmia suggest?
Kallman syndrome - failure of GnRH secreting neurons to migrate from their origin in the olfactory placode to their normal anatomic location in the hypothalamus
Which insulin do we use to treat diabetic ketoacidosis and what is its time course?
Regular insulin (starts working in 30 min, peaks at 2-4 hours, lasts 5-8 hours)
What hormone binds to an intracellular receptor that increases gluconeogenesis in the liver?
Cortisol - receptors are located within the cytoplasm and then translocated to the nucleus
Hypertension in the setting of suppressed plasma renin suggests what?
Elevated aldosterone (primary mineralocorticoid excess)
What would you expect sodium, potassium, and bicarbonate levels to be with primary mineralocorticoid excess?
Low potassium (weakness and paresthesias) and high bicarbonate (metabolic alkalosis)
BUT normal sodium due to aldosterone escape
What is aldosterone escape?
Hypernatremia is rare because increased Na and Cl reabsorption –> hypervolemia –> ANP release –> diuresis and Na loss
Why does fructose-1-phosphate have a much higher rate of metabolism in glycolysis than many other sugars (e.g. G6P, G1P, etc.)?
It bypasses PFK-1, the rate limiting enzyme of glycolysis
What enzyme deficiency causes hereditary fructose intolerance?
Aldolase B
How do you differentiate between partial vs. complete central diabetes insipidus?
Complete diabetes insipidus - in response to vasopressin, rise in urine osmolality typically > 50%
Partial - more moderate response
Hypothalamic destruction will likely cause an increase of what enzyme and why?
Hyperprolactinemia because prolactin is under tonic control by inhibition by dopamine (which is released by the hypothalamus)
Describe serum Ca, PO4, and PTH levels in a celiac patient.
Decreased Ca and PO4 because of decreased absorption of vitamin D
Increased PTH in response
NOTE: Ca is decreased in spite of increased PTH because bone stores often become depleted in these patients (can have bone pain)
What drugs block iodide absorption by the thyroid gland via competitive inhibition?
Anion inhibitors (perchlorate, pertechnetate)
What drug can be used for the treatment of hirsutism?
Spironolactone - antiandrogenic properties
Flutamide - inhibits binding to testosterone receptor
Finasteride - 5 alpha reductase inhibitor
In patients with pyruvate dehydrogenase activity, what amino acids can be safely supplemented to the infant and why?
Lysine and leucine - exclusively ketogenic and would not increase blood lactate level
Patients with pyruvate dehydrogenase have lactic acidosis because pyruvate is shunted to lactic acid pathway since without pyruvate dehydrogenase, it cannot be converted to acetyl coA
Upper GI ulcerations, abdominal pain, diarrhea - what enzyme is likely elevated?
Gastrin
What are 4 symptoms associated with pheochromocytoma?
Episodic secretion of catecholamines leads to episodic increases in:
- Blood pressure
- Flushing
- Diaphoresis
- Headaches
What amino acids do transmembrane proteins tend to have?
Hydrophobic residues - valine, alanine, isoleucine, methionine, phenylalanine
What typically stimulates K channel closure in insulin-producing pancreatic beta cells?
ATP
What is the site of rRNA synthesis?
Nucleolus
What directly modulates the activity of enzymes in the metabolic pathways regulated by insulin?
Protein phosphatase
What is the principal source of blood glucose after 12-18 hours of fasting?
Gluconeogenesis
What is the initial committed step of gluconeogenesis?
Pyruvate –> oxaloacetate –> phosphoenolpyruvate
How can you tell the difference between young female infants with 11-hydroxylase deficiency vs. 21-hydroxylase deficiency?
11-hydroxylase deficiency infants will have hypertension due to excess production of 11-deoxycorticosterone
Describe the intracellular and extracellular potassium levels in patients with DKA.
Extracellular stores - normal to high because of acidosis, lack of insulin
Intracellular stores - low because of loss from osmotic diuresis from glycosuria
What is a characteristic bone finding in hyperparathyroidism?
Subperiosteal thinning appears as erosions in the medial second and third phalanges of the hand and as “salt and pepper” appearance of the calvarium
What tests should be regularly checked for patients taking thiazolidinediones?
Liver function tests
In which organ do glucocorticoids INCREASE protein synthesis rather than have catabolic effect?
Liver - for gluconeogenesis
What is metyrapone testing?
- Metyrapone blocks cortisol synthesis by inhibiting 11-beta-hydroxylase
- When you give metyrapone, you stimulate ACTH
- ACTH stimulates synthesis of 11-deoxycortisol (which can’t be converted to cortisol because of the inhibition of 11-beta-hydroxylase)
- 11-deoxycortisol, unlike cortisol, does not feed back on ACTH
- 11-deoxycortisol metabolites are measurable in the urine as 17-hydroxy-corticosteroids
Describe the interaction between cortisol and catecholamines.
Cortisol is permissive - meaning it allows catecholamines to achieve their full effect of vasoconstriction and bronchial smooth muscle constriction
Transport of glucose into the cells of most tissues occurs by means of what?
Facilitated diffusion - mediated by carrier proteins
Thyroid biopsy - “branching lesions with interspersed concentrically calcified structures”
Diagnosis?
Papillary carcinoma - psamomma bodies and ground glass, grooved nuclei
Which hormones use JAK/STAT signaling?
Colony-stimulating factors, prolactin, growth hormones, cytokines
What is an important determinant of insulin resistance in a type II diabetic?
Visceral obesity (can be measured by hip to waist ratio)
Presentation: recent illness, various features of thyrotoxicosis, tenderness over thyroid gland, increased ESR, markedly reduced radioactive iodine uptake
Diagnosis?
Subacute granulomatous thyroiditis (de Quervain’s)
Why would a patient with a testicular tumor have elevated levels of thyroid hormones?
If the tumor is a teratoma, then it could secrete high levels of hCG which has a structural similarity to TSH and could therefore cause hyperthyroidism.
What causes proptosis in Graves disease?
Inflammatory infiltrate –> cytokines stimulate fibroblasts –> accumulation of glycosaminoglycans
How can TNF-alpha induce insulin resistance?
Phosphorylation of serine and threonine residues
What can happen to PTH in patients with renal failure?
Secondary hyperparathyroidism - calcium is low due to decreased 1 alpha hydroxylase activity which leads to decreased vitamin D activity
What reaction will high concentrations of fructose 2,6-bisphosphate inhibit?
Inhibits the gluconeogenic conversion of alanine to glucose
What is the main side effect of thiazolidinediones?
Weight gain and edema
What happens to sorbitol in the lens in the setting of hyperglycemia?
Metabolized into fructose by sorbitol dehydrogenase
What is the most reliable test to confirm menopause?
Elevated FSH (usually > 30 U/L)
What is the target of acarbose?
Alpha-glucosidase on the intestinal brush border
What happens to TSH, T4 and rT3 if you supplement a patient with T3?
Giving a patient T3 will cause negative feedback on TSH which will decrease T4 and rT3 (T3 cannot be converted to these other forms)
What effect does hydrochlorothiazide have on calcium?
Increases distal tubular reabsorption of calcium leading to increased serum calcium which can suppress PTH
How can you treat unconsciousness brought on by severe hypoglycemia?
Intramuscular glucagon in the non-medical setting and intravenous dextrose in the medical setting
What medical emergency should you beware of with pituitary adenoma?
Pituitary apoplexy - bleeding into a preexisting pituitary adenoma
Presentation: Diabetes mellitus, necrolytic erythema, anemia
Diagnosis?
Glucagonoma
Why do patients with anorexia experience amenorrhea?
Loss of pulsatile GnRH secretion from the hypothalamus
What is a pituitary adenoma most likely to secrete?
Prolactin - likely a prolactinoma
Presentation: Child with decreased exercise tolerance, myoglobinuria, muscle pain with physical activity
Diagnosis?
McArdle’s Syndrome - impaired glycogenolysis from myophosphorylase deficiency
What happens to the adrenal glands in long term steroid use?
Bilateral cortical atrophy
If ACTH fails to increase cortisol levels, what should you be suspicious of?
Primary adrenal insufficiency
