Translational Physiology Block 7 Flashcards
What is a paraneoplastic syndrome?
ability of nonendocrine tissues to produce hormones (primarily peptide)
examples: different types of lung cancers may cause hypercalcemia (secretion of PTH-related peptide), or hyponatremia (secretion of AVP)
Describe pseudohypoparathyroidism
abnormality in Gs g protein
impairment in PTH signaling (low serum calcium, high serum phosphate, and increased circulating PTH; increased risk of hypothyroidism and female gonadal dysfunction
How are steroid receptors quantified in cancer patients?
labeled immunoassay; Scatchard plot: y-axis is steroid/free hormone, x-axis is bound hormone concentration; slope is dissociation constant
Is a high expression of estrogen and progesterone receptors in breast tumors a favorable prognosis?
Yes; suggests advanced state of differentiation and predicts favorable response to hormone therapy
What is Cushing’s syndrome? What causes it?
How is it treated?
truncal adiposity, hypertension, loss of subcutaneous adipose and connective tissue in the extremities with associated bruising, loss of bone mineral, muscle wasting and weakness, and hyperglycemia
primary cortisol-producing adrenal tumor or secondary pituitary tumor
treatment depends on the elucidating the cause and eliminating it
Treatment of glucocorticoid therapy is used in what clinical setting?
chronic inflammatory and neoplastic disorder
What is Addison disease?
What causes it?
Treatment?
increases in circulating concentration of ACTH and other products of POMC (skin hyperpigmentation), hypoglycemia, hypotension, and hyperkalemia
caused by tuberculosis or autoimmune disorders
treated with glucocorticoid and mineralocorticoid therapy
Describe 21alpha-hydroxylase deficiency.
inadequate production of both glucocorticoid and mineralocorticoid hormones
symptoms: hypotension and dehydration; hypoglycemia; body responds by increasing ACTH secretion resulting in: hyperplasia of adrenal gland, greater than normal activity of SCC enzyme, 3beta-HSD, 17alpha-hydroxylase, and 11beta-hydoxylase (net effect is production of adrenal androgens)
Describe the consequences of glucocorticoid therapy.
rounding of the face (moon facies), thinning of the skin, and fragility of cutaneous blood vessels; osteopenia (or osteoporosis; pathologic fractures); increased frequency and severity of infections; wasting of muscle leading to generalized muscle weakness; glucose intolerance (antagonist of insulin); does not result in hypertension
What are common treatment modalities for hypertension?
spironolactone: weak diuretic that directly antagonizes the effects of aldosterone on the renal tubule (patients present with ascites; may be combined with common thiazide diuretics in treatment of hypertension or congestive heart failure to prevent potassium wasting)
ACE inhibitors: captopril and AT1-receptor targeted therapies (most common side effect of ACE inhibitors is chronic cough)
Describe pheochromocytoma. How is it diagnosed?
How is it treated?
tumor caused be hyperplasia of either adrenal medullary tissue or extra-adrenal chromaffin tissue that failed to involute after birth
may be benign or malignant
symptoms: paroxysmal (sudden outburst) hypertension, tachycardia, headache, episodes of sweating, anxiousness, tremor, and glucose intolerance
diagnosis: history, evidence on physical examination of excessive adrenergic tone, and laboratory detection of increased amounts of urinary catecholamines and their metabolites
treatment: locate and resect tumor (if bilateral adrenalectomy is elected, glucocorticoid and mineralocorticoid therapy is required); no therapy is routinely given to replace the adrenal medullary function
Why are patients weaned off of cortisol or its derivatives?
Too allow for the normal CRH-ACTH-cortisol axis to reinitiate
Can beta blockers decrease renin release?
Yes
What pathologies affecting the CRH-ACTH-cortisol axis are ACTH-dependent? independent?
dependent: Cushing, ectopic ACTH, or ectopic CRH
independent: adrenal adenocarcinoma, adrenal adenoma, adrenal hyperplasia, and exogenous steroid administration
Describe pseduo-Cushing’s.
(exogenous steroid) a consequence of obesity, depression, poorly controlled diabetes, alcoholic liver disease, and poly-cystic ovarian syndrome
What is metyraprone?
a drug used to diagnose adrenal insufficiency and occasionally used in the treatment of Cushing’s syndrome;
Metyrapone blocks cortisol synthesis by reversibly inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels (ectopic ACTH-producing tumors do not increase ACTH secretion in response to metyraprone)
What happens to the contralateral adrenal gland in the case of a adrenal adenoma in the right hemisphere?
the left adrenal gland will atrophy (due to the feedback inhibition on ACTH secretion by the increased cortisol production the right adrenal gland)
What is a common symptom of pituitary adenomas?
Papilledema (compression of optic chiasm from below)
How is primary aldosteronism diagnosed?
findings of hypernatermia, hyporeninemia, hypokalamia (muscle weakness and polyuria), metabolic alkalosis, ST-depression and U wave elevation
What is Conn’s syndrome? Barrter syndrome?
Primary aldosteronism secondary to an adrenal adenoma
Secondary hyperaldosteronism as a result of increased renin secretion from renal artery stenosis, congestive heart failure, renal salt-wasting, juxtaglomerular hyperplasia
What are characteristics of iodine deficiency? (geography and pathology)
common in inland areas (seawater and seafood contains large amounts of iodine; Andes Mountains in South America, central Africa, and Southeast Asia); goiter formation; cretinism- mental retardation
How do you calculate the amount of free T4 in the circulation?
[T4 ] free = concentration of T4 bound to TBG divided by the binding constant (T4TBG/T4 x TBG) multiplied by the concentration of TBG
Describe Grave’s disease.
What are key clinical features of this disease that are not associated with the thyroid?
activation of TSH receptor by antibodies secreted from B lymphocytes (not regulated)
increased iodide trapping; increased synthesis of T3 and T4; goiter; Increased metabolic rate with associated weight loss, sweating and heat intolerance, a rapid and more forceful heartbeat, muscle weakness and wasting, tremulousness, difficulty concentration, and changes in hair growth and texture; palpable isthmus
Antibodies are also able to stimulate connective tissue in the extraocular muscles and in the dermis of the lower extremity to synthesize mucus (exopthlamos and pretibial myxedema)
Describe hypothyroidism. (trends, symptoms, causes)
more common in women; peripheral edema, constipation, headache, joint aches, fatigue, and, in women, anovulation (hypothermia and coma in elderly patients); caused by iodine deficiency (sometimes autoimmune disorder known as Hashimoto thyroiditis)
How is thyroid function assessed clinically?
the level of TSH reflects the amount of free, biologically active thyroid hormone in the target tissue (RAI); The health of the thyrotrophs themselves can be tested by injecting a bolus of synthetic TRH and monitoring changes in plasma [TSH] (in hypothyroid patients, there is a larger increase due to decreased negative feedback); radioactive iodine uptake can show whether a solitary thyroid nodule, detected on physical examination, is “hot” (functioning) or “cold” (nonfunctioning; malignant); radioactive iodine uptake can show whether hyperthyroidism is the result of thyroid inflammation (i.e., thyroiditis), in which tracer uptake is minimal, or Graves disease, in which tracer uptake is increased.
What are clinical manifestations of hypoglycemia?
early: palpitations, tachycardia, diaphoresis (sweating), anxiety, hyperventilation, shakiness, weakness, hunger, and nausea
late: confusion, unusual behavior, hallucinations, seizures, hypothermia, focal neurologic deficits, and coma
What are clinical manifestations of hyperglycemia?
early: weakness, polyuria, polydipsia, altered vision, weight loss, and mild dehydration
late: (accompanied by metabolic acidosis or diabetic ketoacidosis): Kussmaul breathing, stupor, coma, hypotension, and cardiac arrythmias
NOTE: severe hyperglycemia produces osmotic diuresis and can lead to severe dehydration, hypotension, and vascular collapse)
Describe nonhuman insulin.
Pork and beef insulin differ from human insulin by one and three amino acids, respectively. The difference, although small, is sufficient to be recognized by the immune system, and antibodies to the injected insulin develop in most patients treated with beef or pork insulin
Describe mutant insulin.
abnormal insulin possesses a single amino acid substitution in either the A or B chain. In each case that has been described, these changes lead to a less active insulin molecule
results in glucose intolerance or diabetes
What is the effect of sulfonylureas?
Can they treat type I diabetics?
Enhance insulin secretion by beta cells by binding to the SUR subunits of ATP-dependent potassium channels (decreasing the probability of the channel being open)
No
What is Leprechaunism?
mutation in insulin receptor that markedly affects growth in utero and after birth (generally fatal within first year of life)
Can people develop antibodies against their insulin receptor?
Yes
Describe pathologic activation of the insulin receptor.
activation of inflammatory pathways involving p38 MAP kinase and nuclear factor-κβ can lead to phosphorylation of the insulin receptor (and of IRS proteins), principally at serine residues. This serine phosphorylation occurs commonly in animal models of insulin resistance and type 2 diabetes, as well as in human diabetes.
Describe diabetes mellitus type 1.
hallmark: elevated blood glucose concentration; caused by an immune-mediated selective destruction of beta cells of the pancreas; osmotic diuresis and metabolic acidosis
death may occur by dehydration and diabetic ketoacidosis
Describe diabetes mellitus type 2.
early presentation: hyperplastic beta cells; Beta cells do not respond normally to increases in plasma glucose by increasing insulin secretion (in addition to resistance of insulin receptor)
comorbidities: hypertension, obesity, and dyslipidemia (elevated triglycerides and low HDL); increased risk for atherosclerosis
What is a clinical measure of excess growth hormone secretion?
an increased circulating concentration of IGF-1 (occurs in cases of acromegaly and gigantism)
Describe Laron dwarfism
How is it treated?
mutation in growth hormone receptor; characterized by normal or elevated plasma growth hormone
treatment with GH is ineffective; treated with recombinant IGF-1
Describe anabolic-androgenic steroids (what are examples, what are the affects, what are the adverse effects?)
testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) (as well as growth hormone)
“performance enhancers”: increase muscle mass and strength
adverse effects: oily skin, acne, hair growth, liver abnormalities, aggressive behavior, and hepatocellular carcinoma
(in addition to alteration in growth and sexual maturation)
What is BMI? what is considered underweight? normal weight? overweight? obese?
Weight in kilograms divided by the height in square meters
underweight: less than 18.5
normal: 18.5-24.9
overweight: 25-29.9
obese: 30 or more
What are some causes of obesity?
most obese persons are not leptin deficient (some may be leptin resistant and eventually respond to sufficiently high levels of the hormone)
Some obese individuals have a mutated leptin receptor gene and other may have a mutation in the POMC gene (leading to loss of the anorexigenic alpha-MSH); others may have a mutation in MC4 receptor
What is the response of lean individuals to administration of leptin?
loss of weight
What drugs have been approved to treat obesity? what may eventually be approved?
serotonin re-uptake inhibitor and an agent that blocks fat digestion (limited by side effects and have minimal effect)
cannabinoid receptors
Describe familial hypocalciuric hypercalcemia (what are the symptoms? treatments?)
Mutation in calcium-sensing receptor on the parathyroid cell; set point at which the calcium turns off PTH secretion is shifted toward higher plasma calcium concentration; similar calcium sensing receptor may be expressed in distal convoluted tubule of the kidney
Remarkably few symptoms (present with decreased calcium excretion through kidney)
treated with CaSR agonist
What is Rickets? What is osteomalacia?
both are result of vitamin D deficiency resulting in unmineralized osteoid of both cortical and trabecular bone (Rickets in children and osteomalacia in adults)
May have impaired ability in the kidney to 1-hydroxylate the 25-hydroxyvitamin D, synthesized in the liver (rare autosomal recessive disorder or consequence of chronic renal failure); this particular type of disorder may be treated with vitamin D
children have bowing of bones; adults have decreases bone strength (prone to fractures); recruitment of new osteoclasts may be diminished resulting in hypocalcemia and sensations of numbness, tingling, or burning (in addition to motor nerve tetany)
may result in secondary hyperparathyroidism leading to bone resorption and worsening osteoporosis (mild deficiency; common in elderly)
Describe osteoporosis. What are risk factors? What are possible treatment options?
weakening of bones; hip fractures are responsible for much of the morbidity associated with osteoporosis
Major risk factor is declining estrogen levels in aging women (in addition to hyperthyroidism, hyperparathyroidism, and Cushing); other risk factors include adequate dietary calcium intake, alcoholism, and lack of exercise
estrogen or calcitonin therapy; bisphosphonates are powerful inhibitors of bone resorption (suggested to take at low doses to prevent impairment of mineralization); vitamin D, and PTH agonists
What is Paget disease of bone? How is it treated?
Characterized by localized regions of bone resorption and reactive sclerosis
may be asymptomatic or may cause pain, deformity, fractures, vertigo, and hearing loss if bony overgrowth occurs in the region of the eight cranial nerve
treated with calcitriol (vitamin D) and bisphosphonates
What are the consequences of decline in serum testosterone in aging males? What are treatments?
decreases in bone formation, muscle mass, growth of facial hair, appetite, and libido (decrease in hematocrit); levels of LH are frequently not elevated (some degree of hypothalamic-pituitary dysfunction accompanies aging)
may be counteracted by testosterone replacement
Describe Sertoli cell-only syndrome (what is the cause, is Leydig cell function preserved, what hormones are elevated, and does this affect the entire organ?)
Virilized men whose testes are small bilaterally and whose ejaculates contain no sperm cells (azoospermia; complete absence of germ cells)
single gene defect or acquired as a result of orchitis, alcoholism, and toxic agents
YES
FSH levels are elevated (plasma testosterone and LH levels are normal)
NO
Describe congenital and acquired ductal obstruction (what are epididymal changes, is spermatogenesis normal, what are hormone levels, and what is the hallmark of the disease?)
Acquired as a result of stricture, infection, or vasectomy (epididymitis, smallpox, Young syndrome, and cystic fibrosis)
congenital absence of the vas deferens (common in patients with cystic fibrosis)
varies from incomplete epididymis to the presence of only small portions of the epididymis (seminal vesicles are absent)
Yes (presence of germ cells on biopsy)
Testosterone and gonadotropin levels are normal in most patients
azoospermia in men with normal testes
Descibe vasectomy. What are pathologic consequences?
a simple surgical procedure in which a small segment of the vas deferens is removed to ensure male infertility, is currently the leading cause of ductal obstruction
Interstitial fibrosis: increased thickness of the tubule wall, an increase in cross-sectional tubular area, and decreased numbers of the Sertoli cells are usually noted
