First Aid for Boards – Physiology – High Yield Topics
p. 346 – Endocrine/Reproductive
1.
Physiologic features of parathyroid diseases,
associated laboratory findings; physiology and pathophysiology of PTHrP
A.
Primary
hyperparathyroidism (PTH is HIGH)
-is most often caused by a parathyroid adenoma (80%), then primary hyperplasia, then parathyroid carcinoma
-is characterized by the following:
- Serum hypercalcemia
- Serum hypophosphatemia
- Increased urinary phosphate excretion (PTH inhibits phosphate reabsorption in the proximal tubule)
- Increased urinary calcium excretion (caused by the increased filtered load of calcium)
- Increased urinary cAMP
- Increased bone reabsorption
Physiology:
1. due to hyperparathyroidism -- bone disease/renal stones
2. due to hypercalcemia – fatigue, weakness and constipation
3. other symptoms -- CNS disturbances/cardiac abnormalities
B.
Hypoparathyroidism
(PTH is LOW)
-is most commonly a result of thyroid surgery, or it is congenital (e.g., DiGeorge ), then autoimmune, then familial hypoparathyroidism
-is characterized by the following:
1. Serum Hypocalcemia and TETANY
2. Serum Hyperphosphatemia
3. Decreased urinary phosphate excretion
Physiology:
- The hallmark of hypocalcemia is TETANY – characterized by neuromuscular irritability. Positive Chvostek (tap along the facial nerve and get muscle contractions) and Trousseau (occlude circulation to forearm with blood pressure cuff and get carpal spasms) signs
- Mental status changes
- Cardiovascular manifestations- characteristic prolongation of QT interval
- Other: intracranial manifestations, ocular disease, dental abnormalities
C.
Pseduohypoparathyroidism type Ia (Albright’s
hereditary osteodystrophy) (PTH is
HIGH)
-is the result of defective Gs protein in kidney and bone which causes end-organ resistance to PTH
-Hypocalcemia and Hyperphosphatemia occur (as in hypoparathyroidism) which are NOT corrected by exogenous PTH
-Circulating PTH levels are elevated (stimulated by hypocalcemia)
Physiology: same as for hypoparathyroidism
D.
Chronic renal failure
(PTH is HIGH)
-Decreased glomerular filtration rate (GFR) leads to decreased filtration of phosphate, phosphate retention, and increased serum phosphate
-Increased serum phosphate complexes with serum calcium and leads to decreased ionized serum calcium
-Decreased production of active Vitamin D (1,25-dihydroxycholecalciferol) by diseased renal tissue also contributes to decreased ionized calcium (i.e., you need Vitamin D to absorb calcium in the GI tract)
-Decreased serum calcium causes secondary hyperparathyroidism
-The combination of increased PTH levels and decreased active Vitamin D produces renal osteodystrophy, in which there is increased bone resorption and osteomalacia
E,.
Physiology and Pathology of PTHrP
The most frequent cause of hypercalcemia with nonmetastatic solid tumors is the release of PTHrP. This protein is immunologically distinct from PTH, yet is similar enough in structure to permit binding to identical receptors and simulation of second messengers. This accounts for the ability of PTHrP to induce most of the actions of PTH including increases in bone resorption and inhibition of proximal tubule phosphate transport. In general, patients with PTHrP-induced hypercalcemia have advanced cancer and a poor prognosis.
References and Additional Information:
A. Costanzo, L. Physiology. Board Review Series, pp. 270-272
B. Robbins. Pathologic Basis of Disease, pp. 1147-1151
C. Roger Grekin’s lecture outline – Disorders of Calcium Metabolism – Endocrine syllabus pp. 200-210. (Phi Chi’s 4/2/2001, 9-11, Deanna & C.J.)
2.
Clinical tests for endocrine abnormalities (e.g.,
dexamethasone suppression tests, glucose tolerance tests, TSH measurements)
The overnight 1 mg dexamethasone suppression test is the most valuable screening test in patients with suspected hypercortisolism. The study employs the administration of 1 mg of dexamethasone at bedtime (11pm) with determination of a plasma cortisol early the following morning. Normal subjects should suppress plasma cortisol. Recall dexamethasone is a powerful glucocorticoid that should shut down the HP cortisol axis.
False negative results occur in some patients with mild hypercortisolism and exquisite negative feedback sensitivity to glucocorticoids and in those with intermittent hypercortisolism. False positive results occur in patients that receive drugs that accelerate dexamethasone metabolism (phenytoin, phenobarbital, rifampin). False positives also occur in patients with renal failure, in patients suffering from endogenous depression, or in any patients undergoing stressful event or serious illness. The test should only be employed a screening tool for consideration of Cushing’s syndrome and biochemical confirmation must rely on urine free cortisol excretion.
24 hour Urine free cortisol. The most useful clinical study to confirm Cushing’s syndrome. Highly accurate and specific. Commonly used drugs and medications don’t interfere except carbamazepine which causes falsely elevated results since the drug elutes with cortisol.
The absence of diurnal rhythm has also been considered a hallmark of the diagnosis of Cushing’s syndrome.
Used to diagnosis diabetes mellitus. Recall the diagnostic criteria for diabetes mellitus:
a. Symptoms of diabetes (thirst, increased urination, unexplained weight loss) plus a random plasma glucose concentration > 200 mg/dL
b. Fasting plasma glucose > 126 mg/dL after an overnight (8 hour) fast
c. Two hour plasma glucose > 200 mg/dL during a standard 75 g oral glucose tolerance test
Aside: oral glucose tolerance test is only rarely indicated as there is a preference in clinical situations to use fasting plasma glucose levels for diagnosis because they are easier and faster to perform, more convenient and acceptable to patients, more reproducible and less expensive.
Test: Adults are given 75g of glucose with water. The glucose load is consumed within 5 minutes. Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose.
Interpretation: An oral glucose tolerance test is normal if the fasting venous plasma glucose value is less than 110 mg/dL and the 2-hour value falls below 140 mg/dL. A fasting value of 126 mg/DL or higher or a 2 hour value of greater than 200 mg/dL is diagnostic of diabetes mellitus.
Question: What is the most sensitive test for hyperthyroidism and hypothyroidism?
TSH. This is a blood test and it’s the first test to do.
Normal serum values - .5 – 5 mU/L.
1. TSH is decreased in primary hyperthyroidism. IF TSH IS NOT DECREASED, PATIENT IS NOT HYPERTHYROID. (secondary and tertiary hyperthyroidism is rare, don’t worry about it).
2. TSH is increased in primary hypothyroidism.
3. TSH is inappropriately low or normal in secondary or tertiary hypothyroidism. That is, T3 and T4 are low, so you would expect TSH is to be high but its not.
Question: What about measuring T4?
Measure free T4, ignore total T4. Why? Various conditions (pregnancy, liver failure) will alter thyroid binding globulin protein and total T4. They do not affect free T4.
Free T4 is elevated in hyperthyroidism and decreased in hypothyroidism.
Free T4 is useful is assessing the severity of hyperthyroidism. Why? TSH is typically 0 giving you zip information about severity.
Question: What about measuring T3?
Again stick to free T3.
Free T3 will be elevated in hyperthyroidism.
Don’t use free T3 to assess hypothyroidism ; it’s less sensitive and specific than free T4.
1. Greenspan and Gardner. (2001). Basic and Clinical Endocrinology. See pages listed above.
2. Also recommend Dr. Koenig’s lectures. Endocrine coursepack, pp.121
3. Dr. Hammer’s lecture. Endocrine coursepack, pp. 171
4. Dr. Kumagai’s lecture, Endocrine coursepack, pp. 270
3.
Disease associated with adrenocortical abnormalities
(e.g., Cushing’s, Addison’s, Conn’s)
CUSHING’S – ADRENOCORTICAL EXCESS
-is most commonly caused by the administration of pharmacological doses of glucocorticoids
-is less commonly caused by bilateral hyperplasia of the adrenal glands
-is called Cushing’s disease when it is caused by overproduction of ACTH (primary hypo-pituitary disease
-may also be caused by an ectopic ACTH producing non-endocrine tumor
is characterized by the following:
-1. Increased cortisol and androgen levels
-2. Increased ACTH (if caused by overproduction of ACTH);
decreased ACTH (if caused by primary adrenal hyperplasia or
pharmacological doses of glucocorticosteroids)
-3. Hyperglycemia - diabetes (caused by elevated cortisol levels)
-4. Increased protein catabolism and muscle wasting
-5. Central/truncal obesity (round face – moon facies, supraclavicular fat, buffalo hump)
-6. Poor wound healing – lose collagen so skin is fragile, think and easily bruised
-7. Virilization of women (caused by elevated levels of adrenal androgens – think hairy, menstrual abnormalities)
-8. Hypertension (caused by elevated levels of cortisol and aldosterone)
-9. Osteoporosis (elevated cortisol levels cause increased bone resorption)
10. Striae – sides of lower abdomen
Diagnosis: 24 hour urine free cortisol level, which is increased, and loss of normal diurnal pattern of cortisol secretion. See information about dexmethasome suppression test (above).
ADDISON’S – PRIMARY ADRENOCORTICAL
INSUFFICIENCY (think JFK)
-is most commonly caused by autoimmune destruction of the adrenal cortex and causes acute adrenal crisis (THIS CAN KILL YOU!)
-is characterized by the following:
-1. Decreased adrenal glucocorticoid, androgen, and mineralocorticoid
-2. Increased ACTH (low cortisol levels stimulate ACTH secretion by negative feedback)
-3. Hypoglycemia (caused by cortisol deficiency)
-4. Weight loss, weakness, nausea, and vomiting
-5. Hyperpigmentation (low cortisol levels stimulate ACTH secretion, ACTH contains the MSH fragment …melanocyte stimulating hormone) …i.e., TAN SKIN is not a sign of health!
-6. Decreased pubic and axillary hair in women (caused by the deficiency of adrenal androgens)
-7. ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis (caused by aldosterone deficiency)
Aside: Secondary adrencortical insufficiency.
- is caused by primary deficiency of ACTH – think pituitary
- no hyperpigmentation – because ACTH is decreased
- no volume contraction, hyperkalemia or metabolic acidosis (because aldosterone levels are normal) – recall aldosterone is under the renin-angiotension-aldosterone axis regulation
Robbins – p. 1159 lists more causes of adrenocortical insufficiency than you probably care to know!
One that you might want to remember is Waterhouse-Friderichsen Syndrome:
- overwhelming bacterial infection
- rapidly progressive hypotension leading to shock
- disseminated intravascular coagulation with widespread purpura, particularly of the skin
- rapidly developing adrenocortical insufficiency associated with MASSVE BILATERAL ADRENAL HEMORRHAGE
CONN’S – HYPERALDOSTERONISM –
IF YOU END UP AT NORTHWESTERN AND GET PIMPED …
CONN WAS THE HEAD OF ENDOCRINE DEPARTMENT AT UM
-is caused by an aldosterone-secreting tumor
-is characterized by the following:
-1. Hypertension (because aldosterone increased sodium’s reabsorption, which leads to increases in ECF and blood volume)
-2. Hypokalemia (because aldosterone increases K+ secretion)
-3. Metabolic alkalosis (because aldosterone increases H+ secretion)
Note: recall all 3 effects occur because aldosterone is hitting a mineralcorticoid receptor in the distal tubule. Activation of this receptor means sodium is reabsorbed while H+ and K+ are excreted. This is your K+ wasting station that can be plugged by spiranolactone and amilorde
-4. Decreased renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback).
YES, via Robbins, secondary hyperaldosteronism exists. Its caused by activation of the renin-angiotensin system. Its characterized by increased levels of plasma renin and is encountered in congestive heart failure, decreased renal perfusion, hypoalbuminemia and pregnancy (due to estrogen-induced increases in plasma renin substrate).
References:
1. Costanzo, L. (l998). Physiology. pp. 261-264. Most of the notes above come from these pages. Time permitting, check out the references listed below.
2. Robbins. Pathologic Basis of Disease. Hypercortisolism (pp. 1152-1155), Adrenal insufficiency (pp. 1159-pp.1162), and Hyperaldosteronism (pp. 1155-1157)
3. Phi Chi notes – Feb 29, 2001 9-11 (Knipp & Newcomb) and they go along with Endocrine course notes pp. 159-177.