Setting: ambulatory care center
CC: “My legs feel like lead.”
VS: BP: 168/98 mm Hg; P: 72 beats/minute
HPI: A 43-year-old man comes to clinic because his “arm and legs feel like they weigh 100 pounds each.” There is a progressive slowness for muscle weakness. It is equal in all four extremities, started 6 months ago, and is slowly progressive and uncomfortable.
ROS:
No visual problems; no diplopia
No respiratory problems
No dyspnea
Yes to significant polyuria
PMHX:
Hypertension: difficult to control
Medication:
Nifedipine
PE:
General: tired, slumped posture while sitting on table
Cardiovascular: S4 gallop
Musculoskeletal: decreased strength throughout
HEENT: no ptosis
S4 from hypertension
S4: atrial systole into stiff noncompliant ventricle
Initial Orders:
CHEM-7, CBC
ECG
UA
Calcium, magnesium, phosphorus
Thyroid function (T4, TSH)
Generalized weakness is hard to evaluate. It has to be distinguished from the fatigue or tiredness of anemia versus decreased motor strength from thyroid, calcium, potassium, or magnesium abnormalities. This patient has actual muscle weakness, not fatigue and shortness of breath after exertion. Because it is generalized and continuous, it is hard to say that it is myasthenia.
• Myasthenia: worse at end of day
• Guillain-Barré: acute, several days, ascends from legs upwards
• Botulism: acute, descends from face
• Tick paralysis: diffuse, overwhelming, sudden
• Hypokalemia: diffuse, can be chronic if undetected; rare with K >2.5 mEq/L
Move the clock forward to get the blood chemistry results immediately. The patient should be brought back no later than the following day.
CHEM-7: sodium normal; K: 2.4 mEq/L
ECG: S wave deep in leads V1 and V2; R wave tall in leads V5 and V6; U waves present
Magnesium: slight decrease
T4, TSH, CBC, UA, calcium, phosphorus: normal
Hypokalemia: U waves from Purkinje fiber repolarization
ECG:
SV1 + RV5 >35mm = Left Ventricular Hypertrophy (LVH)
The most urgent step is to replace the potassium. The route of administration is dependent on the setting of your case. The setting or location of treatment is an essential feature of the Step 3 examination.Because this is an ambulatory care patient who has been living like this for months, you do not need to hospitalize the patient. Use oral potassium replacement for outpatients. If the patient is hospitalized, you should never discharge a patient with an abnormal potassium level—either high or low.
What is the mechanism of the patient’s muscle weakness?
a. The resting membrane potential is excessively low.
b. The Na+/K+-ATPase pump is inactive.
c. The ungated potassium channel is closed.
d. The voltage gate potassium channels stay open.
Answer a. The resting membrane potential is excessively low.
Resting membrane potential is based on potassium levels. The threshold for depolarization is about –45 mV. When you move the resting membrane potential down from –70 to –80 or to –90 mV you are moving further away from threshold. There is no effect on Na+/K+-ATPase. The ungated channels have more potassium leaving the cell.
Potassium Replacement Rates
• Oral: No maximum rate of replacement
• IV: <10 to 20 mEq/h
Muscles cannot contract if they cannot depolarize.
You order potassium tablets and instruct the patient to take them with a lot of water. Ask the patient to return the following day to recheck the potassium level. It is completely possible to replace the potassium over 1 to 2 days.
The Interval History shows that the patient reports much greater mobility and strength and his potassium level is now 3.1 mEq/L.
Low serum potassium (K) pulls potassium ions (K+) out of cells. Hitting the threshold for depolarization is harder when cells have low K+.
Further potassium replacement continues over the next 2 to 3 days. Bring the patient back frequently to recheck his levels. You should also see a resolution of U waves on the ECG.
Both high and low potassium levels cause arrhythmia.
Low K levels decrease conduction through the His-Purkinje system.
By the following week, the potassium level has normalized. All muscle weakness has resolved. The polyuria has resolved as well.
Hypokalemia causes nephrogenic diabetes insipidus.
ADH does not work effectively with low K or high calcium (Ca) levels.
The patient’s repeat blood pressure level is 168/100 mm Hg.
What is the mechanism of hypertension?
a. ANGII constricting arterioles
b. Excess ADH acting as vasopressin
c. Aldosterone increasing sodium absorption at late distal or early collecting duct
d. Smooth muscle hyperplasia of arteries
e. Catecholamine excess
f. Renin excess
Answer c. Aldosterone increasing sodium absorption at late distal or early collecting duct
High BP with low serum potassium level is most likely hyperaldosteronism. Although all the features listed cause hypertension, none of them is particular to this case. The main feature of basic science correlates for the Step 3 examination is not just to know something is happening, but to know precisely why it is happening. Aldosterone works by increasing sodium reabsorption at the cortical portion of the collecting duct. That is the early part of it, where it meets the distal convoluted tubule (DCT).
Hypertension + Hypokalemia = Hyperaldosteronism
What is the difference between ADH and vasopressin?
a. Production site
b. Storage site
c. Chemical structure
d. Amount and target organ
Answer d. Amount and target organ
ADH is made in the hypothalamus at the paraventricular and supraoptic nuclei. It is not made in the posterior pituitary. ADH is transported down the pituitary stalk to the posterior pituitary where it is stored. ADH works at the kidneys on the V2 receptor of the collecting duct. ADH inserts aquaporin to increase permeability to water so it can be reabsorbed. Vasopressin is the same substance, but stimulates the V1 receptor in the vasculature to cause vasoconstriction.
ADH absorbs water.
Vasopressin constricts vessels.
A 1% osmolarity change increases ADH.
A 10% volume change increases ADH.
High ADH levels constrict vessels at high levels and we call it vasopressin.
The patient has persistent hypertension. Because potassium is normal, muscle weakness has resolved, but you need to investigate the diagnosis of primary hyperaldosteronism or Conn syndrome.
Orders:
Plasma aldosterone
Plasma renin
CHEM-7
Which of the following is consistent with primary hyperaldosteronism?
Answer b. Aldosterone high and renin low
When aldosterone is being produced autonomously, the ratio of aldosterone to renin is 20:1. Any cause of dehydration or renal artery stenosis can raise both the renin and aldosterone levels.
The patient returns in 1 week.
Report:
Aldosterone level high, renin level low (ratio 25:1)
Serum bicarbonate level elevated
Metabolic alkalosis is from aldosterone increasing hydrogen ion (H+) excretion.
What is the precise location and mechanism of H+ loss?
a. Proximal tubule
b. Epithelial sodium channel (ENaC)
c. α-Intercalated cells
d. Aquaporin
Answer c. α-Intercalated cells
In the late distal tubule and early collecting duct, there are two cells on which aldosterone has its primary effect (Figure 3-6). The alpha-intercalated cells reabsorb sodium and excrete an H+. The ENaC reabsorbs sodium and excretes potassium. ENaC is the precise site of potassium loss from hyperaldosteronism.
Figure 3-6. Mechanism of aldosterone action. Aldosterone enters principal cells and interacts with cytosolic aldosterone receptors. The aldosterone-bound receptors interact with nuclear DNA to promote gene expression. The aldosterone-induced gene products activate sodium channels and sodium pumps to increase sodium reabsorption. Glucocorticoids, such as cortisol, are also capable of binding to the aldosterone receptor. However, they are inactivated by 11-hydroxysteroid dehydrogenase (11-HSD). ATP, adenosine triphosphate; K, potassium; Na, sodium. (Reproduced with permission from Eaton DC, Pooler JP. Vander’s Renal Physiology, 8th ed. New York: McGraw-Hill; 2013.)
Intercalated: H+
ENaC: K+
What is the most common cause of primary hyperaldosteronism?
a. Unilateral adenoma
b. Bilateral adenoma
c. Unilateral hyperplasia
d. Bilateral hyperplasia
e. Cancer or neoplasia
Answer a. Unilateral adenoma
Unilateral adenoma accounts for 60% to 80% of cases. Only 3% is unilateral hyperplasia. Most of the rest is bilateral hyperplasia. Only 1% to 2% is cancer or neoplasia.
Normal Stimulants to Renin
• Low sodium level
• Beta-1-stimulation
• Low pressure at juxtaglomerular complex
Which test should be done next to confirm the presence of primary hyperaldosteronism?
a. Salt load, then aldosterone level
b. Salt load, then renin level
c. CT of adrenal glands
d. MRI of adrenal glands
e. Exploratory laparotomy
Answer a. Salt load, then aldosterone level
This is a functional test of the adrenal glands. Always do functional tests before scans in endocrinology. If you take out the adrenal glands inappropriately, you cannot put them back in.
• Normal: Salt loading in the diet suppresses aldosterone level.
• Abnormal: Salt loading does not suppress aldosterone level.
The failure of the normal feedback inhibition is a disease. High salt levels in a person with high BP should suppress renin and aldosterone.
The zona glomerulosa makes aldosterone.
The following week the patient’s salt loading test shows a persistent high aldosterone level despite 5000 mEq/day in the diet. The adrenal CT shows a bilateral hyperplasia.
What is the treatment?
a. Open surgical removal
b. Laparoscopic removal
c. Spironolactone
d. Prednisone
e. Removal of pituitary gland
Answer c. Spironolactone
Adenomas and cancer are removed by laparoscopic surgery. Bilateral hyperplasia is treated with the aldosterone receptor antagonist spironolactone. Removing the pituitary gland will do nothing because the pituitary exerts no control on aldosterone production. Aldosterone is controlled by renin.
Direct Stimulants to Aldosterone Synthesis
• Angiotensin II
• Hyperkalemia
There is no edema with hyperaldosteronism because of “sodium escape” at the kidney.
After 1 week on spironolactone, the patient’s BP has lowered to 134/84 mm Hg. He feels less tired.
What do you have to monitor for?
a. Low sodium
b. High sodium
c. High potassium
d. Metabolic alkalosis
Answer c. High potassium
Because spironolactone is an aldosterone receptor antagonist, some people develop high potassium levels. Spironolactone blocks the ENaC and the intercalated cells.
Two months later the patient comes because of pain in his chest. The discomfort is bilateral. There is enlargement of breast tissue consistent with gynecomastia.
What is the mechanism?
a. Spironolactone inhibits androgens.
b. Prolactin levels have increased.
c. Estrogen release has increased.
d. Progesterone level has increased.
Answer a. Spironolactone inhibits androgens.
Spironolactone inhibits androgens. This causes enlargement of breast tissue or gynecomastia. In polycystic ovary syndrome, spironolactone treats hirsutism and helps restore menstruation.
Spironolactone is stopped and eplerenone is started. Eplerenone is an alternate mineralocorticoid receptor antagonist that does not inhibit androgen receptors. Move the clock forward 1 month at a time until the CCS program ends the case. Monitor the patient’s CHEM-7 looking for potassium, sodium, and bicarbonate abnormalities.